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BURGER'S MEDICINAL

CHEMISTRY AND
DRUG DISCOVERY
Sixth Edition
Volume 6: Nervous System Agents

Edited by

Donald j. Abraham
Department of Medicinal Chemistry
School of Pharmacy
Virginia Commonwealth University
Richmond, Virginia

WILEY-
INTERSCIENCE
A john Wiley and Sons, Inc., Publication
CONTENTS

1 ADRENERGICS AND 5 SEDATIVE-HYPNOTICS, 201


ADRENERGIC-BLOCKING Julius Vida
AGENTS, 1 Vida International Pharmaceutical
Robert K. Griffith Consultants
West Virginia University Greenwich, Connecticut
School of Pharmacy Joseph Yevich
Morgantown, West Virginia Pharmaceutical Research Institute
Bristol-Myers Squibb Company
2 CHOLINERGICS, 39 Wallingford, Connecticut
Joseph G. Cannon
The University of Iowa 6 ANTICONVULSANTS, 263
Iowa City, Iowa Kenneth R. Scott
School of Pharmacy
3 ANTICHOLINERGIC DRUGS, 109 Howard University
Washington, DC
B. V . Rama Sastry
School of Medicine
Vanderbilt University 7 NARCOTIC ANALGESICS, 329
Nashville, Tennessee Jane V . Aldrich
Sandra C. Vigil-Cruz
4 CNS STIMULANTS, 167 Department of Medicinal Chemistry
School of Pharmacy
David E. Nichols University of Kansas
Department of Medicinal Chemistry Lawrence, Kansas
and
Molecular Pharmacology
School of Pharmacy and Pharmacal
Sciences
Purdue University
Indiana, West Lafayette

xiii
xiv Contents

8 ANTIDEPRESSANTS, 483 12 THERAPEUTIC AND


DIAGNOSTIC AGENTS FOR
Leslie Iversen PARKINSON'S DISEASE, 711
University of Oxford
Department of Pharmacology John L. Neumeyer
Oxford, United Kingdom Ross J. Baldessarini
Harvard Medical School
Richard A. Glennon McLean Hospital
Virginia Commonwealth University Belmont, Massachusetts
School of Pharmacy
Richmond, Virginia Raymond G. Booth
School of Pharmacy
The University of North Carolina
9 ANTIANXIETY AGENTS, 525 Chapel Hill, North Carolina
Kevin S. Currie
Neurogen Corporation 13 ALZHEIMER'S DISEASE:
Branford, Connecticut SEARCH FOR THERAPEUTICS,
743
10 ANTIPSYCHOTIC AGENTS, 599 W. Janusz Rzeszotarski
Food and Drug Administration
C. Anthony Altar Rockville, Maryland
Psychiatric Genomics, Inc.
Department of Gene Discovery
Gaithersburg, Maryland 14 COGNITION ENHANCERS, 779

Arnold R. Martin Clark N. Eid, Jr.


University of Arizona Yong-Jin Wu
Department of Pharmacology Division of Central Nervous System
Chemistry
College of Pharmacy
Bristol-Myers Squibb
Tucson, Arizona
Pharmaceutical Research Institute
Andrew Thurkauf Wallingford, Connecticut
Neurogen Corporation Gene G. Kinney
Department of Medicinal Chemistry Department of Neuroscience
Branford, Connecticut Merck Research Laboratories
West Point, Pennsylvania
11 INVESTIGATIVE AGENTS FOR
USE IN NEURODEGENERATIVE 15 DRUGS TO TREAT EATING
CONDITIONS, 673 AND BODY WEIGHT
James David Adams Jr. DISORDERS, 837
Department of Molecular Philip A. Carpino
Pharmacology and Toxicology John R. Hadcock
USC School of Pharmacy Pfizer Global Research &
Los Angeles, California Development-Groton Labs
Thomas F. Woolf Department of Cardiovascular and
HyBar BioScience, LLC Metabolic Diseases
Ann Arbor, Michigan Groton, Connecticut

INDEX, 895
CUMULATIVE INDEX, 923
BURGER'S
MEDICINAL CHEMISTRY
AND
DRUG DISCOVERY
CHAPTER ONE

Adrenergics and Adrenergic-


Blocking Agents
ROBERT K. GRIFFITH
School of Pharmacy
West Virginia University
Morgantown, West Virginia

Contents
1 Introduction, 2
2 Clinical Applications, 2
2.1 Current Drugs, 2
2.1.1 Applications of General Adrenergic
Agonists, 9
2.1.2 Applications of a,-Agonists, 12
2.1.3 Applications of a,-Agonists, 13
2.1.4 Applications of p-Agonists, 14
2.1.5 Applications of Antiadrenergics, 14
2.1.6 Applications of Nonselective a-
Antagonists, 15
2.1.7 Applications of Selective a,-
Antagonists, 15
2.1.8 Applications of p-Antagonists,16
2.1.9 Applications of alp-Antagonists, 16
2.1.10 Applications of Agonists/Antagonists,
16
2.2 Absorption, Distribution, Metabolism, and
Elimination, 16
2.2.1 Metabolism of Representative
Phenylethylamines, 16
2.2.2 Metabolism of Representative
Imidazolines and Guanidines, 18
2.2.3 Metabolism of Representative
Quinazolines, 19
2.2.4 Metabolism of Representative Aryl-
oxypropanolamines, 19
3 Physiology and Pharmacology, 21
3.1 Physiological Significance, 21
3.2 Biosynthesis, Storage, and Release
of Norepinephrine, 22
3.3 Effector Mechanisms
Burger's Medicinal Chemistry and Drug Discovery of Adrenergic Receptors, 25
Sixth Edition, Volume 6: Nervous System Agents 3.4 Characterization of Adrenergic
Edited by Donald J. Abraham Receptor Subtypes, 25
ISBN 0-471-27401-1 02003 John Wiley & Sons, Inc. 4 History, 26
1
Adrenergics and Adrenergic-Blocking Agents

5 Structure-Activity Relationships, 28 5.1.5 Imidazolines and Guanidines, 30


5.1 Phenylethylamine Agonists, 28 5.1.6 Quinazolines, 31
5.1.1 R1 Substitution on the Amino Nitrogen, 5.1.7 Aryloxypropanolamines, 32
28 6 Recent Developments, 33
5.1.2 R2 Substitution a to the Basic 6.1 Selective a,-Adrenoceptor Antagonists, 33
Nitrogen, Carbon-2,28 6.2 Selective P,-Agonists, 34
5.1.3 R3 Substitution on Carbon-1, 29
5.1.4 R4 Substitution on the Aromatic Ring,
29

1 INTRODUCTION subdivided. Identification of subclasses of adre


noceptors has been greatly aided by the tools of
In both their chemical structures and biologi- molecular biology and, to date, six distinct a-ad-
cal activities, adrenergics and adrenergic- renoceptors (a,,, a,,, a,,, ~ Z A ~, Z B ,aZd,and
blocking agents constitute an extremely var- three distinct P-adrenoceptors (PI, P,, P,) have
ied group of drugs whose clinical utility been clearly identified (I), with conflicting evi-
includes prescription drugs to treat life- dence for a fourth type of /3 (P,) (13). In general
threatening conditions such as asthma and the most common clinical applications of a,-ago-
hypertension as well as nonprescription med- nists are as vasoconstrictors employed as nasal
ications for minor ailments such as the com- decongestants and for raising blood pressure in
mon cold. This extensive group of drugs in- shock; a,-agonists are employed as antihyper-
cludes synthetic agents as well as chemicals tensives; a,-antagonists (a-blockers) are vasodi-
derived from natural products that have been lators and smooth muscle relaxants employed as
used in traditional medicines for centuries. antihypertensives and for treating prostatic hy-
Many adrenergic drugs are among the most perplasia; p-antagonists (p-blockers) are em-
commonly prescribed medications in the ployed as antihypertensives and for treatingcar-
United States, including bronchodilators, diac arrhythmias; and p-agonists are employed
such as albuterol (13) for use in treating as bronchodilators. The most novel recent ad-
asthma, and antihypertensives, such as ateno- vances in adrenergic drug research have been
lo1 (46) and doxazosin (42). Nonprescription directed toward development of selective p,-ago-
adrenergic drugs include such widely used na- nists that have potential applications in treat-
sal decongestants as pseudoephedrine (5)and ment of diabetes and obesity (4-8).
naphazoline (29). Most of these varied drugs
exert their therapeutic effects through action
2 CLINICAL APPLICATIONS
on adrenoceptors, G-protein-coupled cell sur-
face receptors for the neurotransmitter nor-
2.1 Current Drugs
epinephrine (noradrenaline, I), and the adre-
nal hormone epinephrine (adrenaline, 2). U.S. Food and Drug Administration (FDA)-
approved adrenergic and antiadrenergic drugs
currently available in the United States are
summarized in Table 1.1, which is organized
in general according to pharmacological mech-
anisms of action and alphabetically within
those mechanistic classes. Structures of the
currently employed drugs are given in Tables
1.2-1.6 according to chemical class. Drugs in a
(1) norepinephrine, R = H given mechanistic class often have more than
(2) epinephrine, R = CH3
one therapeutic application, and may or may
not all be structurally similar. Furthermore,
Adrenoceptors are broadly classified into a- drugs from several different mechanistic
and preceptors, with each group being further classes may be employed in a given therapeu-
Table 1.1 Adrenergic and Antiadrenergic Pharmaceuticals
Class and Generic Name Trade Namea Originator Chemical Class Dosebc
General agonists
Amphetamine ( 3 ) Adderall, Dexedrine SmithKline & French Phenylethylamine 5-60 mglday
Dipivefrin ( 4 ) Propine Klinge Phenylethylamine 1 drop 2 X daily 0.1% soln.
Ephedrine erythro-(5) various Phenylethylamine 50-150 mglday for asthma
10-25 mg i.v. for hypotension
Epinephrine ( 2 ) Adrenaline Parke-Davis Phenylethylamine 0.3-1.5 mg S.C.
2-10 pglmin i.v.
160-250 pg inh.
Mephentermine ( 6 ) Wyamine Wyeth Phenylethylamine 30-45 mg, i.m.
Norepinephrine (1) Levophed Sterling Phenylethylamine 0.5-30 pglmin i.v.
Pseudoephedrine threo- various Phenylethylamine 60-240 mglday
(5)
a,-Agonists
Levonordefrin ( 7 ) na Winthrop Phenylethylamine 1:20,000 in local anesthetics
Metaraminol(8) Aramine Sharpe & Dohme Phenylethylamine 2-10 mg, i.m.
w Methoxamine ( 9 ) Vasoxyl Burroughs Wellcome Phenylethylamine 10-20 mg, i.m.
Midodrine (10) Prohatine Oesterreichische Phenylethylamine 30 mglday
Stickstoffwerke
Naphazoline (29) various Ciba Imidazoline 1-2 drops 0.05% nasal
0.03% ophthalmic
Oxymetazoline (30) various Merck Imidazoline 1-2 drops 0.05% nasal
0.025% ophthalmic
Phenylephrine (11) various F. Stearns & Co. Phenylethylamine 1-3 drops
0.25-0.5% soln. nasal
0.1-0.5 mg i.v. for shock
Tetrahydrozoline (31) Various Sahyun Imidazoline 1-2 drops of 0.05%.soln.
Xylometazoline (32) Ciba Imidazoline 2-3 drops of 0.1% soln.
a,-Agonists
Apraclonidine (33) Iopidine Alcon Aminoimidazoline 3-6 drops 0.51% soln.
Brimonidine (34) Alphagan Pfizer Aminoimidazoline 1 drop 0.2% soln., 3 x daily
Clonidine (35) Catapress Boehringer Aminoimidazoline 0.2-1.2 mglday
Guanabenz (36) Wytensin Sandoz Arylguanidine 8-32 mglday
Guanfacine (37) Tenex Wander Arylguanidine 1-3 mglday
Methyldopa (12) Aldomet Merck Aromatic amino acid 500-2000 mglday
Table 1.1 (Continued)
Class and Generic Name Trade Namea Originator Chemical Class Dosebc

Proventil, Ventolin Allen & Hanburys Phenylethylamine 12-32 mg/day p.0.


2.5 mg 3 4 X daily, neb.
Bitolterol(14) Tornalate Sterling Phenylethylamine 0.74-2.22 inh.
Formoterol(15) Foradil Yamanouchi Phenylethylamine 12 pg, 2 x daily inh.
Isoetharine (16) Bronkosol I. G. Farben Phenylethylamine 2 mL 0.25% soln. inh.
Isoproterenol(l7) Isuprel Boehringer Phenylethylamine 120-262 pg, 24% daily inh.
0 5 5 . 0 pg/min, i.v.
Xopenex Sepracor Phenylethylamine 0.63-1.25 mg 3X daily neb.
Alupent, Metaprel Boehringer Phenylethylamine 60-80 mg/day p.0.
1.3-1.95 mg, M x daily, inh.
Maxair Pfizer Pyridylethylamine 0.2-0.4 mg 4-6X daily, inh.
Yutopar Philips Phenylethylamine 150-350 pg/min, i.v.
120 mglday
Salmeterol(21) Serevent Glaxo Phenylethylamine 42 pg, 2X daily, inh.
Terbutaline (22) Brethine Draco Phenylethylamine 7.5-15 mg/day
Antiadrenergics
Guanadrel(38) Hylorel Cutter Guanidine 10-75 mglday
Guanethidine (39) Ismelin Ciba Guanidine 10-50 mg/day
Reserpine (60) reserpine Ciba Alkaloid 0.05-0.5 mg/day
Metyrosine (23) Demser Merck Aromatic amino acid 14 g/day
a-Antagonists
Dapiprazole (61) Rev-Eyes Angelini-Francesco Piperidinlytriazole 2 drops 0.5% soln.
Phenoxybenzamine (62) Dibenzylime SmithKline & French Haloalkylamine 20-120 mglday
Phentolamine (40) Regitine Ciba Imidazoline 5-10 mg i.v.
Tolazoline (41) Priscoline Ciba Imidazoline 40-200 mg/day
Selective
a,-antagonists
Doxazosin (42) Cardura Pfizer Quinazoline 1-16 mg/day
Prazosin (43) Minipress Pfizer Quinazoline 1-9 mglday for BPH
6-20 mglday for hypertension
Tamsulosin (24) Flomax Yamanouchi Phenylethylamine 0.4-0.8 mg/day
Terazosin (44) Hytrin Abbott Quinazoline 5-20 mg/day
Sectral May & Baker Aryloxypropanolamine 200-1200 mglday
Tenormin ICI Aryloxypropanolamine 25-150 mglday
Betoptic, Kerlone Synthelabo Aryloxypropanolamine Hypertension: 10-20 mg orally
Glaucoma: 1-2 drops 0.5% soh. 2 x daily
Bisoprolol(48) Zebeta Merck Aryloxypropanolamine 1.25-20 mglday
Carteolol(49) Cartrol, Ocupress Otsuka Aryloxypropanolamine 2.5-10 mglday
Esmolol(50) Brevibloc American Hospital Supply Aryloxypropanolamine 50-100 pg/kg/min
Levobetaxolol S-(-1447) Betaxon Alcon Aryloxypropanolamine 1 drop 0.5% soln., 2X daily
Levobunolol (51) Betagan Warner-Lambert Aryloxypropanolamine 1-2 drops 0.5% soln., 1-2X daily
Metipranolol (52) OptiPranolol Boehringer Aryloxypropanolamine 1 drop 0.3% soln.., 2 x daily
Metoprolol(53) Lopressor, Toprol-XL AB Hksle Aryloxypropanolamine 100-450 mglday
Toprol-XL XL 50-100 mglday
Corgard Squibb Aryloxypropanolamine 40-320 mglday
Levatol Hoechst Aryloxypropanolamine 20-80 mglday
Visken Sandoz Aryloxypropanolamine 10-60 mglday
Inderal, Inderal LA ICI Aryloxypropanolamine 160-640 mglday
Betapace Mead Johnson Phenylethylamine 160-320 mglday
Timoptic Frosst Aryloxypropanolamine Hypertension: 10-60 mglday
Glaucoma: 1 drop 0.25% soln., 2X daily
alp-Antagonists
Carvedilol(59) Coreg Boehringer Aryloxypropanolamine 13-50 mglday
Labetalol(26) Normodyne Allen & Hanburys Phenylethylamine 200-2400 mglday
AgonistlAntagonists
Dobutamine (27) Dobutrex Lilly Phenylethylamine 2-20 pgkglmin, i.v.
Isoxsuprine
- (28) Vasodilan Philips Arylpropanolamine 30-80 mglday

"Not all trade names are listed, particularly for drugs no longer under patent.
bAU dose information from Drug Facts a n d Comparisons 2002(14).
"Not all doses and dosage forms are listed. For further information consult reference (14).
Table 1.2 Phenylethylamines (Structures 1-28)

R4
4' \
5'
Compound R1 R2 R3 R4 Receptor Activity"
(1) H H OH 3',4'-diOH a+@
(2) CH3 H OH 3',4'-diOH pza!
(3) H CH3 H H (a! + mb
(4) CH3 H OH 3',4'-di-02CC(CH3), (P 2 a!)"
(5) CH3 CH3 OH H (a! + P ) ~
(6) cH3 2,2-diCH3 OH H (a + PIb
m (7) H CH3 OH 3',4'-&OH a
(8) H CH3 OH 3'-OH a!

(9) H CH3 OH 2',5'-diOCH3 a!


(10) COCH,NH2 H OH 2',5'-diOCH3 a!
(11) CH3 H OH 3'-OH a
(12) H 2-CH,, 2-C02H H 3',4'-&OH azC
(13) C(CH3)3 H OH 3'-CH20H, 4'-OH Pz
(14) C(CH3I3 H OH 3',4'-bis(02CC,H4-p-CH,) Pzc
(15) H OH 3'-NHCHO, 4'-OH

Y Q
P2

0CH3
(16) CH(CH3I2 CH2CH3 OH 3',4'-diOH P
(17) CH(CH& H OH 3',4'-&OH P
(18) C(CH& H OH 3',5'-diOH P2
(19) C(CH3I3 H OH 2'-aza, 3'-CH20H, 4'-OH PZ
(20) cH3 OH 4'-OH P2

OH
CH~
"Agonist activity unless indicated otherwise.
bIndirectactivity through release of norepinephrine and reuptake inhibition.
"Prodrug.
dMixeddirect and indirect activity.
'Norepinephrine biosynthesis inhibitor.
fNet sum of effects of enantiomers.
8 Adrenergics and Adrenergic-Blocking Agents

Table 1.3 Imidazolines and Guanidines (Structures 29- 41)


Compound Structure Receptor Activity
2 Clinical Applications

Table 1.3 (Continued)


Compound Structure Receptor Activity

"Inhibit release of norepinephrine.

tic application; for example, p-blockers, a,- raises blood pressure, (1)is used to counteract
blockers, and a,-agonists are all employed to various hypotensive crises and as an adjunct
treat hypertension. treatment in cardiac arrest where its p-activ-
ity stimulates the heart. Although it also lacks
2.1.1 Applications of General Adrenergic oral activity because it is a catechol, epineph-
Agonists. The mixed a- and p-agonist norepi- rine (2) is far more widely used clinically than
nephrine (1)has limited clinical application (1).Epinephrine, like norepinephrine, is used
because of the nonselective nature of its action to treat hypotensive crises and, because of its
in stimulating the entire adrenergic system. greater p-activity, is used to stimulate the
In addition to nonselective activity, it is orally heart in cardiac arrest. When administered in-
inactive because of rapid first-pass metabo- travenously or by inhalation, epinephrine's
lism of the catechol hydroxyls by catechol-0- &activity makes it useful in relieving bron-
methyl-transferase (COMT) and must be ad- choconstriction in asthma. Because it has sig-
ministered intravenously. Rapid metabolism nificant a-activity, epinephrine is also used in
limits its duration of action to only 1 or 2 min, topical nasal decongestants. Constriction of
even when given by infusion. Because its a-ac- dilated blood vessels by a-agonists in mucous
tivity constricts blood vessels and thereby membranes shrinks the membranes and re-
10 Adrenergics and Adrenergic-Blocking Agents

Table 1.4 Quinazolines (Structures 42-44)

Compound R Receptor Activity

duces nasal congestion. Dipivefrin (4) is a pro- mic mixture of R,R and S,S stereoisomers.
drug form of (2), in which the catechol hy- Ephedrine is a natural product isolated from
droxyls are esterified with pivalic acid. several species of ephedra plants, which were
Dipivefrin is used to treat open-angle glau- used for centuries in folk medicines in a vari-
coma through topical application to the eye ety of cultures worldwide (9). Ephedrine has
where the drug (4) is hydrolyzed to epineph- both direct activity on adrenoceptors and indi-
rine (2),which stimulates both a-and P-recep- rect activity, through causing release of nor-
tors, resulting in both decreased production epinephrine from adrenergic nerve terminals.
and increased outflow of aqueous humor, Ephedrine is widely used as a nonprescription
which in turn lowers intraocular pressure. bronchodilator. It has also been used as a va-
Amphetamine (3) is orally active and, sopressor and cardiac stimulant. Lacking phe-
through an indirect mechanism, causes a gen- nolic hydroxyls, ephedrine crosses the blood-
eral activation of the adrenergic nervous sys- brain barrier far better than does epinephrine.
tem. Unlike (1)and (2), amphetamine readily Because of its ability to penetrate the CNS,
crosses the blood-brain barrier to activate a ephedrine has been used as a stimulant and
number of adrenergic pathways in the central exhibits side effects related to its action in the
nervous system (CNS). Amphetamine's CNS brain such as insomnia, irritability, and anxi-
activity is the basis of its clinical utility in ety. It suppresses appetite and in high doses
treating attention-deficit disorder, narco- can cause euphoria or even hallucinations. In
lepsy, and use as an anorexiant. These thera- the United States the purified chemical ephed-
peutic areas are treated elsewhere in this rine is considered a drug and regulated by the
volume. FDA. However, the dried plant material ma
Ephedrine erythro-(5) and pseudoephed- huang is considered by law to be a dietary sup-
rine threo-(5) are diastereomers with ephed- plement, and not subject to FDA regulation.
rine, a racemic mixture of the R,S and S,R As a result there are a large number of ma
stereoisomers, and pseudoephedrine, a race- huang-containing herbal remedies and "nu-
2 Clinical Applications 11

Table 1.5 Aryloxypropanolamines (Structures 45-59)


OH
Rn-o&NH-
Compound ARYL R Receptor Selectivity"
12 Adrenergics and Adrenergic-Blocking Agents

Table 1.5 (Continued)


Compound ARYL R Receptor Selectivitya

Plt Pz

triceuticals" on the market whose active in- 2.1.2 Applications of a,-Agonists. All se-
gredient is the adrenergic agonist ephedrine. lective a,-agonists are vasoconstrictors, which
Pseudoephedrine, the threo diastereomer, has is the basis of their therapeutic activity. The
virtually no direct activity on adrenergic re- sole use of levonordefrin (7)is in formulations
ceptors but acts by causing the release of nor- with parenteral local anesthetics employed in
epinephrine from nerve terminals, which in dentistry. Vasoconstriction induced by the
turn constricts blood vessels. Although it too a-agonist activity of (7) helps retain the local
crosses the blood-brain barrier, pseudoephed- anesthetic near the site of injection and pro-
rine's lack of direct activity affords fewer CNS longs the duration of anesthetic activity. Met-
side effects than does ephedrine. Pseudo- araminol (8) and methoxamine (9) are both
ephedrine is widely used as a nasal deconges- parenteral vasopressors selective for a-recep-
tant and is an ingredient in many nonprescrip- tors and so have few cardiac stimulatory prop-
tion cold remedies. erties. Because they are not substrates for
Mephentermine (8) is another general ad- COMT, their duration of action is significantly
renergic agonist with both direct and indirect longer than that of norepinephrine, but their
activity. Mephentermine's therapeutic utility primary use is limited to treating hypotension
is as a parenteral vasopressor used to treat during surgery or shock. Methoxamine is also
hypotension induced by spinal anesthesia or used in treating supraventricular tachycardia.
other drugs. Midodrine (10) is an orally active glycine-
To%
2 Clinical Applications

Table 1.6 Miscellaneous AdrenergiclAntiadrenergics(Structures 60-62)


Compound Structure Pharmacological Activity
(60) Antiadrenergic

H\\\'
0CH3
CH302C =-
OCH~
0CH3
0CH3
(61) N-N

H3C

amide prodrug, hydrolyzed in vivo to (63), an severe hypotension or shock but is much
analog of methoxamine, and a vasoconstrictor. more widely employed as a nonprescription
Midodrine is used to treat orthostatic hypo- nasal decongestant in both oral and topical
tension. preparations.
The imidazolines naphazoline (29), oxy-
metazoline (301,tetrahydozoline (31),and xy-
lometazoline (32) are all selective a,-agonists,
widely employed as vasoconstrictors in topical
nonprescription drugs for treating nasal con-
gestion or bloodshot eyes. Naphazoline and
oxymetazoline are employed in both nasal de-
congestants and ophthalmic preparations,
whereas tetrahydrozoline is currently mar-
keted only for ophthalmic use and xylometa-
zoline only as a nasal decongestant.

2.1.3 Applications of a,-Agonists. Arnino-


imidazolines apraclonidine (33) and bri-
monidine (34) are selective a,-agonists em-
ployed topically in the treatment of glaucoma.
Stimulation of a,-receptors in the eye reduces
production of aqueous humor and enhances
outflow of aqueous humor, thus reducing in-
Phenylephrine (111, also a selective a-ago- traocular pressure. Brimonidine is substan-
nist, may be administered parenterally for tially more selective for a,-receptors over a,-
Adrenergics and Adrenergic-Blocking Agents

receptors than is apraclonidine. Although both formoterol (15), isoetharine (16),isoprotere-


are applied topically to the eye, measurable no1 (17), levalbuterol [R-(-)-(1311, metapro-
quantities of these drugs are detectable in terenol (18), pirbuterol (191, salmeterol (21),
plasma, so caution must be employed when and terbutaline (22) are used primarily as
the patient is also taking cardiovascular bronchodilators in asthma and other constric-
agents. Structurally related aminoimidazoline tive pulmonary conditions. Isoproterenol(17)
clonidine (35) is a selective a2-agonist taken is a general P-agonist; and the cardiac stimu-
orally for treatment of hypertension. The anti- lation caused by its &-activity and its lack of
hypertensive actions of clonidine are mediated oral activity attributed to first-pass metabo-
through stimulation of a,-adrenoceptors lism of the catechol ring have led to dimin-
within the CNS, resulting in an overall decrease ished use in favor of selective p,-agonists.
in peripheral sympathetic tone. Guanabenz (36) Noncatechol-selective P2-agonists,such as al-
and guanfacine (37) are ring-opened analogs of buterol (13), metaproterenol (181, and ter-
(351, acting by the same mechanism and em- butaline (22), are available in oral dosage
ployed as centrally acting antihypertensives. forms as well as in inhalers. All have similar
Methyldopa (12) is another antihyperten- activities and durations of action. Pirbuterol
sive agent acting as an a,-agonist in the CNS (19) is an analog of albuterol, in which the
through its metabolite, a-methyl-norepineph- benzene ring has been replaced by a pyridine
rine (65). Methyldopa [the drug is the L-(5')- ring. Similar to albuterol, (19) is a selective
stereoisomer] is decarboxylated to a-methyl- P2-agonist,currently available only for admin-
dopamine (64) followed by stereospecific istration by inhalation. Bitolterol(14) is a pro-
p-hydroxylation to the (1R,2S) stereoisomer drug, in which the catechol hydroxyl groups
of a-methylnorepinephrine (65). This stereo- have been converted to 4-methylbenzoic acid
isomer is an a,-agonist that, like clonidine, esters, providing increased lipid solubility and
guanabenz, and guanfacine, causes a decrease prolonged duration of action. Bitolterol is ad-
in sympathetic output from the CNS. ministered by inhalation, and the ester groups
are hydrolyzed by esterases to liberate the ac-
tive catechol drug (66), which is subject to me-
tabolism by COMT, although the duration of
action of a single dose of the prodrug is up to
8 h, permitting less frequent administration
and greater convenience to the patient. More
recently developed selective &-agonist bron-
chodilators are formoterol(l5) and salmeterol
(21),which have durations of action of 12 h or
more. Terbutaline (221, in addition to its use
as a bronchodilator, has also been used for
halting the contractions of premature labor.
Ritodrine (20) is a selective P2-agonist that is
used exclusively for relaxing uterine muscle
and inhibiting the contractions of premature
labor.

2.1.5 Applications of Antiadrenergics. Gua-


nadrel (38) and guanethidine (39) are orally
active antihypertensives, which are taken up
into adrenergic neurons, where they bind to
the storage vesicles and prevent release of
neurotransmitter in response to a neuronal
2.1.4 Applications of fi-Agonists. Most of impulse, which results in generalized decrease
the /3-selective adrenergic agonists, albuterol in sympathetic tone. These drugs are available
(13; salbutamol in Europe), bitolterol (141, but seldom used.
2 Clinical Applications

in pheochromocytoma tumors, it is not useful


for treating essential hypertension.

2.1.6 Applications of Nonselective a-An-


tagonists. Because antagonism of a,-adreno-
ceptors in the peripheral vascular smooth
muscle leads to vasodilation and a decrease in
blood pressure attributed to a lowering of pe-
ripheral resistance, alpha-blockers have been
employed as antihypertensives for decades.
However, nonselective a-blockers such as phe-
noxybenzamine (62), phentolamine (40), and
tolazoline can also increase sympathetic out-
put through blockade of inhibitory presynap-
tic a,-adrenoceptors, resulting in an increase
in circulating norepinephrine, which causes
reflex tachycardia. Thus the use of these
agents in treating most forms of hypertension
has been discontinued and replaced by use of
selective a,-antagonists discussed below. Cur-
Reserpine (60)is an old and historically im- rent clinical use of the nonselective agents
portant drug that affects the storage and re- (40), (41), and (62) is primarily treatment of
lease of norepinephrine. Reserpine is one of hypertension induced by pheochromocytoma,
several indole alkaloids isolated from the roots a tumor of the adrenal medulla, which se-
of Rauwolfia serpentina, a plant whose roots cretes large amounts of epinephrine and nor-
were used in India for centuries as a remedy epinephrine into the circulation. Dapiprazole
for snakebites and as a sedative. Reserpine (61) is an ophthalmic nonselective a-antago-
acts to deplete the adrenergic neurons of their nist applied topically to reverse mydriasis in-
stores of norepinephrine by inhibiting the ac- duced by other drugs and is not used to treat
tive transport Mg-ATPase responsible for se- hypertension.
questering norepinephrine and dopamine
within the storage vesicles. Monoamine oxi- 2.1.7 Applications of Selective a,-Antago-
dase (MAO) destroys the norepinephrine and nists. Quinazoline-selective a,-blockers dox-
azosin (42), prazosin (43), and terazosin (44)
dopamine that are not sequestered in vesicles.
have replaced the nonselective a-antagonists
As a result the storage vesicles contain little
in clinical use as antihypertensives. Their abil-
neurotransmitter; adrenergic transmission is
ity to dilate peripheral vasculature has also
dramatically inhibited; and sympathetic tone made these drugs useful in treating Raynaud's
is decreased, thus leading to vasodilation. syndrome. The a,-selective agents have a fa-
Agents with fewer side effects have largely re- vorable effect on lipid profiles and decrease
placed reserpine in clinical use. low density lipoproteins (LDL) and triglycer-
Metyrosine (23, a-methyl-L-tyrosine), a ides, and increase high density lipoproteins
norepinephrine biosynthesis inhibitor, is in (HDL).
limited clinical use to help control hyperten- Contraction of the smooth muscle of the
sive episodes and other symptoms of catechol- prostate gland, prostatic urethra, and bladder
amine overproduction in patients with the neck is also mediated by a,-adrenoceptors,
rare adrenal tumor pheochromocytoma (10). with a,, being predominant, and blockade of
Metyrosine, a competitive inhibitor of ty- these receptors relaxes the tissue. For this rea-
rosine hydroxylase, inhibits the production of son the quinazoline a,-antagonists doxazosin
catecholamines by the tumor. Although mety- (42), prazosin ( 4 9 , and terazosin (44) have
rosine is useful in treating hypertension also found use in treatment of benign pros-
caused by excess catecholamine biosynthesis tatic hyperplasia (BPH). However, prazosin,
Adrenergics and Adrenergic-Blocking Agents

doxazosin, and terazosin show no significant 2.1.9 Applications of dj3-Antagonists. Car-


selectivity for any of the three known a,-adre- vedilol (591, an aryloxypropanolamine, has
noceptor subtypes, a,,, a,,, and a,, (11).The both a- and p-antagonist properties and is
structurally unrelated phenylethylamine a,- used both as an antihypertensive and to treat
antagonist tamsulosin (24) is many fold more cardiac failure. Both enantiomers have selec-
selective for a,,-receptors than for the other tive a,-antagonist properties but most of the
a,-adrencoceptors. Tamsulosin is employed p-antagonism is attributable to the S-(-)iso-
only for treatment of BPH, given that it has mer. Labetalol(26) is also an antihypertensive
little effect on the a,,- and a,,-adrenoceptors, with both selective a,-antagonist properties
which predominate in the vascular bed (12) and nonselective p-antagonism. Labetalol is
and have little effect on blood pressure (13).
an older drug than carvedilol and is not as
potent as carvedilol, particularly as a p-antag-
onist.
2.1.8 Applications of &Antagonists. p-An-
tagonists are among the most widely employed
antihypertensives and are also considered the 2.1 .I 0 Applications of Agonists/Antago-
nists. Dobutamine (27) is a positive inotropic
first-line treatment for glaucoma. There are
agent administered intravenously for conges-
16 p-blockers listed in Table 1.1 and 15 of
tive heart failure. The (+)-isomer has both a
them are in the chemical class of aryloxypro-
and p agonist effects, whereas the (-)-isomer
panolamines. Only sotalol(25) is a phenyleth- is an a-antagonist but a P-agonist like the en-
ylamine. Acebutolol (451, atenolol (46), biso- antiomer. The p-stirnulatory effects predomi-
pro101 (481, metoprolol (53), nadolol (54), nate as the a-effects cancel. As a catechol it
penbutolol (551, pindolol (561, and proprano- has no oral activity and even given intrave-
lo1 (57)are used to treat hypertension but not nously has a half-life of only 2 min. Isoxsu-
glaucoma. Betaxolol (471, carte0101 (49), and prine (28) is an agent with a-antagonist and
timolol(58)are used both systemically to treat P-agonist properties, which has been used for
hypertension and topically to treat glaucoma. peripheral and cerebral vascular insufficiency
Levobetaxolol [S-(-)-(47)], levobunolol (51), and for inhibition of premature labor. Isoxsu-
and metipranolol (52) are employed only in prine is seldom used any more.
treating glaucoma. Betaxolol (racemic 47) is
available in both oral and ophthalmic dosage 2.2 Absorption, Distribution, Metabolism,
forms for treating hypertension and glau- and Elimination
coma, respectively, but levobetaxolol, the en-
Because of the large numbers of chemicals act-
antiomerically pure S-(-)-stereoisomer is cur- ing as either adrenergics or adrenergic-block-
rently available only in an ophthalmic dosage ing drugs, only representative examples will
form. Esmolol (50) is a very short acting be given and limited to metabolites identified
p-blocker administered intravenously for in humans. Because drugs with similar struc-
acute control of hypertension or certain su- tures are often metabolized by similar routes,
praventricular arrhythmias during surgery. the examples chosen are representative of
Sotalol(25)is a nonselective p-blocker used to each structural class. Although it contains no
treat ventricular and supraventricular ar- structural details of metabolic pathways,
rhythmias not employed as an antihyperten- Drug Facts and Comparisons (14) is an out-
sive or antiglaucoma agent. P-Antagonists standing comprehensive compilation of phar-
must be used with caution in patients with macokinetic parameters such as absorption,
asthma and other reactive pulmonary diseases duration of action, and routes of elimination
because blockade of P,-adrenoceptors may ex- for drugs approved by the FDA for use in the
acerbate the lung condition. Even the agents United States.
listed as being &-selective have some level of
p,-blocking activity at higher therapeutic 2.2.1 Metabolism of Representative Phenyl-
doses. Betaxolol is the most p,-selective of the ethylamines. Norepinephrine (1) and epi-
currently available agents. nephrine (2) are both substrates for MAO,
2 Clinical Applications

which oxidatively deaminates the side chain of shown. Any catechol-containing drug will also
either to form the same product DOPGAL likely be subject to metabolism by COMT.
(67), and for catechol-0-methyltransferase Ephedrine (51, a close structural analog of
(COMT), which methylates the 3'-phenolic (2), having no substituents on the phenyl ring,
OH of each to form (68). Metabolite (68) is is well absorbed after an oral dose and over
subsequently oxidized by MA0 to form alde- half the dose is eliminated unchanged in the
hyde (69), and aldehyde (68) may be methyl- urine. The remainder of the dose is largely
ated by COMT to also form (69). This alde- desmethylephedrine (72), deamination prod-
hyde may then be either oxidized by aldehyde uct (73), and small amounts of benzoic acid
dehydrogenase (AD) to (70) or reduced by al- and its conjugates (16). No aromatic ring-hy-
dehyde reductase to alcohol (71). Alternate droxylation products were detected. This is in
routes to (70) and (71) from (67) are also marked contrast to the case with amphet-
shown. Several of these metabolites are ex- amine (3), in which ring-hydroxylated prod-
creted in the urine as sulfate and glucuronide ucts are major metabolites.
conjugates (15).As previously mentioned, nei- Albuterol(13) is not subject to metabolism
ther (1)nor (2) is orally active because of ex- by COMT and is orally active but does have a
tensive first-pass metabolism by COMT, and 4'- OH group subject to conjugation. The ma-
both have short durations of action because of jor metabolite of albuterol (13) is the 4'-0-
rapid metabolic deactivation by the routes sulfate (74) (17). The sulfation reaction is ste-

c H 3 0CHO~ H" (68)

HO \
Adrenergics and Adrenergic-Blocking Agents

reoselective for the active R-(-)-isomer (18-


201, resulting in higher plasma levels of the
less active S-(+)-isomer after oral administra- urine and the remainder oxidized by the liver
tion or swallowing of inhaled dosages. on both the phenyl ring and imidazoline ring
Tamsulosin (24)is metabolized by CYP3A4 to (771, (781, and (79).Oxidation of the imida-
to both the phenolic oxidation product (75) zoline ring presumably leads to the ring-
and deaminated metabolite (76) and their con- opened derivatives (80) and (81). All metabo-
jugation products (21-23). The other products lites are inactive but do not appear to be
generated from the remainder of the drug further conjugated.
molecule during formation of (76) were not In contrast, less than 2% of guanabenz
explicitly identified. Tamsulosin is well ab- (36), a ring-opened analog of (351, is excreted
sorbed orally and extensively metabolized. unchanged in the urine (24). The major me-
Less than 10% excreted unchanged in urine. tabolite (35%) is the 4-hydroqdated com-
pound (82) and its conjugates, whereas guana-
2.2.2 Metabolism of Representative Imida- benz-N-glucuronide accounts for about 6%.
zolines and Cuanidines. In humans, clonidine Also identified were 2,6-dichlorobenzyl alco-
(35)is excreted about 50% unchanged in the hol (83) (as conjugates) and the 2-isomer of
2 Clinical Applications

with little or no first-pass metabolism, and


about 38% of administered terazosin is elimi-
nated unchanged in urine and feces. The re-
mainder is metabolized by hydrolysis of the
amide bond to afford (84) and by O-demethyl-
ation to form the 6- and 7-0-demethyl metab-
olites (85)and (86), respectively (25). Diamine
(87) has also been identified as a minor metab-
olite of terazosin, probably arising from oxida-
tion and hydrolysis of the piperazine ring, al-
though the intermediate products have not
been identified.
Doxazosin (42) is well absorbed, with 60%
bioavailability, but only about 5% is ex-
creted unchanged. The major routes of me-
tabolism are, like terazosin, 6- and 7-0-
demethylation t o afford (88) and (891,
respectively (26). Hydroxylation a t 6' and 7',
to form (90) and (91), forms the other two
identified metabolites.

2.2.4 Metabolism of Representative Aryl-


oxypropanolamines. Propranolol ( 5 7 ) , the
first successful p-blocker, is also the most li-
pophilic, with an octanol/water partition coef-
ficient of 20.2 (27), and is extensively metabo-
lized. At least 20 metabolites of propranolol
have been demonstrated (28), only a few of
which are shown. The 4'-hydroxy metabolite
guanabenz. About 15 other trace metabolites (92) is equipotent with the parent compound
were detected by chromatography but not (29). CYP2D6 is responsible for the 4'-hy-
identified. droxylation and CYPlA2 for oxidative re-
moval of the isopropyl group from the nitro-
2.2.3 Metabolism of Representative Quina- gen to form (93) (30). The metabolites as well
zolines. Terazosin (46) is completely absorbed, as the parent drug are extensively conjugated

CH20H
+ conjugates + Z-isomer of (36)

C1
20 Adrenergics and Adrenergic-Blocking Agents
3 Physiology and Pharmacology 21

A
OH 0/\f\cH20H
'OZH+ many conjugates

@ O"
/ / / /

as sulfates and glucuronides. The high lipophi-


licity of propranolol provides ready passage
across the blood-brain barrier and leads to the
significant CNS effects of propranolol(27).
On the other hand, atenolol (461, with an
octanollbuffer partition coefficient of 0.02
(27),does not cross the blood-brain barrier to
any significant extent and is eliminated al-
most entirely as the unchanged parent drug in
the urine and feces. Very small amounts of
hydroxylated metabolite (94) and its conju-
gates have been identified (31), but well over
90% of atenolol is eliminated unchanged.
Metoprolol(53) is cleared principally by he-
patic metabolism and is only 50% bioavailable
because of extensive first-pass metabolism.
The major metabolite (65%) is the carboxylic
acid (951, produced by CYP2D6 O-demethyl-
ation followed by further oxidation (32-34).
Benzylic oxidation CYP2D6 forms an active
- + conjugates
metabolite (961, which retains beta-blocking
activity (35). The N-dealkylated product is a
minor metabolite.

3 PHYSIOLOGY AND PHARMACOLOGY


normally activated by the neurotransmitter
norepinephrine (1, noradrenaline), or they
The physiology and pharmacology of adrener-
may act on the neurons that release the neu-
gic and adrenergic-blocking drugs are well
rotransmitter. The term adrenergic stems
covered in standard pharmacology textbooks
from the discovery early in the twentieth cen-
(36,371.
tury that administration of the adrenal med-
ullar hormone adrenaline (epinephrine) had
3.1 Physiological Significance
specific effects on selected organs and tissues
Adrenergic and adrenergic-blocking drugs act similar to the effects produced by stimulation
on effector cells through receptors that are of the sympathetic nervous system, which was
Adrenergics and Adrenergic-Blocking Agents

(96) active

originally defined anatomically (38).Today of the axon near the junction with the effector
the terms adrenergic nervous system and sym- cell. The amino acid L-tyrosine(97)is actively
pathetic nervous system are generally used in- transported into the neuron cell (411,where
terchangeably. The sympathetic nervous sys- the cytoplasmic enzyme tyrosine hydroxylase
tem is a division of the autonomic nervous (tyrosine-3-monooxygenase) oxidizes the 3'-
system, which innervates organs such as the position to form the catechol-amino-acid L-
heart, lungs, blood vessels, glands, and smooth dopa (98) in the rate-limiting step in norepi-
muscle in various tissues and regulates func- . nephrine biosynthesis (42). L-Dopa is
tions not normally under voluntary control. decarboxylated to dopamine(99)by aromatic-
The effects of the sympathetic stimulation on L-amino acid decarboxylase, another cytoplas-
a few organs and tissues of particular rele- mic enzyme. Aromatic-L-aminoacid decarboxyl-
vance to current pharmaceutical interven- ase is more commonly known as dopa
tions are shown in Table 1.7 (39,40). Excellent decarboxylase. Doparnine is then taken up by
overviews of the adrenergic nervous system active transport into storage vesicles or granules
and its role in control of human physiology are located near the terminus of the adrenergic neu-
provided in Katzung (39) and Hoffman and ron. Within these vesicles, the enzyme dopa-
Palmer(40). mine P-hydroxylase stereospecifically intro-
duces a hydroxyl group in the R absolute
3.2 Biosynthesis, Storage, and Release
configuration on the carbon atom beta to the
of Norepinephrine
amino group to generate the neurotransmitter
Biosynthesis of norepinephrine takes place norepinephrine (1).Norepinephrine is stored in
within adrenergic neurons near the terminus the vesicles in a 4:l complex, with adenosine
3 Physiology and Pharmacology 23

Table 1.7 Selected Tissue Response to Adrenergic Stimulation


Tissue Principal Adrenergic Receptor Effect
Heart PI (minor Pz, P3) Increased rate and force
Blood vessels
Skin, mucosa, visera a1 Constriction
Skeletal muscle Pz Dilation
Renal a1 Constriction
Lungs (bronchial muscle) Pz Relaxation
Eye
Radial muscle, iris a1 Contraction (pupilary dilation)
Ciliary muscle Pz Relaxation
Uterus (pregnant) Pz Relaxation
Liver a,, Pz Glycogenolysis, gluconeogenesis
Fat cells P3 Lipolysis
Kidney
Renin release PI Increased renin secretion
minor a1 Decreased renin secretion

triphosphate (ATP)in such quantities that each nephrine biosynthesis, release, and fate is
vesicle in a peripheral adrenergic neuron con- given in Fig. 1.1.After release, norepinephrine
tains between 6000 and 15,000 molecules of nor- diffuses through the intercellular space to
epinephrine (43). The pathway for epinephrine bind reversibly to adrenergic receptors (alpha
(2) biosynthesis in the adrenal medulla is the or beta) on the effector cell, triggering a bio-
same, with the additional step of conversion of chemical cascade that results in a physiologic
(1)to (2) by phenylethanolamine-N-methyl- response by the effector cell. In addition to the
transferase. receptors on effector cells, there are also adre-
Norepinephrine remains in the vesicles un- noreceptors that respond to norepinephrine
til it is released into the synapse during signal (a2-receptors) or epinephrine (P2-receptors)
transduction. A wave of depolarization reach- on the presynaptic neuron, which modulate
ing the terminus of an adrenergic neuron trig- the release of additional neurotransmitter
gers the transient opening of voltage-depen- into the synapse. Activation of presynaptic a,-
dent calcium channels, causing an influx of adrenoceptors by (1)inhibits the release of ad-
calcium ions. This influx of calcium ions trig- ditional (I),whereas stimulation of presynap-
gers fusion of the storage vesicles with the tic P,-adrenoceptors by (2) enhances the
neuronal cell membrane, spilling the norepi- release of (I),thus increasing overall sympa-
nephrine and other contents of the vesicles thetic activation. Removal of norepinephrine
into the synapse through exocytosis. A sum- from the synapse is accomplished by two
mary view of the events involved in norepi- mechanisms, reuptake and metabolism, to in-
Epinephrine

Adrenergic neuron Effector cell

enhancement of
NE release

Storage vesicle

Dopamine-
depolarization
and Ca++influx
rn - biochemical
cascade
t 2 NE

I
Tyrosine
\\
recycling

Mitochondria1
DOPGAL, 67 4 MA0
t Uotake-1
I
I
Tyrosine metabolism

Figure 1.1. Diagram of synapse between an adrenergic neuron and its effector cell. NE, norepineph-
rine; aR, a-adrenoceptor; pR, P-adrenoceptor.
3 Physiology and Pharmacology

active compounds. The most important of ceptors, except that linkage through a G-pro-
these mechanisms is transmitter recycling tein (G,) leads to inhibition of adenylyl cyclase
through active transport uptake into the pre- instead of activation.
synaptic neuron. This process, called up- The a,-adrenoreceptor, on the other hand,
take-1, is efficient and, in some tissues, up to is linked through yet another G-protein to a
95% of released norepinephrine is removed complex series of events involving hydrolysis
from the synapse by this mechanism (44).Part of polyphosphatidylinositol (46). The first
of the norepinephrine taken into the presyn- event set in motion by activation of the a,-
aptic neuron by uptake-1 is metabolized by receptor is activation of the enzyme phospho-
MA0 through the same processes discussed lipase C, which catalyzes the hydrolysis of
earlier under norepinephrine metabolism, but phosphatidylinositol-4,5-biphosphate(PIP,).
most is sequestered in the storage vesicles to This hydrolysis yields two products, each of
be used again as neurotransmitter. This up- which has biologic activity as second messen-
take mechanism is not specific for (1)and a gers of the a,-receptor. These are 1,2-diacyl-
number of drugs are substrates for the uptake glycerol (DAG) and inositol-1,4,5-triphos-
mechanism and others inhibit reuptake, lead- phate (IP,). IP, causes the release of calcium
ing to increased adrenergic stimulation. A less ions from intracellular storage sites in the en-
efficient uptake process, uptakeS, operates in doplasmic reticulum, resulting in an increase
a variety of other cell types but only in the in free intracellular calcium levels. Increased
presence of high concentrations of norepi- free intracellular calcium is correlated with
nephrine. That portion of released norepi- smooth muscle contraction. DAG activates cy-
nephrine that escapes uptake-1 diffuses out of tosolic protein kinase C, which may induce
the synapse and is metabolized in extraneuro- slowly developing contractions of vascular
nal sites by COMT. MA0 present at extraneu- smooth muscle. The end result of a complex
ronal sites, principally the liver and blood series of protein interactions triggered by ag-
platelets, also metabolizes norepinephrine. onist binding to the a,-adrenoceptor includes
increased intracellular free calcium, which
3.3 Effector Mechanisms
leads to smooth muscle contraction. Because
of Adrenergic Receptors
smooth muscles of the wall of the peripheral
Adrenoceptors are proteins embedded in the vascular bed are innervated by a,-receptors,
cell membrane that are coupled through a G- stimulation leads to vascular constriction and
protein to effector mechanisms that translate
.
an increase in blood pressure.
conformational changes caused by activation 3.4 Characterization of Adrenergic
of the receptor into a biochemical event within
Receptor Subtypes
the cell. All of the P-adrenoceptors are coupled
through specific G-proteins (G,) to the activa- The discovery of subclasses of adrenergic re-
tion of adenylyl cyclase (45). When the recep- ceptors and the ability of relatively small mol-
tor is stimulated by an agonist, adenylyl cy- ecule drugs to stimulate differentially or block
clase is activated to catalyze conversion of these receptors represented a major advance
ATP to cyclic-adenosine monophosphate in several areas of pharmacotherapeutics. An
(CAMP),which diffuses through the cell for at excellent review of the development of adreno-
least short distances to modulate biochemical ceptor classifications is available in Hiebel et
events remote from the synaptic cleft. Modu- al. (47).
lation of biochemical events by CAMPincludes The adrenoceptors, both alpha and beta,
a phosphorylation cascade of other proteins. are members of a receptor superfamily of
CAMPis rapidly deactivated by hydrolysis of membrane-spanning proteins, including mus-
the phosphodiester bond by the enzyme phos- carine, serotonin, and dopamine receptors,
phodiesterase. The a,-receptor may use more that are coupled to intracellular GTP-binding
than one effector system, depending on the proteins (G-proteins), which determine the
location of the receptor; however, to date the cellular response to receptor activation (48).
-

best understood effector system of the a,-re- All G-protein-coupled receptors exhibit a
ceptor appears to be similar to that of the p-re- common motif of a single polypeptide chain
Adrenergics and Adrenergic-Blocking Agents

that is looped back and forth through the cell including the actual peptide sequence and
membrane seven times, with an extracellular length. Each of the adrenoceptors is encoded
N-terminus and intracellular C-terminus. on a distinct gene, and this information was
One of the most thoroughly studied of these considered crucial to the proof that each adre-
receptors is the human P,-adrenoreceptor noreceptor is indeed distinct, although re-
(49). The seven transmembrane domains, lated. The amino acids that make up the seven
TMD1-TMD7, are composed primarily of li- transmembrane regions are highly conserved
pophilic amino acids arranged in a-helices among the various adrenoreceptors, but the
connected by regions of hydrophilic amino ac- hydrophilic portions are quite variable. The
ids. The hydrophilic regions form loops on the largest differences occur in the third intracel-
intracellular and extracellular faces of the lular loop connecting TMD5 and TMD6, which
membrane. In all of the adrenoceptors the ag- is the site of linkage between the receptor and
onistlantagonist recognition site is located its associated G-protein. Sequences and bind-
within the membrane-bound portion of the re- ing specificities have been reported for numer-
ceptor. This binding site is within a pocket ous a- and P-adrenoceptor subtypes (47, 53-
formed by the membrane-spanning regions of 56). For purposes of drug design and
the peptide. All of the adrenoceptors are cou- therapeutic targeting, the most critical recep-
pled to their G-protein through reversible tors are the a,, on prostate smooth muscle,
binding interactions with the third intracellu- a,, on vascular smooth muscle and in the kid-
lar loop of the receptor protein. ney, a, in the CNS, P, in heart, P, in bronchial
Binding studies with selectively mutated smooth muscle, and p, in adipose tissue.
P,-receptors have provided strong evidence
for binding interactions between agonist func-
tional groups and specific residues in the 4 HISTORY
transmembrane domains of adrenoceptors
(50-52). Such studies indicate that Asp,,, in In 1895 Oliver and Schafer reported (57) that
transmembrane domain 3 (TMD3) of the P,- adrenal gland extracts caused vasoconstric-
receptor is the acidic residue that forms a tion and dramatic increases in blood pressure.
bond, presumably ionic or a salt bridge, with Shortly thereafter various preparations of
the positively charged amino group of cate- crude adrenal extracts were being marketed
cholamine agonists. An aspartic acid residue is largely to staunch bleeding from cuts and
also found in a comparable position in all of abrasions. In 1899 Abel reported (58) isolation
the other adrenoceptors as well as other of a partially purified sample of the active con-
known G-protein-coupled receptors that bind stituent (2), which he named epinephrine.
substrates having positively charged nitro- Shortly thereafter von Fiirth (59)employed an
gens in their structures. Elegant studies with alternative procedure to isolate another im-
mutated receptors and analogs of isoprotere- pure sample of (2), which he named suprare-
no1 demonstrated that Ser,,, and Ser,,, of nin, claiming it to be a different substance
TMD5 are the residues that form hydrogen than that isolated by Abel. The pure hormone
bonds with the catechol hydroxyls of &-ago- (2) was finally obtained in 1901 by both Taka-
nists. Furthermore, the evidence indicates mine (60) and Aldrich (61). Takamine gave (2)
that Ser,,, interacts with the meta hydroxyl yet a third name, adrenalin. Although the
group of the ligand, whereas Ser,,, interacts chemical structure was still not definitively
specifically with the para hydroxyl group. known, a pure preparation of (2) was first
Serine residues are found in corresponding po- marketed by Parke, Davis & Co. under the
sitions in the fifth transmembrane domain of trade name Adrenaline (62, 63). Adrenaline
the other known adrenoceptors. Evidence in- eventually became the generic name employed
dicates that the phenylalanine residue of outside the United States, whereas epineph-
TMD6 is also involved in ligand-receptor rine became the U.S. approved name. By 1903
bonding with the catechol ring. Structural dif- Pauly (64) had demonstrated that "adrena-
ferences exist among the various adrenocep- line" was levorotatory and proposed two pos-
tors with regard to their primary structure, sible structures consistent with the available
4 History

data. The structure of racemic (2) was conclu- chlorines, was discovered to be a P-antagonist
sively proved through nearly simultaneous that blocked the effects of sympathomimetic
synthesis by Stolz at Farbwerke Hoechst (65) amines on bronchodilation, uterine relax-
and Dakin at the University of Leeds (66), but ation, and heart stimulation (75). Although
it had only one half the activity of the natural DCI had no clinical utility, replacement of the
levorotatory isomer (67). The racemate was 3,4-dichlorosubstituents with a carbon bridge
resolved by Flacher in 1908 (68). to form a naphthylethanolamine derivative
The earliest major clinical application of (2) did afford a clinical candidate, pronethalol
was the report in 1900 (69) of the utility of (1011, introduced in 1962 only to be with-
injected adrenal extracts in treating asthma drawn in 1963 because of tumor induction in
attacks, followed in 1903 by a report (70)of the animal tests.
use of purified (2) for the same purpose. In-
jected epinephrine rapidly became the stan-
dard therapy for treatment of acute asthma
attacks. A nasal spray containing epinephrine
was available by 1911 and administration
through an inhaler was reported in 1929. Also,
early in the 1900s Hoechst employed the vaso-
constrictor properties of epinephrine to pro-
long the duration of action of their newly de-
veloped local anesthetic procaine (63).
It had been recognized early on (71) that
there were similarities between the effects of
administration adrenal gland- extracts and
stimulation of the sympathetic nervous sys-
tem. Elliot (72) suggested that adrenaline
might be released by sympathetic nerve stim-
ulation and over the years the term adrenergic
nerves became effectively synonymous with
sympathetic nerves. In 1910 Barger and Dale Shortly thereafter, a major innovation was
(73) reported a detailed structure-activity re- introduced when it was discovered that an
lationship study of epinephrine analogs and oxymethylene bridge, OCH,, could be intro-
introduced the term sympathomimetic for duced into the arylethanolamine structure of
chemicals that mimicked the effects of sympa- pronethalol to afford propranolol(57), an ary-
thetic nerve stimulation, but they also noted loxypropanolamine and the first clinically suc-
some important differences between the ef- cessful P-blocker.
fects of administered adrenaline and stimula- To clarify some of the puzzling differential
tion of sympathetic nerves. It was not until effects of sympathomimetic drugs on various
1946 that von Euler demonstrated that the tissues, in 1948 Ahlquist (76) introduced the
actual neurotransmitter released at the termi- concept of two distinct types of adrenergic re-
nus of sympathetic neurons was norepineph- ceptors as defined by their responses to (11,
rine (1)rather than epinephrine (2) (74). In (2), and (17), which he called alpha receptors
1947 compound (17), the N-isopropyl analog and beta receptors. Alpha receptors were de-
of (1)and (21, was reported to possess bron- fined as those that responded in rank order of
chodilating effects similar to those of (2) but agonist potency as (2) > (1)>> (17). Beta re-
lacking its dangerous pressor effects. In 1951 ceptors were defined as those responding in
(17) was introduced into clinical use as isopro- potency order of (17) > (2) > (1).Subse-
terenol (isoprenaline) and became the drug of quently, P-receptors were further divided into
choice for treating asthma for two decades. PI-receptors, located primarily in cardiac tis-
In the 1950s, dichloroisoprotereno1 (DCI, sue, and &-adrenoceptors, located in smooth
loo), a derivative of isoproterenol, in which muscle and other tissues, given that (1)and
the catechol hydroxyls had been replaced by (2) are approximately equipotent at cardiac
Adrenergics and Adrenergic-Blocking Agents

P-receptors, although (2) is 10 to 50 times ture of the other substituents determines re-
more potent than (1)at most smooth muscle ceptor selectivity and duration of action.
P-receptors (77). Alpha receptors were also
subdivided into a, (postsynaptic) and a, (pre- 5.1.1 R' Substitution on the Amino Nitrogen.
synaptic) adrenoceptors (78). Development of As R1 is increased in size from hydrogen in
selective agonists and antagonists for these norepinephrine to methyl in epinephrine to
various adrenoceptors has been thoroughly re- isopropyl in isoproterenol, activity at a-recep-
viewed in Ruff010 et al. (79). tors decreases and activity at P-receptors in-
creases. Activity at both a- and P-receptors is
maximal when R1 is methyl as in epinephrine,
5 STRUCTURE-ACTIVITY RELATIONSHIPS
but a-agonist activity is dramatically de-
creased when R1 is larger than methyl and is
Comprehensive reviews of the structure-activ-
negligible when R1 is isopropyl as in (17), leav-
ity relationships (SAR) of agonists and antag-
ing only P-activity. Presumably, the P-recep-
onists of a-adrenoceptors (80) and P-adreno-
tor has a large lipophilic binding pocket adja-
ceptors (81) are available, which thoroughly
cent to the amine-binding aspartic acid
cover developments through the late 1980s.
residue, which is absent in the a-receptor. As
Only summaries of these structure-activity re-
R1 becomes larger than butyl, affinity for a,-
lationships are provided here.
receptors returns, but not intrinsic activity,
which means large lipophilic groups can afford
5.1 Phenylethylamine Agonists
compounds with a,-blocking activity [e.g.,
The structures of the phenylethylamine ad- tamsulosin (24) and labetalol (26)l. Tarnsulo-
renergic agonists were summarized in Table sin (24) is more selective for a,,, the a,-adre-
1.2. Agents of this type have been extensively noceptor subtype found in the prostate gland,
over those found in vascular tissue. In addi-
tion, the N-substituent can also provide selec-
tivity for different P-receptors, with a t-butyl
group affording selectivity for &-receptors.
For example, with all other features of the
molecules being constant, (66) [the active
metabolite of prodrug bitolterol (1411 is a se-
lective P,-agonist, whereas (17) is a general
P-agonist. When considering its use as a bron-
studied over the years since the discovery of chodilator, it must be recognized that a gen-
the naturally occurring prototypes, epineph- eral P-agonist such as (17) has undesirable
rine and norepinephrine, and the structural cardiac stimulatory properties (because of its
requirements, and tolerances for substitu- &-activity) that are greatly diminished in a
tions at each of the indicated positions have selective P,-agonist.
been well established and reviewed (79,82).In
5.1.2 RZ Substitution a to the Basic Nitro-
general, a primary or secondary aliphatic
gen, Carbon-2. Small alkyl groups, methyl or
amine separated by two carbons from a substi-
ethyl, may be present on the carbon adjacent
tuted benzene ring is minimally required for to the amino nitrogen. Such substitution
high agonist activity in this class. Tertiary or slows metabolism by MA0 but has little over-
quaternary amines have little activity. Be- all effect on duration of action of catechols be-
cause of the basic amino groups, pK, values cause they remain substrates for COMT. Re-
range from about 8.5 to 10, and all of these sistance to MA0 activity is more important
agents are highly positively charged at physi- in noncatechol indirect-acting phenylethyl-
ologic pH. Most agents in this class have a amines. An ethyl group in this position dimin-
hydroxyl group on C-1 of the side chain, P to ishes a-activity far more than P-activity, and is
the amine, as in epinephrine and norepineph- present in isoetharine (16). Substitution on
rine. Given these features in common, the na- this carbon introduces an asymmetric center,
5 Structure-Activity Relationships

producing pairs of diastereomers when an OH substituent does not affect the ability of the
group is present on C-1. These stereoisomers drug to bind to the a,-receptor but does affect
can have significantly different biologic and the ability of the molecule to activate the re-
chemical properties. For example, maximal ceptor; that is, the stereochemistry of the
direct activity in the stereoisomers of a-meth- methyl group affects intrinsic activity but not
ylnorepinephrine resides in the erythro ste- affinity. Because both stereoisomers are
reoisomer (65), with the (1R,2S) absolute con- p-agonists, with the (+)-isomer about 10
figuration (83), which is the active metabolite times as potent as the (-)-isomer, the net ef-
of the prodrug methyldopa (12) (84). The con- fect is p-stimulation. Dobutamine is used as a
figuration of C-2 has a great influence on re- cardiac stimulant after surgery or congestive
ceptor binding because the (1R,2R) diaste- heart failure. As a catechol, dobutamine is
reomer of a-methylnorepinephrine has readily metabolized by COMT and has a short
primarily indirect activity, even though the ab- duration of action with no oral activity.
solute configuration of the hydroxyl-bearing C-1
is the same as that in norepinephrine. In 5.1.4 R4 Substitution on the Aromatic
addition, with respect to a-activity, this addi- Ring. The natural 3',4'-dihydroxy substituted
tional methyl group also makes the direct-acting benzene ring present in norepinephrine pro-
(1R,2S) isomer of a-methylnorepinephrine se- vides excellent receptor activity for both a-
lective for a,-adrenoceptors over a,-adrenocep- and p-sites, but such catechol-containing com-
tors, affording the central antihypertensive pounds have poor oral bioavailability and
properties of methyldopa. short durations of action, even when adminis-
tered intravenously, because they are rapidly
5.1.3 R3 Substitution on Carbon-1. In the metabolized by COMT. Alternative substitu-
phenylethyamine series, a hydroxyl group at tions have been found that retain good activity
this position in the R absolute configuration is but are more resistant to COMT metabolism.
preferred for maximum direct agonist activity For example, 3'3'-dihydroxy compounds are
on both a- and p-adrenoceptors. If a hydroxyl not good substrates for COMT and, in addi-
is present in the S absolute configuration, the tion, provide selectivity for p,-receptors.
activity is generally the same as that of the Thus, because of its ring-substitution pattern,
corresponding chemical with no substituent. metaproterenol (18) is an orally active bron-
This is the basis for the well-known Easson- chodilator having little of the cardiac stimula-
Stedman hypothesis of three-point attachment tory properties possessed by isoproterenol
of phenylethanolamines to adrencoceptors (17).
through stereospecific bonding interactions Other substitutions are possible that en-
with the basic amine, hydroxyl group, and ar- hance oral activity and provide selective p,-
omatic substituents (85). A comprehesive and activity, such as the 3'-hydroxymethyl, 4'-hy-
excellent review of the stereochemistry of ad- droxy substitution pattern of albuterol (131,
renergic drug-receptor interactions was writ- which is also not a substrate for COMT. A re-
ten by Ruff010 (86). cently developed selective p,-agonist with an
An example of a phenethylamine agonist extended duration of action is salmeterol(21),
lacking an OH group on C-1 is dobutamine which has the same phenyl ring substitution
(27), which has activity on both a- and p-re- R4 as that of (13)but an unusually long and
ceptors but, because of some unusual proper- lipophilic group R1 on the nitrogen. The octa-
ties of the c h i d center on R1, the bulky nitro- noltwater partition coefficient log P for salme-
gen substituent, the overall pharmacologic terol is 3.88 vs. 0.66 for albuterol and the du-
response is that of a selective PI-agonist (87). ration of action of salmeterol is 12 vs. 4 h for
he (-)-isomerof dobutamine is an a,-agonist albuterol (88).
. . There is substantial evidence
and vasopressor. The (+)-isomer is a n a,- that the extended duration of action is attrib-
antagonist; thus, when the racemate is used uted to a specific binding interaction of the
clinically, the a-effects of the enantiomers ef- extended lipophilic side chain with a specific
fectively cancel, leaving the p-effects to pre- region of the P,-receptor, affording salmeterol
dominate. The stereochemistry of the methyl a unique binding mechanism (89). The long
Adrenergics and Adrenergic-Blocking Agents

lipophilic nitrogen substituent of salmeterol of enantiomers (1R,2R) and (1S,2S) consti-


has been shown, through a series of site-di- tute pseudoephedrine (?-ephedrine). Analo-
rected mutagenesis experiments, to bind to a gous to the catechol a-methylnorepinephrine
specific 10 amino acid region of transmem- (65, the active metabolite of methyldopa), the
brane domain 4 of the p,-adrenoceptor. This ephedrine stereoisomer with the (1R,2S) ab-
region, amino acids 149-158, is located at the solute configuration has direct activity on the
interface of the cyctoplasm and TMD4. Thus receptors, both a and P, as well as an indirect
"anchored" by the side chain, the remaining component. The ephedrine (IS,%) enantio-
part of the molecule can pivot and repetitively mer has primarily indirect activity. Pseudo-
ephedrine, the threo diastereomer of ephed-
stimulate the receptor through binding to as-
rine, has virtually no direct activity in either of
partate 113 of TMD3 and serines 204/207 of
its enantiomers and far fewer CNS side effects
TMD5. This lipophilic anchoring is postulated than those of ephedrine.
to keep the drug localized at the site of action
and produce the long duration of action of
salmeterol.
At least one of the phenyl substituents
must be capable of forming hydrogen bonds
and, if there is only one, it should be at the
4'-position to retain P-activity. For example,
ritodrine (20) has only a 4'- OH for R4, yet (1R:2S) (1S:2R)
retains good p-activity with the large substitu- Ephedrine
ent on the nitrogen, making it P, selective.
If R4 is only a 3'- OH, however, activity is
reduced at a-sites and almost eliminated at
p-sites, thus affording selective a-agonists
such as phenylephrine (11)and metaraminol
(8). Further indication that a-sites have a
wider range of substituent tolerance for ago- (1R:2R) (1S:2S)
Pseudoephedrine
nist activity is shown by the 2',5'-dimethoxy
substitution of methoxamine (91, which is a
selective a-agonist that also has p-blocking ac-
Other phenylethylamines, such as amphet-
tivity at high concentrations.
amine and methamphetamine, which lack
When the phenyl ring has no substituents
both ring substituents and a side chain hy-
(i.e., R4 = H), phenylethylarnines may have droxyl, are sufficiently lipophilic to readily
both direct and indirect activity. Direct activ- cross the blood-brain barrier and cause dra-
ity is the stimulation of a receptor by the drug matic CNS stimulation, principally through
itself, whereas indirect activity is the result of indirect activity. The clinical utility of am-
displacement of norepinephrine from its stor- phetamine and its derivatives is entirely based
age granules, resulting in stimulation of the on CNS stimulant and central appetite sup-
receptor by the displaced norepinephrine. Be- pressant effects.
cause norepinephrine stimulates both a- and Thus, tamsulosin has no utility in treating
p-sites, indirect activity itself cannot be selec- hypertension, but far fewer cardiovascular
tive; however, stereochemistry of R1, R2, side effects than those of terazosin and dox-
andlor R4 may also play a role. azosin in treating BPH.
For example, ephedrine erythro-(5) and
pseudoephedrine threo-(5) have the same sub- 5.1.5 lmidazolines and Cuanidines. Although
stitution pattern and two asymmetric centers, nearly all P-agonists are phenylethanolamine
so there are four possible stereoisomers. The derivatives, a-adrenoceptors accommodate a
drug ephedrine is a mixture of the erythro en- far more diverse assortment of structures
antiomers (1R,2S) and (IS,%); the threo pair (80). Naphazoline (291, oxymetazoline (301,
5 Structure-Activity Relationships

tetrahydrozoline (311, and xylometazoline


(32)are selective a,-agonists and thus are va-
soconstrictors. They all contain a one-carbon
bridge between C-2 of the imidazoline ring and
a phenyl substituent; thus, the general skeleton
of a phenylethylarnine is contained within the
structures. Lipophilic substitution on the phe-
nyl ring ortho to the methylene bridge appears
to be required for agonist activity at both types
of a-receptor. Bulky lipophilic groups attached
The other imidazolines, (33)and (34), were
to the phenyl ring at the meta or para positions synthesized as analogs of (35) and were dis-
provide selectivity for the a,-receptor by dimin- covered to have properties similar to those of
ishing amnity for a,-receptors. a,-agonists. After the discovery of clonidine,
Closely related to the imidazoline a,-ago- extensive research into the SAR of central a,-
nists are the aminoimidazolines, clonidine agonists showed that the imidazoline ring was
(SS),apraclonidine (33), brimonidine (34); and not necessary for activity in this class. For ex-
the structurally similar guanidines, guana- ample, two ring-opened analogs of (35)result-
benz (36) and guanfacine (37). Clonidine was ing from this effort are guanabenz (10) and
originally synthesized as a vasoconstricting guanfacine (37). These are ring-opened ana-
nasal decongestant but in early clinical trials logs of clonidine, and their mechanism of ac-
was found to have dramatic hypotensive ef- tion is the same as that of clonidine.
fects, in contrast to all expectations for a vaso- Tolazoline (41) has clear structural simi-
constrictor (90). Subsequent pharmacologic larities to the imidazoline a-agonists, such as
investigations showed not only that clonidine naphazoline and xylometazoline, but does not
does have some a,-agonist (vasoconstrictive) have the lipophilic substituents required for
properties in the periphery but also that agonist activity. Phentolamine (40) is also an
clonidine is a powerful agonist at a,-receptors imidazoline a-antagonist but the nature of its
in the CNS. Stimulation of central postsyri8p- binding to a-adrenoceptors is not clearly un-
tic a,-receptors leads to a reduction in sympa- derstood.
thetic neuronal output and a hypotensive
5.1.6 Quinazolines. Prazosin (43),the first
effect. A very recent review thoroughly dis-
known selective a,-blocker, was discovered in
cusses the antihypertensive mechanism of ac-
the late 1960s (92) and is now one of a small
tion of imidazoline a,-agonists and their rela-
group of selective a,-antagonists, which in-
tionship to a separate class of imidazoline cludes two other quinazoline antihyperten-
receptors (91). sives, terazosin (44) (25, 93) and doxazosin
Similar to the imidazoline a,-agonists, (42). The latter, along with tamsulosin (241,
clonidine has lipophilic ortho substituents on was discovered to block a,-receptors in the
the phenyl ring. Chlorines afford better activ- prostate gland and alleviate the symptoms of
ity than methyls at a, sites. The most readily benign prostatic hyperplasia (BPH).
apparent difference between clonidine and the The first three agents contain a Camino-
a,-agonists is the replacement of the CH, on 6,7-dimethoxyquinazoline ring system at-
C-1of the imidazoline by an amine NH. This tached to a piperazine nitrogen. The only
makes the imidazoline ring part of a guanidino structural differences are in the groups at-
group, and the uncharged form of clonidine tached to the other nitrogen of the piperazine,
exists as a pair of tautomers. Clonidine has a and the differences in these groups afford dra-
pK, value of 8.05 and at physiologic pH is matic differences in some of the pharmacoki-
about 82% ionized. The positive charge is netic properties of these agents. For example,
shared over all three nitrogens, and the two when the furan ring of prazosin is reduced to
rings are forced out of coplanarity by the bulk form the tetrahydrofuran ring of terazosin,
of the two ortho chlorines as shown. the compound becomes significantly more wa-
Adrenergics and Adrenergic-Blocking Agents

ter soluble (94), as would be expected, given Labetalol(26) and carvedilol(59) have un-
tetrahydrofuran's greater water solubility usual activity, in that they are antihyperten-
than that of furan. sives with a,-, PI-, and Pz-blockingactivity. In
terms of SAR, you will recall from the earlier
5.1.7 Aryloxypropanolamines. In general, discussion of phenylethanolamine agonists
the aryloxypropanolamines are more potent that, although groups such as isopropyl and
P-blockers than the corresponding aryletha- t-butyl eliminated a-receptor activity, still
nolamines, and most of the p-blockerscurrently larger groups could bring back a,-affinity but
used clinically are aryloxypropanolamines. not intrinsic activity. Thus these two drugs
Beta-blockers have found wide use in treating have structural features permitting binding to
hypertension and certain types of glaucoma. both the a,- and both P-receptors. The
At approximately this same time, a new se- P-blocking activity of labetalol is approxi-
ries of Csubstituted phenyloxypropanolo- mately 1.5 times that of its a-blocking activity.
lamines emerged, such as practolol, which The more recently developed carvedilol has an
selectively inhibited sympathetic cardiac stim- estimated P-blocking activity 10 to 100 times
ulation. These observations led to the recogni- its a-blocking activity.
tion that not all preceptors were the same, A physicochemical parameter that has clin-
which led to the introduction of P, and P, no- ical correlation is relative lipophilicity of dif-
menclature to differentiate cardiac P-recep- ferent agents. Propranolol is by far the most
tors from others. lipophilic of the available P-blockers and en-
6 Recent Developments

ters the CNS far better than less lipophilic on efforts to discover new selective a,,-antag-
agents, such as atenolol or nadolol. Lipophilic- onists for treatment of prostatic hypertrophy
ity as measured by octanollwater partitioning and to develop selective P,-agonists for use in
also correlates with primary site of clearance. treating obesity and type 2 diabetes.
The more lipophilic drugs are primarily
cleared by the liver, whereas the more hydro- 6.1 Selective a!,,-Adrenoceptor Antagonists
philic agents are cleared by the kidney. This
The successful application of tamsulosin (24)
could have an influence on choice of agents in
to the treatment of BPH with minimal cardio-
cases of renal failure or liver disease (27).
vascular effects has led to an extensive effort
to develop additional antagonists selective for
6 RECENT DEVELOPMENTS the a,,-receptor. Phenoxyethylamine (102,
KMD-3213), a tamsulosin analog, has been re-
Recently, major research efforts in develop- ported to be in clinical trial in Japan, as has
ment of adrenergic drugs have focused largely (103) (95).
Adrenergics and Adrenergic-Blocking Agents

very thorough reviews of this field have re-


cently been published (96,97).

6.2 Selective P,-Agonists


The other major area of recent emphasis in
adrenergic drug research has been develop-
ment of selective &-agonists to induce lipoly-
sis in white adipose tissue. This area has been
extensively reviewed (4, 7, 8, 55, 98). Because
obesity and diabetes are reaching epidemic
proportions in the United States, an effective
weight reduction has enormous therapeutic
and market potential (99). As a consequence,
there is a veritable avalanche of potential new
drugs being published. To date several com-
pounds that looked promising in receptor as-
says and animal studies have entered clinical
trials and failed. The reader should consult
the listed reviews for extensive descriptions of
Other series of highly selective a,,-antag- the progress in this field through 2000. Some
onists, and representative examples, are of the most promising recent candidates have
arylpiperazines, arylpiperidines, and piperi- been an extensive series of 3'-methvlsulfon-
"

dines, represented by (104), (1051, and (1061, amido-4'-hydroxyphenylethanolamines pre-


respectively. Several compounds in these se- pared by competing groups. Compounds (107)
ries have entered clinical trials, but little has (BMS-194449) and (108) (BMS-196085) have
been reported about the outcomes (95). In ad- both gone into clinical trial but are reported to
dition to the review by Bock (951, two other have failed (100,101).
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CHAPTER TWO

Cholinergics
JOSEPH G. CANNON
The University of Iowa
Iowa City, Iowa

Contents
1 Introduction, 40
2 Cholinergic (Acetylcholine) Receptors, 41
3 Acetylcholine and Analogs, 43
3.1 Variations of the Quaternary
Ammonium Group, 43
3.2 Variations of the Acyl Group, 45
3.3 Variations of the Ethylene Bridge, 46
3.4 Substitution of the Ester Group
by Other Groups, 47
4 Cholinergics Not Closely Related Structurally to
Acetylcholine, 49
4.1 Nicotine, Its Analogs and Congeners, and
Other Nicotinic Receptor Stimulants, 49
4.2 Muscarine, Muscarone, and Related
Compounds, 57
4.3 Pilocarpine and Analogs and Congeners, 61 .
4.4 Arecoline and Analogs and Congeners, 62
4.5 Oxotremorine and Analogs and Congeners,
71
4.6 Miscellaneous, Structurally Unique
Muscarinic Agonists, 78
5 Conformation-Activity Relationships of Some
Cholinergic Agonists, 80
6 Anticholinesterases, 84
6.1 Quaternary Ammonium Reversible
Inhibitors, 85
6.2 Reversible, Noncovalent Inhibitors Related
to 1,2,3,4-Tetrahydro-
9-Aminoacridine, 86
6.3 Carbamate-Derived Inhibitors, 88
6.4 Phosphorus-Derived Inhibitors, 90
6.5 Miscellaneous Inhibitors, 93
7 Acetylcholine-Release Modulators, 97

Burger's Medicinal Chemistry and Drug Discovery


Sixth Edition, Volume 6: Nervous System Agents
Edited by Donald J. Abraham
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc.
Cholinergics

1 INTRODUCTION Therapeutic indications for cholinergics,


anticholinesterases, and/or acetylcholine re-
The transmission of impulses throughout the leasing agents in contemporary practice or
cholinergic nervous system is mediated by ace- those contemplated for future use include the
tylcholine (I), and compounds that produce following:

1. Relief of postoperative atony of the gut and


the urinary bladder. In such conditions,
cholinergic stimulation may relieve the sta-
sis by stimulating peristaltic movements of
their pharmacologic effects by mimicking or the intestine and ureters and by constric-
substituting for acetylcholine are called cho- tion of the bladder.
linergics or parasympathomimetics. 2. Reduction of intraocular pressure in some
Compounds that inhibit or inactivate the
types of glaucoma, by increasing the drain-
body's normal hydrolysis of acetylcholine by
acetylcholinesterase in nervous tissue and/or age of intraocular fluid through the canal of
by butyrylcholinesterase (pseudocholinester- Schlemm.
ase, cholinesterase) in the plasma are called 3. Relief of muscular weakness in myasthenia
anticholinesterases. The gross observable gravis. This condition reflects a failure of
pharmacological effects of both types of com- an appropriate amount of acetylcholine to
pounds are quite similar. More recently, com- reach cholinergic receptors on the post-
pounds have been found that enhance the re- myoneural junctional membrane following
lease of acetylcholine from cholinergic nerve rapidly repetitive nerve impulses. The re-
terminals, thus (like the anticholinesterases) duced level of acetylcholine may result
producing cholinergic effects by an indirect from excessive enzyme-catalyzed hydroly-
mechanism. sis of it or from diminished production or
Choline is taken into the nerve terminal release; the etiology of the disease usually
from the synaptic cleft by a sodium-depen- involves an autoimmune response phe-
dent, high-affinity active transport process, nomenon, primarily to the acetylcholine re-
which is the rate-limiting step in the biosyn- ceptor at the postjunctional end plate (5).
thesis of acetylcholine in the nerve terminal However, in approximately 10%of patients
(1). In the nerve terminal, choline reacts with demonstrating the myasthenic syndrome,
acetylcoenzyme A in a process catalyzed by the cause is congenital and in these individ-
choline acetyltransferase. The acetylcholine uals, traditional cholinergic therapy is inef-
thus synthesized is sequestered in the synap- fective (5).
tic storage vesicles in the nerve terminal for 4. Relief of the symptoms of Alzheimer's dis-
future use as a neurotransmitter. The active ease and some other types of senile demen-
transport of acetylcholine into the storage ves- tia. A deficiency of functional cholinergic
icles has been reviewed (2). Vesamicol (2) at neurons, particularly those extending from
micromolar concentrations blocks transport the lateral basalis, has been observed in pa-
of acetylcholine into the vesicles (3,4). tients with progressive dementia of the
Alzheimer type (6). Cholinomimetic ther-
apy has been directed at compensating for
the inadequate cholinergic activity in these
neurons. However, clinical results with
cholinergics
- and anticholinesterases have
often been disappointing or inconsistent
due, in some instances, to the inability of
quaternary ammonium drugs to penetrate
2 Cholinergic (Acetylcholine) Receptors

the blood-brain barrier or to a lack of spec-


ificity or selectivity of the drug for the cho-
linergic receptorb) involved in the patho-
logical condition. There continues to be
great emphasis on the search for and study
of nonquaternary ammonium molecules
(having greater lipophilic character) that
will penetrate the blood-brain barrier and
interact with appropriate acetylcholine re-
ceptors in the brain. Thus older tertiary
amine drugs such as pilocarpine and areco-
line, which demonstrate only modest cho-
linergic activity and are classed as partial
agonists, have been the subjects of intense
structure-activity studies. Relief of Alzhei-
mer symptoms by reinforcement of central
cholinergic activity by inhibition of acetyl-
cholinesterase has been the subject of a tre- is a true cholinergic agonist, it is recognized
mendous research effort (see Section 6). that nicotine lacks agonist effect in some parts
The utility of cholinergics in correction of of the nervous system; some of its peripheral
other types of deficits in memory and learn- actions are indirect and probably involve pre-
ing has been investigated for many years synaptic release of acetylcholine (10-14).
(7),with largely inconclusive results. How- Muscarinic receptors occur peripherally at
ever, this remains a fascinating and a po- parasympathetic postsynaptic sites on glands
tentially significant area of research. and smooth (nonstriated) muscles, and they
5. Relief from pain. Selected cholinergic are involved in gastrointestinal and ureteral
agents have been found that display an- peristalsis, pupillary constriction, peripheral
tinociceptive (analgesic) effects grossly vasodilatation, reduction of heart rate, and
similar to those of morphine. Most of these promotion of exocrine glandular secretion
are nicotinic receptor agonists, but a mod- (salivary glands, sweat glands, tear glands).
est number of muscarinic agonists have Autonomic ganglia also contain muscarinic re-
been found that also display antinocicep- ceptors. Peripheral nicotinic receptors are
tive effects. found postsynaptically on striated (voluntary)
6. Relief of symptoms of Parkinson's disease. muscle fiber membranes and in all autonomic
Acetylcholine receptors of the nicotinic ganglia (sympathetic as well as parasympa-
type have been implicated in the Parkinso- thetic). There are also nicotinic and musca-
nian syndrome (7-9). rinic pathways in the central nervous system.
Muscarinic receptors are subcategorized as
M,, M,, M,, M,, and M, (15). By definition, M,
2 CHOLlNERGlC (ACETYLCHOLINE) receptors occur especially in the cerebral cor-
RECEPTORS tex and hippocampus, where they are thought
to play an important role in learning and
Acetylcholine receptors have been subdivided memory processes (16). It has been assumed
into two major pharmacological types (musca- for some years that M, receptor agonists are
rinic and nicotinic), based on their selective the most likely candidates for treatment of
response to two alkaloids: muscarine (3) and cholinergic deficits involved in Alzheimer's
nicotine (4). disease (17). MI receptors are found peripher-
Neither nicotine nor muscarine is a normal ally in autonomic ganglia where they are in-
physiological component of the mammalian volved in membrane depolarization, which is
body; hence the muscarinic/nicotinic classifi- mediated by stimulation of phospholipase C
cation of acetylcholine receptors is artificial. and subsequent production of inositol-1,4,5-
Although it is well established that muscarine triphosphate and diacyl glycerol (18). M, re-
Cholinergics

ceptors are present in the cerebellum, heart, have a similar pentameric structure, but they
smooth muscle, and at some potassium chan- vary considerably in the nature of the subunit
nels (15); M, receptors are found in secretory combinations (29).
. .

glands and smooth muscle. M, receptors are At least some neuronal nicotinic subunits
located in the basal forebrain and the stria- are homologous to those found in muscle.
tum. M, receptors are found in the substantia These have been designated as a if they con-
nigra. MI, M,, and M, receptors modulate tain vicinal cysteine residues analogous to
some potassium, chloride, and calcium chan- Cys192-Cys193of the Torpedo receptor, or P if
nels, and M, and M, receptors modulate some they do not. Stimulation of these receptors
calcium channels (19). All of these ion channel produces depolarization (a result of cation
effects are indirect and complex. The central channel opening) and firing of the postgangli-
nervous system contains all known subtypes onic neuron. Nine homologous nicotinic recep-
of muscarinic receptors (18).Both muscarinic tor subunits have been identified thus far in
M, (20) and nicotinic (21) receptors decrease mammalian nervous systems (30). Two main
in numbers with the progression of Alzhei- categories of nicotinic receptor pentamers
mer's syndrome, whereas the numbers of have been identified in the brain, based on
M, receptors do not decrease (22). Alzheimer their high affinity for either nicotine or for the
patients also show reduced activity of acetyl- nicotinic receptor blocker a-bungarotoxin.
cholinesterase; of high affinity, sodium-depen- The former are considered to be formed by a4-
dent choline uptake; and of choline acetyl- and P2-subunit receptors, and the latter are
transferase (23). Contemporary and projected thought to be a7 or a7* nicotinic receptors
therapeutic roles for muscarinic receptors in (30). Nicotinic receptor glycoprotein has been
the central nervous system have been re- isolated and extensively " studied (31-33). Re-
viewed (24). views of the classification, recommended no-
Muscarinic receptors are glycoproteins menclature, and function of nicotinic receptor
with molecular weights of approximately subtypes are available (29,30,34-36).
80,000. They are located on the outer surface A family of presynaptic ion channel-type
of the cell membrane, and they are of the G- acetylcholine receptors in the brain modulates
protein-linked type; M,, M,, and M, receptors the release of acetylcholine, dopamine, and
couple with G, proteins to stimulate phospho- other neurotransmitters implicated in learn-
lipase-C, whereas M, and M, receptors couple ing and memory processes (37). There is con-
with Gi proteins to inhibit adenylate cyclase vincing evidence to implicate a deficit in nico-
(25). The molecular basis of muscarinic recep- tinic receptors in the symptomatology of
tor function has been reviewed (26). Nordvall Alzheimer's disease. Furthermore, the neuro-
and Hacksell (27) proposed a molecular model toxin P-amyloid attenuates nicotine-induced
of the transmembrane domains of the M, re- release of acetylcholine and dopamine (37).
ceptor, to explain the three-dimensional inter- Although acetylcholine is optically inac-
action of the receptor with its ligands. How- tive, its in vivo receptors exhibit discrimina-
ever, the authors specified that the model is tion between enantiomers of synthetic and
"primarily of qualitative value". naturally occurring cholinergic stimulants.
Postsynaptic nicotinic receptors in the pe- Both central and peripheral muscarinic recep-
ripheral nervous system are designated as N, tors are highly stereospecific; peripheral nico-
(in autonomic ganglia) and N, (at myoneural tinic receptors seem to be less so, although
junctions). Nicotinic receptors are of the ion these usually show preference for one or the
channel type. They are pentameric proteins other member of enantiomeric pairs. Central
that are composed of one, two, or more distinct nicotinic receptors frequently demonstrate a
subunits, each of which contains multiple higher degree of stereoselective binding char-
membrane-spanning regions, and the individ- acter than is noted with the peripheral recep-
ual subunits surround an internal channel tors. Understanding of nicotinic receptor ste-
(28). Nicotinic receptors are highly heteroge- reoselectivity and specificity is complicated by
neous, and subcategorization has been diffi- the liklihood that, as was mentioned previ-
cult; those in neuronal tissue are believed to ously, at some in vivo sites, some nicotinic
3 Acetylcholine and Analogs

stimulant agents function indirectly by pro- these older studies were performed before the
moting presynaptic release of acetylcholine. exquisite heterogeneity of both muscarinic
and nicotinic receptors was recognized; thus,
3 ACETYLCHOLINE AND ANALOGS many compounds were classified merely as
"muscarinic" or "nicotinic." The observed ef-
Acetylcholine has virtually no clinical uses. Its fectiveness of a cholinergic agent in producing
rapid rate of hydrolysis in the gastrointestinal a biological response depends, inter alia, on its
tract precludes oral administration, and a sim- inherent potency and intrinsic activity as well
ilarly rapid hydrolysis by esterases in the as on the rate at which it is metabolically in-
blood and by acetylcholinesterase in the ner- activated and/or excreted. Frequently, these
vous tissue limits its usefulness. individual factors were not separately and in-
The need for therapeutically satisfactory dividually assessed. This problem has been
cholinergic agents coupled with the simple cited (40) with regard to the lack of consis-
and easily synthesized structures necessary tency among laboratories in the methods used
for cholinergic activity have stimulated prep- to determine cholinergic receptor subtype se-
aration and study of a great number of analogs lectivity. Therefore, in the following discus-
of acetylcholine. The following structural vari- sion of the relationship of chemical structure
ations have been addressed: to cholinergic activity, frequently only gener-
alized (and tentative) conclusions can be
1. Alteration of the quaternary ammonium made, and these may have been based on a
head. composite of the cholinergic activities for
2. Replacement of the acetyl group by other which the compound was tested.
acyl moieties.
3.1 Variations of the Quaternary
3. Alteration of the ethylene bridge connect- Ammonium Croup
ing the quaternary ammonium and the es-
ter groups. Two types of alterations of the quaternary
4. Substitution of another group for, or elim- head have been studied: replacement of the
ination of, the ester moiety. nitrogen by other atoms and replacement of
the N-methyl groups by hydrogen, alkyl, ni-
trogen, or oxygen. Acetyl phosphonocholine
The "five atom rule," first suggested by
( 5 ) (391, acetylarsenocholine (6) (391, and ace-
Alles and Knoefel (38) and stated more for-
mally by Ing (39), proposes that, for maximum
muscarinic activity, there should be attached
to the quaternary nitrogen atom, in addition
to three methyl groups, a fourth group with a
chain of five atoms, as illustrated for acetyl-
choline: C-C-0-C-C-N. This empirical obser-
vation has been found to be valid for a large
number of molecules, regardless of the precise tylsulfonocholine (7) (41) exhibit muscarinic
nature of the five atoms involved. effects, but they are considerably less potent
Studies of a large number of compounds than acetylcholine.
have supplied considerable information on Ing (39) noted that the potencies of acetyl-
structural requirements for cholinergic activ- choline analogs containing charged atoms
ity; however (especiallyin the older literature) other than nitrogen (phosphorus, arsenic, sul-
these data must be interpreted with caution. fur) are in inverse order to the volumes occu-
They have been obtained using a variety of in pied by these atoms. The carbon isostere (8) of
vivo and in vitro testing procedures and bio- acetylcholine exhibits no cholinergic activity,
logical preparations in a variety of animal spe- but it is an excellent substrate for acetylcho-
cies, and different biological responses associ- linesterase (42). Studies of the role of nitrogen
ated with stimulation of the cholinergic substituents in the acetylcholine molecule in-
nervous system were measured. Additionally, dicate that the N,N,N-trimethyl quaternary
Cholinergics

Table 2.1 Representative Esters of Choline

Number R Reference
HCO
BrCH2C0
C2H5C0
N-methyl,N,N-diethylcholine,and it is decid-
H,NCH2C0 edly more potent than the diethylcholine es-
n-C3H7C0 ter.
i-C3H7C0 However, in general, incorporation of the
n-C4H,C0 choline nitrogen into a heterocyclic ring mark-
C6H5C0 edly lowers the potency compared with acetyl-
C6H5CH2C0 choline (47,48).
C6H5CH=CHC0 The report (49) that the tertiary amine (12)
(C$,)&XOH)CO is a full and nonselective muscarinic agonist
CH,(CH2),,CO
CH3(CH2),4C0
HOCH,CO
CHflHCO
CH,COCO
CH,CHOHCO
O2N
H2NC0
(CH,O),PO

lends credence to proposed significance of mo-


lecular rigidity in muscarinic agonism.
ammonium pattern of acetylcholine itself Replacement of one N-methyl group of ace-
is optimum for potency and activity. The ace- tylcholine by ethyl permits retention of most
tate esters of N,N-dimethylethanolamine,N- of the cholinergic activity, but as more
methylethanolamine, and ethanolamine pos- N-methyl groups are replaced by ethyl, there
sess weak muscarinic activity, and they show is a progressive loss of cholinergic effect (50).
no nicotinic activity (43). The tertiary m i n e When one N-methyl is replaced by n-propyl or
congener of carbamyl choline (Table 2.1, 19) n-butyl, there is almost complete loss of cho-
exhibits greatly diminished nicotinic and mus- linergic activity (41).
carinic effects compared with the N,N,N-tri- The hydrazinium congener (9), in which
methyl quaternary compound (44).These con- one N-methyl is replaced by NH,, was less ac-
clusions seem valid for cholinergic agents tive than acetylcholine in all assays performed
having, like acetylcholine,a high degree of mo- (51). The tris-(trideuteromethyl) congener
lecular flexibility. In contrast, in certain ace- (10) showed similar potency to acetylcholine
tylcholine congeners in which the nitrogen is a in a dog blood pressure assay (52).
part of a relatively rigid ring system (pyrroli- Replacement of one N-methyl in acetylcho-
dine, morpholine, piperidine, quinuclidine), line and in three congeners (13-16) by me-
tertiary amine salts are more potent musca-
rinics than their quaternary derivatives (45).
This enhanced activity of the tertiary amines
has been rationalized on conformational
grounds. It is assumed that the tertiary
amines are protonated at their in vivo sites of
action.
The pyrrolidine compound (11)is 20-33%
as potent as acetylcholine (46); this compound
can be viewed as a cyclic congener of acetyl
3 Acetylcholine and Analogs

thoxyl permits retention of some cholinergic 3.2 Variations of the Acyl Croup
effects, and in certain compounds, nicotinic or
Qualitatively, choline has the same pharmaco-
muscarinic activities are enhanced over the
parent N,N,N-trimethyl system (53). logical actions as acetylcholine, but it is far
The reverse N-alkoxy systems (17) demon- less active at most sites (58). However, choline
strated only extremely weak muscarinic activ- has been reported (34) to be a full agonist at
one nicotinic receptor subtype, and at some
other nicotinic subtypes it can act as a partial
agonist or a coagonist.
Acetylation of the alcohol function of cho-
line greatly increases the potency. However,
(17) R = CH3 or NH2 formylcholine is less potent than acetylcho-
line, and homologation of the acetate methyl

-
R', R = combinations of H, CH3
group of acetylcholine generally produces
compounds that are much less potent than
ity (54). These compounds violate the five acetylcholine (see Table 2.1). Polar groups
atom rule. such as OH (Table 2.1,17) and NH, (4) mark-
Amine oxide analogs of the cholinergic ago- edly decrease muscarinic potency, but a
nists (18-21) exhibit little or no cholinergic group (16) permits retention of considerable
effect, and they are not substrates for cho- activity. Bromoacetylcholine (number 2) is a
linesterases (55). muscarinic and nicotinic agonist (59) and, un-
der reducing conditions, it binds covalently to
nicotinic receptors but not to muscarinic re-
ceptors (60).
Acrylylcholine (Table 2.1, 151, which has
been isolated from tissues of a marine gastro-
pod (72), has relatively high cholinergic activ-
ity. Higher fatty acid esters (12 and 13) were
prepared for testing as hemolytic agents, but
apparently they have never been evaluated for
cholinergic activity. A study of acetylcholine
congeners derived from relatively high molec-
ular weight acids (73), most of which con-
The observed biological effects of several tained a benzene ring, revealed that as the
variations of the quaternary head of acetyl- molecular weight of the acid increases para-
choline and its congeners may be rationalized sympathetic stimulant activity dimninishes,
by invoking results of molecular orbital calcu- and there is a gradual change to atropine-like
lations (56), which indicate that in both mus- (muscarinic blocking) activity.
carine and acetylcholine the nitrogen atom is In general, carbamic acid esters of choline
nearly neutral and a large part (70%) of the and its congeners are more potent and more
formal charge is distributed among the three toxic than the corresponding acetates. Car-
attached methyl groups, which form a large bamyl choline (19 in Table 2.1) is a potent
ball of spreading positive charge. muscarinic agent, and it demonstrates pro-
Furthermore, Kimura and coworkers (57) nounced nicotinic stimulant effects a t auto-
determined that chain extension of one alkyl nomic ganglia. It is likely that these ganglionic
group of the tetramethylammonium cation actions are due, at least in part, to release of
produces a great decrease in the charge den- endogenous acetylcholine from the terminals
sity on the nitrogen, and they proposed that of cholinergic fibers (74).
cholinergic agonist activity for a quaternary Carbamyl choline is is a poor substrate for
ammonium compound requires a minimum acetylcholinesterase and nonspecific cholines-
level of charge density on the nitrogen. terases (74). The nitrate ester (18, Table 2.1)
Cholinergics

has marked nicotinic and muscarinic agonist 3.3 Variations of the Ethylene Bridge
effects, and it also displays an intense paralyz- The distance between the ester moiety and the
ing nicotine action. The dimethylphosphate
cationic head of acetylcholine seems to be crit-
ester (20,Table 2.1) has powerful nicotinic ac- ical. Acetoxytrimethylammonium (27), com-
tion but little muscarinic effect.
The "reversed ester" congener (22)of ace-
tylcholine exhibits weak muscarinic and no

pletely lacking the ethylene bridge of acetyl-


choline, showed a pharmacological profile
quite similar to acetylcholine (79), but it was
nicotinic effects (75). In contrast, the carbon- much less potent.
ate congener (23) is a full agonist at musca- Acetoxymethyltrimethylammonium (28)
rinic and nicotinic receptors, with an activity appeared to have little or no muscarinic effect

on a guinea pig ileum preparation (76). The


approximately one order of magnitude less profound instability of this compound in solu-
than that of acetylcholine (76). tion precluded collection of quantitative data.
Acetylthiocholine (24) and acetylseleno- An older report (68) had indicated that struc-
choline (25) exert acetylcholine-like effects on ture (28) has "intense muscarinic action" and
the guinea pig ileum and on the frog rectus "marked nicotine stimulant action." Acetyl
abdominis, but they are somewhat less potent y-homocholine (29) is decidedly less potent1
than acetylcholine (77). active than acetylcholine (73). CAcetoxybu-
Unesterified thiocholine and selenocholine tyltrimethylammonium (30) exhibits ex-
display a relatively high degree of acetylcho- tremely weak muscarinic and nicotinic effects
line-like potency and activity compared with
(80).
their acetate esters, in contrast to the dra-
matic potency difference between choline and
acetylcholine. The biological effects of these
unesterified thiols and selenols have been sug-
gested to be due to their oxidation to disulfide
and diselenide derivatives (77). The amide
congener (26) of acetylcholine has little or no
Replacement of one or more of the hydro-
gen atoms of the ethylene bridge with alkyl
groups produces marked changes in potency
and activity. Acetyl p-methylcholine (31) is
equipotent to acetylcholine as a muscarinic
agonist, but it has a much weaker nicotinic
action (74). A factor in the observed potency of
acetyl p-methylcholine is its slower rate of hy-
cholinergic activity (68). Acetylthionocholine, drolysis by acetylcholinesterase because of
in which the carbonyl oxygen of acetylcholine poor affinity of the compound for the enzyme's
is replaced by sulfur, displayed some acetyl- catalytic site (81) and its extremely high resis-
choline-like effects in an electroplax prepara- tance to hydrolysis by nonspecific serum cho-
tion (78). linesterases.
3 Acetylcholine and Analogs

num sites (86) and of 915 using guinea pig


intestinal muscle (87); the S antipode is the
eutomer.
(5)-erythro-Acetyl-a,fhdimethylcholine
(33)exhibits 14% of the muscarinic potency of
acetylcholine, and it is almost completely re-
sistant to a~et~lcholinesterase; the (+)-threo
isomer is inert as a cholinergic and is a poor
Acetyl a-methylcholine (32) is a more po- substrate for acetylcholinesterase (88). These
tent nicotinic than a muscarinic, but both racemic mixtures have apparently never been
effects are decidedly less than those of acetyl- resolved.gem-Dimethyl substitution of acetyl-
choline (82); it is hydrolyzed by acetylcho- choline, either on the a,a or the p,p positions
linesterase at a rate similar to that of acetyl- of the choline moiety, greatly reduces but does
choline (73). The carbarnate ester of (*I+- not abolish muscarinic activity (89). Both
methylcholine (34), bethanechol, is a useful compounds are relatively poor substrates for
bovine erythrocyte acetylcholinesterase. Re-
placement of the C-methyl groups in the eth-
ylene bridge by longer chains causes an in-
crease in toxicity and a reduction in
muscarinic activity, e.g., the acetate esters of
p-n-propyl- and p-n-butylcholines (90, 91).

3.4 Substitution of the Ester Group


therapeutic agent, and acetyl p-methylcholine by Other Groups
(31) has some limited diagnostic uses (84).
The introduction of the C-methyl group into The ester moiety of acetylcholine does not ap-
the acetyl a- and P-methylcholine molecules pear to be essential for cholinergic activity. In
creates a chiral center, and the enantiomers general, alkyl ethers of choline and of thiocho-
exhibit different properties (Table 2.2). line are less potent and less active than acetyl-
S-(+)-Acetyl-p-methylcholine(the euto- choline (47); thio ethers are less potent than
mer) is hydrolyzed by acetylcholinesterase at the corresponding oxygen compounds. Con-
about half the rate of acetylcholine; the R-(-1- trary to some earlier literature reports, the
enantiomer is a weak inhibitor of the enzyme vinyl ether of choline (36) is not a more potent
(82). Work of Ringdahl (85) suggests that the muscarinic agent than the ethyl ether (35)
markedly lower pharmacological activity of (both are weak muscarinics), but it is a better
R-(-)-acetyl-p-methylcholineis a result both nicotinic agent, displaying higher potency
of lower affinity for the muscarinic receptor(s) than acetylcholine (92).
and lower intrinsic activity. The antipodes of a-Methyl substitution of choline in its ethyl
carbamyl-p-methylcholine (bethanechol) (34) and vinyl ethers (compounds 38 and 40)
displayed a eudismic ratio of 740 at rat jeju- greatly diminishes muscarinic potencies but

Table 2.2 Muscarinic Activities of Acetyl C-Methylcholinesa


Number Moles Equivalent to 1 Mole
of AcCh as Agonist in Guinea Pig Activity Ratio,
Substituent Stereochemistry Ileum (+)I(-)
a-CH3 RS 49
S-(-1- 232 8
R-(+)-(eutomer) 28
p-CH3 RS 1.58
S-(+)-(eutomer) 1.01 240
R-(-1- 240
"Adapted from Ref. 83. Courtesy of Plenum Press.
Choiinergics

ethers (43) in which the choline moiety was a


part of the ring system.

permits retention of potent nicotinic effects. It was concluded that the nicotinic activity
p-Methyl substitution (compounds 37 and 39) of choline phenyl ether and of choline o-tolyl
permits retention of some degree of musca- ether is a reflection of the ability of the mole-
rinic effect, but nicotinic effects are com- cule to assume a "planar" conformation when
pletely abolished (92). A series of open-chain interacting with the ganglionic nicotinic re-
congeners of muscarine, typified by structure ceptor. In contrast, the inactive 2,6-xylylether
(41), exhibited low muscarinic potency, which of choline cannot assume this planar disposi-
tion. Evaluation of additional conformation-
ally restricted aryl choline ethers (44-47) re-
vealed that only the piperidine derivative (47)
is a ganglionic stimulant (98).

was ascribed by Friedman (47) to the com-


pounds' stereochemical heterogeneity.
An open chain analog (42) of desmethyl-
muscarine lacking chiral centers exhibited ex-
tremely low muscarinic activity (93).

Some aromatic ethers of choline display


marked nicotinic activity, but they are inac-
tive at muscarinic sites (94). The o-tolyl ether
of choline is a potent ganglionic stimulant Ketonic systems (48a-c), carbon isosteres
(95), but the 2,6-xylyl ether of choline is inert of the ester moiety, display weak activities,
as a nicotinic agent (96). and they are predominantly more nicotinic
Additional ring-substituted phenyl ethers than muscarinic (47).
of choline were described by Hey (94). Clark The secondary alcohol analogs of these ke-
and coworkers (97) studied conformationally tones are even weaker and the thio ketones
restricted racemic bicyclic choline phenyl are also weak (48).
4 Cholinergics Not Closely Related Structurally to Acetylcholine

4 CHOLINERGICS NOT CLOSELY


RELATED STRUCTURALLY TO
ACETYLCHOLINE

4.1 Nicotine, Its Analogs and Congeners,


and Other Nicotinic Receptor Stimulants
Naturally occurring levorotatory nicotine (4)
has the S- absolute configuration. Its enantio-
mer, R-(+)-nicotine, was decidedly less potent
than the naturally occurring material in as-
says for peripheral effects (99). The pyrroli-
dine methyl quaternary derivative of S-(-1-
nicotine (50) shows peripheral activity com-

parable to that of nicotine itself (100) but it


lacks the secondary blocking action of the ter-
tiary arnine. In contrast, N-alkylation of the
(48a) R = CH3; alkylene = CH2-CH2 pyridine ring nitrogen of S-nicotine produces
(48b) R = CH3; alkylene = (CHz)3 quaternary compounds that are potent and se-
(48c) R = CzH5; alkylene = CH-CH2 lective antagonists at nicotinic receptor sub-
I types (101). The dimethiodide salt of S-nico-
tine has a low order of potency (100).
Nornicotine, in which the N-methyl is re-
In a series in which an alkyl chain (methyl placed by hydrogen, is somewhat less potent
through n-amyl) replaces the acetate ester and active than nicotine in most assays (102).
moiety (49), minimum activity occurs in most R- and S-nornicotine are equipotent with
assays when R = ethyl or n-propyl, and maxi- R-(+)-nicotine, the less active, unnatural en-
antiomer, in a rat brain membrane-binding
assay (103). In that study, S-(-)-nicotinewas
13 times more potent than its R- enantiomer.
Replacement of the N-methyl of nicotine with
ethyl or n-propyl causes an exponential loss of
peripheral nicotinic effect (102). Anabasine
mum muscarinic potency is demonstrated (51),a relatively minor alkaloidal constituent
when R = n-amy1(47,48), consistent with the of tobacco, demonstrated approximately 1/10
five-atom rule. the affinity of nicotine in a binding assay
Above heptyl, the compounds become an- (104). A synthetic azetidine congener (52) of
tagonists to acetylcholine. Numerous exam- nicotine binds with the same affinity as nico-
ples of ketones and N-alkyl congeners have tine to rat brain membrane tissue, and it dis-
been tabulated (47,481. played a greater potency than nicotine in a rat
An earlier review (47) descibes the pharma- behavioral assay (105). Evaluation of a series
cology of additional analogs and congeners of of 6-substituted nicotine derivatives (53) led
acetylcholine. to the conclusion that affinity for rat brain
Cholinergics

(without cerebellum) nicotinic receptors is re-


lated to the lipophilicity of the 6-substituent,
as well as to the size of the substituent (106).
Electronic factors seem to play a less signifi-
cant role.

A nicotine structural isomer (57) retains a


considerable degree of nicotine-like activity
(102). The piperidine congener (58) is some-
what less potent and active, and the perhy-
droazepine congener (59) is inert. The pyr-
rolidine and piperidine ring N-methyl quater-
nary derivatives of compounds (57) and (58)
are slightly less active than the corresponding
tertiary bases (107). Glennon and coworkers
(108) reported that the 6,7,8,9-tetrahydro-5H-
pyrido[3,4-dlazepines (60a and 60b) showed
high aMinity for nicotinic receptors in rat
brain (without cerebellum). The pyrido[3,4-.
clazepines (61a and 61b) had much less aMin-
Synthetic compounds (54) representing ity for the receptors (cf. compound 59). These
structures in which each of the bonds of the workers (108) reported additional &substi-
pyrrolidine ring of nicotine is cleaved, one by tuted pyridine systems in which the substitu-
one, produced a series of "seconicotines" ent was w-aminoalkyl, aminopropenyl, amino-
(102). propynyl, and aminoethoxy. Some of these
derivatives bound to nicotinic receptors, but it
was not possible to arrive at structure-activity
conclusions from these data.

Only the open chain congeners (55) and


(56) display nicotine-like activity. The potency
of compound (55) is increased in its N,N-di-
methyl congener; in contrast, the N,N-di-
methyl derivative of compound (56) is inert.
4 Cholinergics Not Closely Related Structurally to Acetylcholine 51

When n = 2, all positions of attachment to


the pyridine ring (carbon 2, 3, or 4) result in
extremely low potency and activity. When n =
1, attachment to positions 2 and 4 produces
practically inert compounds (102). Replace-
ment of the pyridine ring of structure (57) by
bioisosteric benzene, 2-thienyl, 2-furanyl, and
2-pyrrolyl ring systems abolishes almost all
nicotine-like activity.
The findings that S-nicotine ameliorates
some of the symptoms of the Alzheimer syn-
drome (110) and has a neuroprotective effect
in animals (111)have stimulated increased in-
terest in nicotine analogs and congeners.
Members of a series of 3'-, 4'-, and 5'-substi-
tuted nicotine analogs (64) were evaluated as

ligands for a nicotinic receptor from rat brain


The R-enantiomer of the pyridylquinucli- membranes (112).
dine (62) has a slightly higher affinity for a$, Only a small substituent is tolerated at posi-
nicotinic sites than the S-enantiomer (109). tion 4'; the (2'-S,4'-R)-methyl congener is the
most potent of the entire series, but it is some-
what less potent than S-nicotine itself. None
of the 3'- or 5'-substituted analogs approach
this binding affinity. 2-Chloronicotine (65) is
exponentially less potent than nicotine in an
a,& nicotinic receptor binding assay, whereas
6-chloronicotine (66) is twofold more potent

The S-enantiomer is 20 times less potent at


ganglionic subtypes than is the R.
Further modifications of compound (57)
are illustrated in structure (63).

than nicotine (113). The stereochemistry of


these chloronicotines was not addressed.
From a study of insecticidal nicotinic
agents (114) imidacloprid (67) was reported to
Cholinergics

act selectively at the insect versus the mam-


malian nicotinic acetylcholine receptor(s). In
contrast, the desnitro compound (68),a mam-

and active of the enantiomeric pair. Its effects


were blocked by the nicotinic antagonist
mecamylamine.
Antinociceptive (analgesic) activity of (S)-
(-)-nicotine has been observed and docu-
mented in many animal species (117). (- )-Epi-
malian minor metabolite of (67), is selective batidine (711, extracted from the skins of a
for the mammalian versus the insect nicotinic
receptor(s) and it is similar to (-)-nicotine in
potency in a mouse brain binding assay (115).
In a series of substituted 2-arylpyrrolidines
in which the substituted aryl group is a bio-
isosteric replacement for the pyridine ring of
nicotine, it was found that the isoxazole deriv-
ative (69) is a potent cholinergic channel acti-
vator (116).

South American frog, Epipedobates tricolor, is


200-400 times more potent than morphine as
an analgesic (118).
The stereochemistry of (-)-epibatidine
(lR,2R,4S)has been established by several to-
tal syntheses, of which ref. 119 is representa-
tive. The antinociceptive effect of (-)-epibati-
All substitutions on the pyrrolidine ring di- dine is antagonized by pretreatment with
minished the binding affinity compared with mecamylamine (120) (a ganglionic blocking
that of compound (69). The primary metabo- agent), but not by naloxone (121) nor, surpris-
lism of compound (69) involves oxidation at ingly, by hexamethonium (122). It is estab-
the 5'-position. It was therefore unexpected lished (120,121) that epibatidine is a nicotinic
that the 5'-methyl congener of compound (69) receptor agonist. Both enantiomers of epibati-
has in vitro half lives equivalent to or shorter dine I(+)-epibatidine is synthetic] had potent
than those of (69) itself. antinociceptive activity (121), and the only
Nicotine decelerates aging of nigrostriatal central receptors at which potent affinity
dopaminergic neurons (8) and it has been sug- was found were nicotinic. Epibatidine did not
gested that nicotine may relieve the symptoms bind to p, K , or 6 analgesic receptors, nor to
of Parkinson's disease (7). muscarinic or 5-HT, receptors. There was no
5-Ethynylnicotine (70) was designed as a significant binding to adenosine, adrenergic,
potential anti-Parkinsonian agent (9). dopaminergic, GABA, substance P, chole-
This compound was more potent than nic- cystokinin, NMDA, or u receptors (121). Epi-
otine in releasing dopamine from rat striatal batidine has very high affinity for the major
slices. The (S)-compoundwas the more potent nicotinic subtype in the brain, a& (123).
4 Cholinergics Not Closely Related Structurally to Acetylcholine 53

However, the alkaloid is nonselective in its ac- positions 5 or 6 in the 3-pyridyl fragment are
tions on nicotinic receptors, including the gan- potent nicotinic receptor ligands (126).
glionic (a3&) and neuromuscular (a1P18y~)
subtypes, as a consequence of which there is a
very narrow therapeutic index between bene-
ficial analgesic actions and toxic and ulti-
mately lethal actions on the cardiorespiratory
system. Replacement of the chlorine atom of
(+)-epibatidinewith hydrogen resulted in re-
tention of comparable affinity for nicotinic
sites, whereas replacement with methyl or io-
dine lowered affinity (118).
ABT-594 (721, described as an azetidine
bioisostere of nicotine with the (Rbabsolute

These as well as the 2-fluoro analog possess


subnanomolar affinity for the receptors in rat
forebrain. The 5-iodo compound showed the
highest affinity, comparable to that of epibati-
configuration, retains analgesic actions while dine. Additional 3-pyridyl ether congeners of
showing areduced propensity toward the toxic (73)/(74)have been cited from the patent lit-
side effects seen with epibatidine (123). erature (109); some of these bind with high
ABT-594 was approximately 70 times more affinity to 3H-cytisine and 3H-epibatidine
potent than morphine in a spectrum of acute sites, but exhibit much lower aMinity for 1251-
and chronic nociceptive models, and unlike bungarotoxin sites. Compound (751, the
morphine, it showed no evidence of tolerance 2-methyl congener of (741, was described (127)
or opioid-like dependence liability, nor did it as a nicotinic receptor ligand for receptor sub-
show effects on respiration or gastrointestinal types having mainly a, and P2 subunits. It
motility. It is said (113) not to demonstrate the showed positive effects in rodent and primate
addictive effects of nicotine. The (5')-enantio- models of cognitive enhancement, and a re-
mer of ABT-594 also showed potent analgesic duced propensity (compared to nicotine) to ac-
activity and, like the (R)-enantiomer, it was tivate peripheral ganglionic-like nicotinic re-
active after intraperitoneal or oral adminis- ceptors and to elicit seizures.
tration (124). Structure-activity studies sug-
gested that the N-unsubstituted azetidine
moiety and the 2-chloro substituent on the
pyridine ring are important contributors to
the potent analgesic activity. The deschloro
compounds (73) and (74) possess subnanomo-
lar affinity for brain nicotinic receptors (125),
but no analgesic testing data were reported for
these compounds. Computational studies indi-
cated that a reasonable superimposition of a A series of pyridine-based nicotine conge-
low energy conformer of (73) with (S)-nicotine ners (76-80) in which R, and R, were H or a
and (-)-epibatidine can be achieved. Further, variety of substituents was subjected to 3D-
it was concluded that the optimal internitro- QSAR analysis of their ability to bind to cen-
gen distance for binding of these types of com- tral a$, receptors (128).
pounds to nicotinic receptor(s) is 5.5 A. Deriv- Bulky substituents at the 6-position of the
atives of (73) having a halogen atom at pyridine ring reduce the affinity of the com-
Cholinergics

(109) to bind tightly to 3H-nicotine receptors


in rat cerebrum and to induce calcium flux
through a4P2receptors with potency compa-
rable to that of nicotine.
DBO-83 (86) showed powerful affinity for
a$, nicotinic receptors, and it demonstrated
antinociceptive activity (123).
In a series of substituted 3,8-diazabi-
cycloL3.2.lloctane derivatives, described as
structurally related to epibatidine (131), the
most interesting was (87). This compound
showed analgesic properties after subcutane-
pounds, whereas bulky ring systems including ous injection, which were reversed by
an sp3 nitrogen increase the affinity of the mecamylamine but not by naloxone. It had
compounds, consistent with results reported high affinity for binding at the a,& nicotinic
earlier by Glennon et al. (129). subtype, but it had no effect at the myoneural
A series of pyridyl ethers, typified by (81) junction. The S-(-)-spiro compound (88)is a
and (82),exhibited high binding affinity at 3H- potent full agonist in vitro at the rat a, nico-
cytisine rat forebrain sites (cytisine is a nico- tinic receptor (132); it is highly selective over
tinic receptor partial agonist), but only mod- the a subtype. However, even minor
erate affinity at 3H-epibatidine sites (109, changes in structure result in significant loss
130). in a, affinity. A synthetic analog (89) of the
A group of thio ethers (831, (84), (851, re- marine worm toxin anabaseine (90) is "func-
ported from the patent literature, was stated tionally selective" for the a, nicotinic receptor
4 Cholinergics Not Closely Related Structurally to Acetylcholine 55

H-C
II
C-H

(133). The structural dissimilarity between


the two a, receptor stimulants (88)and (89)is
striking.
The phenylisoxazole (91)showed moderate
binding aMinity to 3H-cytisinebinding sites in
Cholinergics

rat cortex, but it also demonstrated a mark-


edly lower toxicity compared to epibatidine
(109). Antinociceptive activity of this com-
pound was not reported.
Lobeline (92), an alkaloid obtained from
Lobelia inflata, binds with high affinity a t
some nicotinic receptors, and it produces some
(but not all) of the effects of (-)-nicotine (134).
stimulant. However, unlike nicotine, the ini-
tial stimulation is not followed by a dominant
blocking action (137).
Applying an extension of techniques of dis-
tance geometry to analysis of a number of
known nicotinic receptor agonists, Sheridan
et al. (138) proposed a definition of the nico-
tinic agonist pharmacophore, the essential
features of which were proposed to be: A, a
cationic center; B, an electronegative atom;
Lobeline also demonstrates antinociceptive and C, an atom that forms a dipole with B. It
effects, but these are complex (135): they are was concluded that there is only one arrange-
observed after intrathecal but not after subcu- ment possible for superimposition of these es-
taneous administration. Subcutaneous ad- sential groups: a triangle having dimensions
ministration of lobeline enhanced nicotine-in- A-B (4.8 A), A-C (4.0 A), and B-C (1.2 A). f i r -
duced antinociception in a dose dependent ther consideration of this proposed nicotinic
manner. Removal of one or both oxygen func- agonist pharmacophore by computational
tions from lobeline permits retention of the chemical studies of nicotine, epibatidine, and a
analgesic potency and activity of lobeline itself series of oxazolyl-azabicycloalkanes (139) led
(134). Moreover, removal of one or both oxy- to the conclusion that future modeling of nic-
gens diminishes, by at least 25 times, the af- otinic agonists should utilize the global energy
finity for nicotinic receptor(s) in rat brain ho- mimimum of epibatidine as the reference
mogenates. It was concluded that there is no structure, in which the torsion angle r = rl"
direct relationship between neuronal nicotinic (structure 95).
receptor (primarily a,& type) affinity and an-
algesia as measured by the tail-flick assay.
(+)-Anatoxin-A (93), produced by a fresh
water cyanobacterium, is more potent than
nicotine or acetylcholine in stimulation of
some subpopulations of nicotinic receptors
(136). The compound also stimulates release
of acetylcholine from hippocampal synapto-
somes.
With resped to the oxazolylazabicycloodanes
(structure 96), the optimum a-b distance was
concluded to be 7-8 Additionally, it was con-
cluded that the receptor area is sensitive to
changes in steric bulk and electrostatic potential
in the aliphatic area around the sp3 nitrogen.
Numerous nicotinic ligands interact with
muscarinic acetylcholine receptors, and vice
versa (109). Compounds (97) and (98) are ex-
amples of this varying selectivity: the nico-
1,l-Dimethyl-4-phenylpiperazinium (DMPP) tinic/muscarinic selectivity ratio in these sys-
(94), like nicotine, is an autonomic ganglion tems depends on the size of the substitution on
4 Cholinergics Not Closely Related Structurally to Acetylcholine

(3)is almost inert, as are both enantiomers of


the other three diastereomers of structure
(99) (epimuscarine, allomuscarine, and epial-
lomuscarine) (141). A point of interest is the
absolute configurational identity of the C2 PA-
sition of muscarine (3) and of the S-(+)-eu-
tomer of acetyl p-methylcholine (101).

The oxidation product of (+)-(2S,3R,5S)-


muscarine, muscarone (102), shows even
more structural analogy to the acetylcholine
the hydrogen bond acceptor geometrically op-
posite to the cationic moiety. Smaller substi-
tutions favor nicotinic binding, whereas larger
substitutions favor muscarinic binding (140).
Additional recent advances in nicotinic mo-
lecular design and therapies are reviewed in
Ref. 109.

4.2 Muscarine, Muscarone, and Related


Compounds
molecule; it is an active muscarinic agonist,
and it also exhibits a nicotinic component of
The muscarine molecule (3)may be viewed as activity not possessed by muscarine.
a cyclic analog of acetylcholine in which the For many years, the literature (e.g., Ref.
carbonyl and /3-carbons are linked by a bi- 142) consistently presented misleading andlor
methylene bridge (cf. structures 99 and 100). incorrect information concerning the stereo-
chemistry of the muscarone molecule, and
there were accompanying hypotheses, based
on this misinformation, rationalizing the
seemingly confusing relationship of the abso-
lute configuration of muscarone enantiomers
to their pharmacological properties. This con-
fusion was resolved by the proof (143)that the
eutomer of muscarone has chirality at C2 and
C5 (2S, 5 s ) identical with natural muscarine.
Naturally occurring (+)-muscarine is one The earlier literature (141,144) had reported
of eight stereoisomers of structure (99).The small eudismic ratios (2.4-10.1) for the mus-
(-)-enantiomer of (+)-(2S,3R, 5s)-muscarine carone enantiomers, in contrast to the large
Cholinergics

values established for muscarine enantio-


mers. This pharmacological inconsistency has
been explained by De Amici and coworkers
(145) on the basis of optical heterogeneity of
the muscarone enantiomers used in the ear-
lier studies. These workers performed enan-
tiospecific syntheses to obtain the two musca-
rone enantiomers in >98% enantiomeric
excess. In both binding and functional studies,
(-)-(2S, 5s)-muscarone was the eutomer, and
the eudismic ratios of the muscarone enanti-
omers were in the range of 280-440, which
are quantitatively similar to those for musca-
rine.
Enantiomerically pure 4-deoxy-4-fluoro- the C2 methyl of compound (106) to ethyl
muscarines have been reported (146). The (148) or replacing the C2 methyl with hydro-
most active member of the series was the gen (41). The data on these furan derivatives
2S,4R,5S-enantiomer (103), whose pharma- are consistent with the rule of five.
cology is much like that of muscarine itself, Muscarinic activity of 2-methyl-4-trimeth-
except that the fluoro compound showed a one ylammoniummethyl-1,3-dioxolane(107) re-
order of magnitude increase in affinity for car- sides in the cis isomer (149); stereospecific
diac M, receptors (those controlling rate). synthesis of the two enantiomers of the cis
isomer revealed that the L-(+) enantiomer

Beckett and coworkers (147) reported the (C4 = R ) is more than 100 times more potent
approximate equivalence of muscarinic action than the D-(-) enantiomer (C4 = S), and is
shown by enantiomers of 4,5-dehydromusca- approximately six times more potent than ace-
rone (104). tylcholine in a guinea pig ileum assay. The
more active L-(+) compound is related config-
urationally to the most potent muscarine ste-
reoisomer (3),although it should be noted that
several authors in the older literature incor-
rectly assigned the S absolute configuration to
position 4 of the L-(+)-cis compound (1071,
apparently through misapplication of priority
rules. 2,2-Dialkyl analogs of these dioxolanes
are much weaker muscarinic agonists than
dl-Dehydromuscarine (105)retains consid- the parent systems (107), and the difference
erable muscarinic agonist activity, but it in potency between the C4 R and S enan-
shows no effects at nicotinic receptors (141). tiomers diminishes sharply with increasing
Incorporation of the elements of the musca- size of substituents at C2 (150). Both enantio-
rine structure into an aromatic ring has pro- mers of the cis- and trans-oxathiolane system
duced some systems, such as compound (1061, (lOS), bioisosteres of the dioxolanes, were
which approach acetylcholine in muscarinic evaluated for nicotinic and muscarinic effects
potency (41). Activity is lowered by changing (151).
4 Cholinergics Not Closely Related Structurally to Acetylcholine 59

lective muscarinic agent with a large eudismic


ratio (152). (Note that the presence of the sul-
fur atom reverses the R,S designations of the
chiral centers, compared with muscarine.)
Compound (110) is exponentially less po-
tent than (111)at muscarinic receptors. Both
compounds demonstrate low nicotinic potency
The (+)-cis isomer of (108) was the most and activity. The sulfone congeners (112) of
potent muscarinic of the series. It demon- the enantiomers (2R,5R and 2S,5S) of the cis-
strated a eudismic ratio of the same high order structure are weak muscarinics with a eudis-
of magnitude as that for muscarine and the mic ratios of unity.
dioxolanes. This (+)-cis enantiomer has the
same absolute configuration as the muscarini-
cally most active L-(+)-muscarine (2) and the
(+)-cis-dioxolane (109). The other isomers
represented by structure (1081, although
much less potent than the (+)-cis isomer, also
demonstrated a degree of muscarinic agonist
effect. All four isomers of structure (108)
showed similar nicotinic potency and activity,
close to that of carbamyl choline, and eudismic Neither is an extremely potent nicotinic,
ratios were small. although the 2R,5R enantiomer is more po-
tent than the 2S,5S.
The cis and trans isomeric mixtures of di-
oxolane congeners bearing sulfur, phospho-
rus, or arsenic cationic heads (113-115) dis-
play lower muscarinic effects than the
corresponding nitrogen system (153).

Studies of the diastereomeric cis-sulfox-


ides (110) (2R,3S,5R) and (111)(2R,3R,W
indicated that compound (Ill), which has H3C CH2-X

H3CA0%H2--h(CH3)3 Both of the racemic cis-1- and cis-3-des-


etherdioxolane compounds (116 and 117)
(110) demonstrate muscarinic activity not substan-

the same absolute configuration as (+I-


H3C * 0ACH2-N(CH3)3

(2S,3R,SS)-muscarine (3),is a potent and se- (117)


Cholinergics

tially lower than that of the "supermusca-


rinic" L-(+)-cis-dioxolane (109) (153). It was
suggested (154) that occupation of only one of
the two receptor subsites proposed to be react-
ing with the ring oxygens of the cis-dioxolane
(109) is sufficient to induce muscarinic activ-
ity.
The moderately high potency (1110 acetyl-
choline) of the spirodioxolane (118)compared
with the low muscarinic potency (11300 acetyl-
choline) of a mixture of isomers of a more flex-
ible system (119), led Ridley and coworkers
(155) to speculate that the three-dimensional
geometry imposed by the molecular rigidity of
compound (118) may approximate the shape
of the L-(+)-cis-dioxolane (109) when it binds
to muscarinic receptor(s).

A more complex spirodioxolane molecule


(120), bearing a tertiary arnine rather than a
quaternary moiety, was resolved (156). The
3R,2'S isomer (121) was more potent in bind-
ing studies, but the 3R,2'R isomer (122) dis-
played larger selectivity between MI receptors
(ganglion) and M, receptors (heart). Additional 1,2,4-oxadiazole derivatives
The 3R stereochemistry of the most potent containing 1-azanorbornane (124a and 124b)
isomers (121) and (122) is consistent with and isoquinuclidine (125) rings were studied
that of other potent l,3-dioxolane derivatives. (158). These compounds can exist as geomet-
Extension of these studies (157) led to a race- ric isomers, and the exo-1-azanorbornane iso-
mic 1,2,4-oxadiazolederivative (123) that has mer (124b) was described as one of the most
high affinity and efficacy at central muscarinic potent and efficaceous muscarinic agonists
receptors. known.
4 Cholinergics Not Closely Related Structurally to Acetylcholine 61

muscarone may not play a critical role in ago-


nist-muscarinic receptor interactions. Beckett
and coworkers (147) had suggested the prime
importance of the keto group of muscarone
(compared with the ring oxygen), and the im-
portance of the ring C-methyl group has been
cited previously.
Certain cyclohexane analogs of desether-
muscarine and desethermuscarone showed
greatly diminished muscarinic activity (164).
These compounds, however, lacked the pre-
sumably important ring C-methyl group.

4.3 Pilocarpine and Analogs and Congeners


Pilocarpine (128), the chief alkaloid from the
leaflets of shrubs of the genus Pilocarpus, has
a dominant muscarinic action, but it causes

A carbocyclic muscarine analog, (+)-des-


ethermuscarine (1261, exhibits striking mus-
carinic effects (1591, although the compound

anomalous cardiovascular responses, and the


sweat glands are particularly sensitive to the
drug (165).
Its structure is distinguished by the lack of
a quaternary ammonium head; however it is
is considerably less potent than was originally presumed that a nitrogen-protonated cation is
reported (160). The other three stereoisomers the biologically active species. Pilocarpine has
of desethermuscarine (epi-, allo-, and epiallo-) been described as a muscarinic partial agonist
are weaker cholinergic agents (161,162). Two (166). Structural and conformational analo-
attempts (159, 163) to obtain (2)-desether- gies and interatomic distance similarities be-
muscarone (127) resulted in inseparable mix- tween pilocarpine and muscarinic agonists
such as acetylcholine, acetyl P-methylcholine,
muscarine, and muscarone have been invoked
(167) to rationalize pilocarpine's pharmaco-
logic properties. The potential utility of pilo-
carpine in treatment of glaucoma is limited by
its low ocular bioavailability. A double pro-
drug strategy (168, 169) involves hydrolytic
cleavage of the lactone ring of pilocarpine and
esterification of the freed carboxyl and alcohol
tures of epimers, which were reported (159) to groups (129) to produce derivatives with a
be equipotent to acetylcholine in assays for greatly enhanced lipophilic character. In the
nicotinic and muscarinic effects. The high po- presence of human plasma or rabbit eye ho-
tencies of desethermuscarine (126) and of the mogenates, pilocarpine was reformed from
mixture of desethermuscarone epimers sug- these derivatives in quantitative amounts be-
gest that the ring oxygens in muscarine and cause of the action of tissue esterases.
Cholinergics

Cyclic carbamate analogs (130-132) of pi-


locarpine were designed (170) to extend pilo-
carpine's duration of action, which is a reflec-
tion of its metabolic inactivation by hydrolytic
cleavage of the lactone ring.
of arecoline) varies with the nature of the al-
cohol: from the methyl ester (133a) to the
ethyl (133b), the affinity for the muscarinic
receptor(s) increases (175), but there is a
sharp drop in affinity and intrinsic activity
with the n-propyl ester (133~). However, the
ally1 ester (133d) is more potent and active
than the n-propyl (although less potent than
the assay's reference standard compound, car-
bamyl choline); the propargyl ester (133e)is
more active than carbamyl choline and indeed
was described (175) as a more potent musca-
rinic agonist than acetylcholine. Data were
presented suggesting that the triple bond of
Analog (130),having the same substitution the propargyl ester contributes to recept,or
pattern as pilocarpine,was equipotent to pilo- binding. Reduction of the ring double bond in
carpine in a guinea pig ileum assay. In vitro, the methyl (133a) (arecoline) and ethyl
base-catalyzed epimerization of pilocarpine at (133b) esters of arecaidine causes a 250 to
the C-ethyl group position forms the diaste- 1000 times reduction in muscarinic receptor
reomer isopilocarpine in which pharmacologic affinity.
activity is lost (171). The ester group positional isomer (134) is
less potent and less active than arecoline in
4.4 Arecoline and Analogs and Congeners the guinea pig ileum assay (1761, and the N,N-
Arecoline (133a),an alkaloidal constituent of dimethyl quaternary derivative of (134) is
the seeds of Areca catechu, is a cyclic "reverse slightly more potent than the tertiary amine.
ester" bioisostere of acetylcholine (cf. com-
pound 22).
In contrast to pilocarpine, arecoline acts at
nicotinic receptors as well as at muscarinic
sites; it has been described (172) as a partial
agonist at MI and M, receptors. Arecoline is
equipotent to its quaternary analog, N-meth-
ylarecoline, as a muscarinic agonist (172). The
secondary amine, norarecoline, is a somewhat
weaker muscarinic agonist than arecoline
(173,174).The muscarinic activity of esters of
arecaidine (the free carboxylic acid derivative
4 Cholinergics Not Closely Related Structurally to Acetylcholine

The five-membered ring congener (135)of


arecoline is approximately 50% as muscarini-
cally potent as arecoline in a guinea pig ileum
assay, and the five-membered ring analog

0
II
C-OR
(136)of dihydroarecoline is approximately 1% I
as potent as arecoline in this assay (175). The
sulfur bioisostere (137)of arecoline (R = CHJ
is more potent and active than its N,N-di-
methyl quaternary ammonium congener, be-
ing approximately equipotent to arecoline it-
self (176).The ester group positional isomer of
the sulfur bioisostere (138)(R = CH,) retains
muscarinic effects, but it is somewhat less po-
tent and less active than the &substituted
compound (137). In both (137) and (138)the
ethyl and n-propyl esters are inferior to the It was proposed that the amidine moiety of
methyl. the tetrahydropyrimidine ring would be a suit-
able ammonium bioisostere, lacking the per-
manent cationic head present in a quaternary
ammonium system. This might facilitate pen-
etration of the blood-brain barrier. Of this se-
ries, the methyl ester (139a)shows high a n -
ity for muscarinic receptors in rat brain, and it
stimulates phosphoinositide metabolism in
the rat hippocampus. It ameliorated memory
deficits associated with lesions in the septohip-
pocampal cholinergic system in rats. In a sub-
sequent communication (178) it was reported
that compounds (139b), (139e), (1401, and
(141) exhibited marked functional selectivity
for MI vs. M, receptors.
The potential utility of arecoline in produc-
ing significant cognitive improvement in Alz-
heimer patients (179) and in enhancing learn-
ing in normal young humans and in aged
nonhuman primates (180, 181) is largely ne-
gated by its short duration of action, which has
Further application of the bioisosterism been ascribed (182) to rapid in vivo hydrolysis
strategy replaced the tetrahydropyridine ring of the ester group. This metabolic lability
of arecoline with tetrahydropyrimidine stimulated preparation of metabolically stable
(139a-e) (177). aldoxime derivatives (142) (183); compounds
Cholinergics

posed to demonstrate a separation of CNS


from peripheral effects. Structural variations
based on (144) in which R' = CH, and the R
group is such that the carbonyl moiety is a

N-OR'
II

N-OR'
II

part of a carbonate, carbamate, or carboxylate


ester provided compounds having little or no
muscarinic activity. Some of the carbamate
derivatives demonstrated in vitro cholinester-
ase inhibitory activity (184).
were prepared in which R and R' = alkyl, cy-
Both enantiomers of the reversed ester
cloalkyl, olefinic, or acetylenic groups.
congener (145) of arecoline are (approxi-
Derivatives of structure (142) in which R =
mately equally) weak muscarinic agonists
CH, and R' = CH, or propargyl are musca-
(175),as are their N-methyl quaternary deriv-
rinic agonists, both in vivo and in vitro. These
atives.
compounds are two to three orders of magni-
tude more potent than arecoline, and they
have a longer duration of action. They are
orally effective. A large number of carbamate
derivatives (143), where R = aryl or alkyl,
were prepared as possible prodrugs to the al-
doximes (142). The derivative where R = p-
chlorophenyl had high potency and activity
(181); it was more active in an assay for CNS
effect than in an assay for peripheral cholin-
ergic effect. Thus, this compound was pro-
4 Cholinergics Not Closely Related Structurally to Acetylcholine

Ketoxime ethers derived from structures


(146)and (147) where R = H, methyl, propar-
gyl, or C-alkyl-substituted propargyl showed
M, agonist activity in a rat aorta preparation,
but no M, agonist activity (185).

All four isomers of the thianium system


(150) have been prepared and studied (175).
The sulfur atom in sulfonium salts may form a
chiral center, and the stereoisomers can be
isolated, given that the energy barrier to pyra-
midal inversion is substantially higher (- 100
kJ/mol) than it is in the case of the correspond-
ing ammonium compounds (-38 kJ/mol). The
(+ )-trans-thianium isomer (150) demon-
strated high muscarinic potency, slightly
higher than that of the S-quinuclidine (149),
but the (-)-trans-enantiomer (150) and the
(?)-&isomer (150) demonstrated low po-
tency. These data on the piperidine, quinucli-
dine, and thianium derivatives were rational-
ized (175) on conformational bases.

Modification of the aldoxime ether group


by introduction of an electron withdrawing
moiety led to the finding (186) that the Z-N-
methoxyimidoyl nitrile group serves as a sta-
ble methyl ester bioisostere. An example of
this molecular modification, compound (1481,

In an alternate strategy to provide resis-


tance to in vivo ester cleavage of arecoline
(187), bioisosteric replacement of the methyl
ester groups of arecoline and norarecoline by a
3-alkyl-1,2,4-oxadiazole ring (151)was inves-
tigated (188).
Analogs of structure (151),where R = un-
is a functionally selective Ml partial agonist branched Cl-, alkyl, are muscarinic agonists,
for which potential utility in treatment of Alz- and most of these show strong affinity in two
heimer's syndrome was suggested. binding assays in rat brain membranes. Deriv-
In contrast to the enantiomers of (1451, atives of structure (151), in which R = a
both enantiomers of 3-acetoxyquinuclidine branched alkyl chain or a cyclic system, are
(aceclidine, 149) are potent muscarinics, and muscarinic antagonists. Analogs in which the
the S-enantiomer is only approximately one R group contains an ether moiety (e.g., CH,-
order of magnitude less potent than acetylcho- 0-CH,) are also muscarinic agonists, but they
line. have lower receptor binding affinity than the
Cholinergics

alkyl derivatives. Congeners of (151)in which


the 1,2,5,6-tetrahydropyridinering was re-
placed by quinuclidine or tropane, are potent
antagonists with high affinity for central mus-
carinic receptors. Introduction of a methyl
substituent at position 5 or 6 of the tetrahy-
dropyridine ring of (151) (R = n-C,H,) de-
stroyed agonist effect and produced a musca-
rinic antagonist in the single example
reported. The N-desmethyl analog of (1511,
where R = n-butyl, retains potent muscarinic
agonism. Additional members of the series of
derivatives of (151)have been reported (1891,
and molecular mechanics calculations indi-
cated a preference for the E rotameric form
(152).
In continuation of efforts to identify MI-
selective muscarinic agonists capable of cross-
ing the blood-brain barrier, the 3-carbo-
methoxy group of arecoline was replaced by
bioisosteric 1,2,5-oxadiazole(154) or by 1,2,5-
thiadiazole rings with oxygen ether substitu-
ents at position 3 (155)or with thioether sub-
stituents at position 3 (156) (190). muscarinic receptors. However, all members
The ring-oxygen bioisosteres (154) (R = n- of the thiadiazole oxygen ether series (155),
butyl or n-hexyl) show low affinity for central where R varied from CH, through n-C,H,,

E Rotamer Z Rotamer
4 Cholinergics Not Closely Related Structurally to Acetylcholine 67

and also included some branched chain C, al- antinociceptive effects from undesirable mus-
kyl groups, demonstrated high potency in dis- carinic side effects (salivation, tremors).
placing tritiated oxotremorine-M (a nonse- These efforts were unsuccessful. As a result of
lective muscarinic agonist) and tritiated a concurrent study of rigid, conformationally
pirenzepine (a selective M, antagonist) from restricted analogs of (156), it was proposed
rat brain membrane tissue. The n-butyloxy that the biologically active conformation of
and n-pentyloxy substituents provided maxi- (156) has a torsion angle T C3-C4-C3'-N2'
mal pharmacological effects. A subsequent "close to 180°."
communication (191) reported that a deriva- Study of a series of arecoline congeners
tive of (155) in which R = n-hexyl (xanome- (158)in which the carbomethoxy group is re-
line) is an M, agonist with potential value in placed by a pyrazine moiety (R = CH,-
treatment of Alzheimer's syndrome. The pri- C,H,,) revealed that M, agonist activity is re-
mary site of oxidative metabolism of xanome- lated to chain length, with n-hexyl providing
line is the hexyloxy side chain (192), and a maximum activity (195). A comparison of MI
secondary metabolic process involves N-de- agonist efficacy of these pyrazines and related
methylation. To prevent this oxidative N-de- 1,2,5-thiadiazoles (155)and 1,2,5-oxadiazoles
methylation, the N-methyl group was incorpo- (154) suggested that M, efficacy may be re-
rated into a series of azabicyclic and tricyclic lated to the magnitude of electrostatic poten-
systems, illustrated by (159)and (160). tial located over the nitrogens of the respec-
Some members of the series exhibited se- tive heterocycles. The heteroatom directly
lectivity for M, receptor binding. The alkyl- attached to the 3 position of the pyrazine or of
thio analogs (156) demonstrated a similar the 1,2,5-thiadiazole markedly influences the
structure-activity relationship to the alkoxy M, efficacy of the compounds by determining
series (155); however, the thio ethers have the energetically favorable conformers for ro-
higher receptor affinity and higher potency. tation about the bond connecting the tetrahy-
Thus, these systems (155) and (156) show a dropyridyl ring and the heterocycle. A three-
higher degree of selectivity for M, receptors dimensional model for the M, agonist
than for M,. The unsubstituted system (157) pharmacophore was proposed as a result of
(R = H) is a potent but nonselective musca- these studies.
rinic agonist. Derivatives of (1571, where R =
n-propyl, n-pentyl, n-heptyl, or n-octyl, have
10 to 100 times less affinity for central musca-
rink receptors than the corresponding alkoxy
and alkylthio derivatives.

Compound (156)was reported (193) to be a


potent antinociceptive agent, but there was
little difference between an analgesic dose and
one producing salivation. Analogs of (156)
were prepared (194) in attempts to separate
Cholinergics

The tetrahydropyridine ring was fused


with a 3-alkoxyisoxazole moiety in a series of
compounds (161a-g)(174). Both (161a)and

&T OR'

Another tetrahydroazepine congener (163)


displays higher affinity for muscarinic recep-
tors but somewhat lower efficacy than the
analogous fused piperidine compounds (161)
(197); it was described as a partial agonist.
Studies (198)of sulfur analogs and congeners
(164-167) of the isoxazolotetrahydropyri-

(161b)are muscarinic agonists in a guinea pig


ileum assay, and as with arecoline and
norarecoline, the N-methyl tertiary amine
congener (161a)is somewhat more potent
than the nor derivative (161b).
Variation of the 0-alkyl (R') group in the
nor series (l6lb-g) produced pharmacologi-
cal activities and potencies parallel to those
described for the esters of arecaidine (113a-
el: the 0-n-propyl and n-butyl homologs
(161d)and (161e1,respectively, demonstrate
only weak muscarinic agonist effect; however,
the 0-ally1 and propargyl homologs displayed
prominent muscarinic agonism, with the 0-
propargyl compound being one order of mag-
nitude more potent that the 0-allyl. However,
there is no apparent correlation between the dines (161)demonstrated that the thiapyran
derivatives (164) and (165) are inactive as
effects of the compounds on central and pe-
muscarinic agonists. However, the S-methyl
ripheral cholinergic receptors. It was specu-
lated (174) that the effects observed in the il- sulfonium derivative (167a)binds to brain
eum preparation are mediated primarily by and heart muscarinic receptors, albeit not as
M, receptors, whereas the rat brain mem- strongly as arecoline. Compound (167a)is
brane-binding data may represent a nonde-
scriminate binding to all types of muscarinic
binding sites.
The tetrahydroazepine congener (162) of
the tetrahydropyridine isoxazole systems
(161) is said to possess high affinity for the
central MI receptor, coupled with only limited
toxicity (196).
4 Cholinergics Not Closely Related Structurally to Acetylcholine

also inferior in potency and activity to "sul-


foarecoline" (137). However, the numerically
large ratio of agonist activity at M, receptors
to that at M, receptors for compound (167a) is
slightly greater than for arecoline or sul-
foarecoline, which is a desirable parameter for
therapy of Alzheimer's disease. The 0-ethyl
homolog (16%) is a muscarinic antagonist, in
contrast to its tetrahydropyridine bioisostere
(16lc),which is described as a muscarinic par-
tial agonist (198). The 0-isopropyl-S-methyl
(167~) and 0-propargyl-S-methyl(167d)sul-
fonium homologs demonstrate pharmacologi-
cal properties similar to those of the 0-methyl
homolog (167a). The single structure (166a)
derivative tested was a weak muscarinic ago-
nist in all assays, but it demonstrated a de-
cided preference for M, receptors over M, re-
ceptors.
olism in rat cortex and hippocampus. Increas-
ing the length of the alkyl substituents
(168b-h) increased the affinity for musca-
rinic receptors, albeit not in a linear fashion,
yet decreased activity in the phosphoinositide
turnover assay. It was concluded that at low
concentrations, compound (168a) selectively
stimulates M, receptors.
Regioisomers of an exocyclic amidine sys-
tem (169a-d) bioisosteric with arecoline were
tested as their racemic modifications (200).

Further modification of the arecoline struc-


ture involved replacement of the ester group Only the 5-carbomethoxy isomer ( 1 6 9 ~ )
of tetrahydropyrimidine derivatives (as in displayed high affinity and activity at musca-
structures 139a-f) with a 1,2,4-oxadiazole rinic receptors coupled to phosphoinositide
ring (structures 168a-h) (199). metabolism in rat cortex. Evaluation of other
Each of the test com~ounds
* (168a-h) alkyl esters (170a-c) of the 5-carboxylic acid
bound with high afiinity to muscarinic recep- revealed that only the propargyl derivative
tors from rat brain. The &methyl homolog (170c) retained substantial agonist activity.
(168a) displayed high efficacy at muscarinic In a series of cyclic guanidines, (2-amino-
receptors coupled to phosphoinositide metab- tetrahydro-pyrimidines, 171a-e), all mem-
Cholinergics

ity in rat cortex (201); compounds (173a and


(173b) (spiro-4-piperidine derivatives) showed
marked muscarinic agonist effects in a phos-
bers showed high binding affinities in a rat
phatidyl inositol turnover assay. Compounds
brain membrane assay (200). However, only
(173a) and (173b) also showed moderate bind-
the methyl and propargyl esters (171a and
ing ability against [3Hl-N-methylscopolamine
171d) showed high muscarinic agonist activ-
and [3H]oxotremorinein rat cortex tissue. Com-
ity in a phosphoinositide metabolism assay.
pound (173a) compared favorably with areco-
Computational chemical studies revealed a
line in terms of receptor efficacy although it, like
common minimum energy conformation for
(173b), demonstrated much lower receptor af-
all of the muscarinically active members of
finity. The 2-ethyl homolog ( 1 7 3 ~ )demon-
several series (169, 170, 139, and 171),which
strated decidedly lower receptor efficacy than
suggests that all of the subject compounds in
(172a) or (172b), and it also demonstrated
this study interact with muscarinic receptors
lower receptor affinity. Variations of structure
in a similar fashion. The utility of amidine sys-
(173)are represented by (174) and (175),which
tems as suitable replacements for the quater-
are agonists at rat central MI receptors (202).
nary ammonium group of acetylcholine in de-
signing ligands for MI receptors is suggested
by the results of these studies.

Studies of extended series of other spiropi-


peridine derivatives demonstrated that com-
pound (176) is a partial muscarinic agonist
The spiropiperidine systems (172a, 172b) that reverses carbon dioxide-induced impair-
(diastereomers, stereochemistry unspecified) ment in mice (203), and that compound (177)
are hybrids of the arecoline molecule and of is a muscarinic agonist with an affinity for cor-
the spirodioxolanes (121 and 122). tical M, receptors (204). The (2)-spiroquinu-
Compounds (172a) and (172b) (spiro-&pi- clidine derivative (178) is a selective M, ago-
peridine derivatives) show weak binding abil- nist (205).
4 Cholinergics Not Closely Related Structurally to Acetylcholine

which is approximately equipotent to acetyl-


choline as a muscarinic agent but lacks nico-
tinic effects (213).
As with pilocarpine and arecoline, in-
creased interest in pharmacotherapy of Alz-
heimer's disease and other memory deficit
conditions has led to renewed and expanded
studies of oxotremorine. This compound has
Some quinuclidine and azabornane deriva- little or no effect on serum or red cell butyryl-
tives bearing oximino or heterocyclic ring sub- cholinesterase. Oxotremorine has been de-
stituents at position 3 (e.g., 179 and 180) dem- scribed as a potent muscarinic partial agonist
onstrate potent muscarinic agonism. Some (172). However, an earlier report (11) pre-
compounds of these types are selective for M, sented evidence that oxotremorine has an in-
and M, receptors (206-210). direct action in the CNS, perhaps by stimula-
tion of choline acetyltransferase, resulting in
4.5 Oxotremorine and Analogs and
elevation of acetylcholine levels. The periph-
Congeners
eral actions of oxotremorine, including effects
Tremorine (lsl),a synthetic compound with on cardiovascular mechanisms, have been as-
weak cholinergic activity (211, 212) is metab- cribed (172) to preferential activation of M,
olized to the lactam oxotremorine (182), receptors. Brimblecomb (211, 212) reported
72 Cholinergics

pharmacological data on a large number of To assess the validity of conclusion 2 above,


tremorine-oxotremorine derivatives, from Brimblecomb (211) compared the trimethyl-
which the following conclusions were drawn. ammonium quaternary moiety with the l-pyr-
rolidino group in a series of compounds (Table
1. The carbonyl group of oxotremorine is 2.3).
essential. Variations are apparent in the activities of
2. The pyrrolidine nitrogen of oxotremorine the quaternary ammonium salts, but the vari-
may be replaced by a trimethylammonium ation is not nearly as great as that demon-
quaternary group ("oxotremorine-M"), but strated by the tertiary amines (pyrrolidines).
replacement with a tertiary amine (di- The Brimblecomb group (214) described an
methylamino or diethylamino) results in additional series of some 23 tremorine-ox-
great loss of activity. otremorine congeners, but none of these com-
3. The acetylenic bond is essential; partial or pounds showed significant muscarinic agonist
complete saturation results in complete effects in the guinea pig ileum or the cat blood
loss of activity. pressure assay.
4. Increase in the size of the lactam ring re- In a series of compounds (183a-c)in which
sults in a change from agonism to the pyrrolidine ring of oxotremorine is re-
antagonism. placed by imidazole, the parent compound

Table 2.3 Muscarinic Activities of Oxotremorine Congeners and Analogs Containing


Trimethylammonium or Pyrrolidino Groups
R-4H2-*-Hz-R'
Muscarinic Activity (isolated guinea pig ileum,
acetylcholine = 1)

Compound R' = N(CH,),


Number R + R' = 1-pyrrolidino

'2-
(1) 1.74 1.48

Q 0

0.001

(4)
(5)
(6)
(7)
06
CH,CON(CH,)-
(CH,),NCON(CH,)-
(CH3)2NCOO-
CH3COCH2-
0.87
0.03
0.15
2.10
1.15
0.04
0.004
0.005
(8) CH,COO- 0.47 0.005
4 Cholinergics Not Closely Related Structurally to Ac

(183a) resembles oxotremorine in its musca-


rink efficacy (215);addition of a methyl group
to the imidazole ring (183b)greatly decreased
muscarinic activity (216), whereas addition of
methyl groups to both the imidazole and the
pyrrolidone rings (183~) produced a potent
muscarinic antagonist (215).

I" R
N-CH2-C-C-CH2-N

(l83a) R = R' = H
(183b) R = H; R' = CH3
,yR'
b N

(186) R = H or CH3; R' = H, CH3, CH3C0, or HCO


(183c) R = R' = CH3

Studies (219,220) of methyl group substi-


All members of a series of oxotremorine an- tution into the oxotremorine molecule (com-
alogs (184a-e), in which the pyrrolidone ring pounds (187a-g), all of which were tested as
iscontracted to a p-lactam moiety (217), dem- their racemates) revealed that the 3'-methyl
onstrated uniformly weak cholinergic effects. isomer (187a) has weak muscarinic stimulant
activity in intact mice.

.-+ R'
N-CH2-CrC-CH2-R

(184a) R = R' = H; R" = cNC4H8


(184b) R = CH3; R' = H; R" = cNC4H8
( 1 8 4 ~R
) = H; R' = CH3; R" = cNC4H8
(184d) R = H; R' = CH3; R" = N(CH3)2
(184e) R = H; R' = CH3; R" = N(CH3)3
+

Compound (184a) is the most potent mus-


carinic agonist of the series, being 6 times less
potent than its pyrrolidone congener (182).
Compound (184b) is a weak partial musca- Similarly, the N,N-dimethyl congener
rink agonist; ( 1 8 4 ~is
) a muscarinic antago- (188) displays weak oxotremorine-like activ-
nist; (184d) and (184e) are muscarinic ago- ity. The remaining isomers (187b-g) have
nists, 220 times less potent than (184a). An
N-acetylated piperidine derivative (185)is a
potent muscarinic agonist (40).
Conversion of the pyrrolidone ring of ox-
otremorine and some congeners into an imid-
azolidone ring (186) produces compounds
(generally of low potency) with a variety of
effects at muscarinic receptors (218).
central atropine-like antimuscarinic effects
but only weak peripheral parasympatholytic
actions.
Compounds (187d-f), as well as the C1, C 2
dimethyl derivative (1891, were resolved and
6' N-CH2-C-C-CH2-R

CH3

(190a) R = N(CH3)2
(190b) R = N(CH3)3
+

a
CH3-C-N-CH-C=C-
CH3
I

the enantiomers were evaluated (221). Some


\
CH3
compounds are agonists, some are partial ago-
nists, and some are antagonists at muscarinic (191)
sites. In some instances. the eudismic ratio is
large, and in some instances the ratio is rela- Racernic (191) (226), as well as its pure en-
tively small. Structure-activity conclusions antiomers (227),blocks oxotremorine-induced
cannot be drawn from these data. Arnstutz tremors. In other regions of the brain (e.g.,
and coworkers (222) resolved the 5'-methyl those involved in analgesia and hypothermia),
pyrrolidone derivative (187c) as well as the (191) acts as a muscarinic agonist (228). Re-
N,N-dimethyl tertiary amine (190a) and its placement of the acetamido group of (191)
quaternary ammonium derivative (190b). with an oximino moiety and homologation of
The pyrrolidone derivative [(R)-187~1 is a cen- the chain (192) resulted in a fivefold greater
tral and peripheral muscarinic antagonist, as selectivity for M, receptors (229).
has been reported earlier for the racemate.
Compounds (R)-(190a)and (R)-(190b)are po-
tent muscarinic agonists in the guinea pig il-
eum. Compound (R)-(190a) (the tertiary
amine) shows both central muscarinic (hypo-
thermia) and central antimuscarinic activity
(antagonism of oxotremorine-induced tremor)
in vivo. These central agonist-antagonist
C N-CH2-C-C-CH2

properties probably reflect interactions of the (192)


drug with different subpopulations of musca-
rinic receptors. For all three compounds in A series of congeners (193) addressed re-
this study (187c, 190a, 190b), the (R)-enan- placement of the acetamide moiety of com-
tiomers are considerably more potent than the pound (191) by methanesulfonamido, triflu-
(S)-,both in vivo and in vitro, irrespective of oroacetamido, methylsulfonimido,or acetimido;
whether agonist or antagonist effects were introduction of a methyl into the C1 position of
measured. Substitution of a benzene ring into
various positions of the oxotremorine mole- R'\
cule destroys muscarinic stimulant activity; N-CH-C=C-CH2-R"'
these derivatives are competitive muscarinic / I
R R
antagonists (223). The N-methylacetamide
congener (191), closely related to compound (193)
(4) in Table 2.3, was reported (224,225) to be R = CH3S02;CF3CO;CH3C0
a presynaptic antagonist and a postsynaptic R' = CH3;CH3S02;CH3C0
agonist at muscarinic receptors in vitro and in R = H, CH3
vivo. R = 1-pyrrolidyl;N(CH3)2;N(CzH&; +N(CH&
4 Cholinergics Not Closely Related Structurally to Acel

the Qbutyne chain; and variation of the C4 ter- to form a six- or seven-membered ring pre-
tiary amino group or quaternary group (230). served affinity for muscarinic receptor(s), but
Replacement of the acetyl group or the N- abolished efficacy (232).
methyl group in (191) and its analogs by a In a series of oxotremorine and oxotremo-
methansulfonyl group abolishes efficacy and n e (196) analogs (197, 198), all com-
decreases affinity at guinea pig ileal receptors. pounds studied (tertiary and quaternary
The trifluoroacetamide analogs of (191) also amines) demonstrated analgesic effects in
exhibited diminished affinity and efficacy. neurogenic and inflammatory pain models
Substitution of an acetyl group for the (233). It was concluded that these compounds
N-methyl group of (191) decreases efficacy, were acting as muscarinic analgesics. The an-
but has little effect on affinity for the recep- tinociceptive effects were blocked by atropine
tor(~). Most of the tertiary amines showed cen- but not by naloxone or mecamylamine. Mem-
tral antimuscarinic effects. Bioisosteres of bers of the series varied as to classic musca-
(191)bearing a urea moiety (194) in which the rinic agonist effects (e.g., salivation).
R, R', and R"groups were combinations of CH,
and H, displayed muscarinic agonism, partial
agonism, or antagonism (218); a structure-ac-
tivity relationship is not apparent in this se-
ries.

A nitrogen mustard congener (199) of ox-


otremorine is a potent and selective musca-
rinic agonist (234).
When (199) was administered to an intact
Conformationally restricted analogs of animal, the signs of muscarinic stimulation
(191)and (195a-i) have been described (231). were followed by a phase of long-lasting anti-
muscarinic effects (235). Both the stirnulatory
and the blocking effects are elicited by the
aziridinium ion (201) formed by in viuo cy-
clization of the parent 2-chloroalkylamine.
This aziridinium system is closely related
structurally to "oxotremorine-M" (196), which
is an extremely potent muscarinic agonist
(212). The blocking activity is correlated with
alkylation (covalent bond formation) of the
muscarinic receptor(s) by the aziridinium ion.
The bromine-derived mustard (200) shows
threefold greater in uitro muscarinic stimu-
lant activity than the chloro compound (1991,
and this can be rationalized on the basis that
bromine is a better leaving group, and aziri-
dinium ion formation is more facile in (200)
These structural modifications resulted in than in (199). Neither of these mustards dis-
decreased affinity for rat cerebral cortex tissue plays a significant amount of effect at nicotinic
and in most cases abolished efficacy at both receptors. These compounds may be useful in
central and peripheral muscarinic receptors. receptor inactivation studies. The slower rate
Other conformationally restricted analogs of of cyclization of the chloro compound (199)
(195) in which the amide moiety and the may permit its penetration of the blood-brain
methyl group on the butynyl chain were joined barrier before formation of the aziridinium
4 Cholinergics Not Closely Related Structurally to Acetylcholine 77

3-5 in Table 2.4) and the pyrrolidinium prod- of compound (203) (239). The (5')-enan-
uct of the 4-halobutylamine moiety of com- tiomers of (204) and (205) exhibit low eudis-
pound (6) in Table 2.4 should be much less mic ratios (1.5 and 4.9, respectively). Com-
susceptible to nucleophilic attack in vivo, and pound (205) has been described (240)as one of
hence these quaternary systems, unlike the the most potent MI-selective agonists (sic)
aziridinium moiety, should have little or no known.
tendency to bond covalently with the musca- Dimethylsulfonium (206a and 206b) and
rinic receptor(s) to produce blockade. Central thiolanium (206c and 206d) analogs of ox-
muscarinic effects (tremors, analgesia) of this otremorine demonstrate higher affinities for
series of compounds correlated well with the peripheral muscarinic receptors than the cor-
k, and t,,, data. The slow cyclization rate of responding trimethylammonium and N-meth-
compound (3)and the extremely rapid cycliza- ylpyrrolidinium compounds (241).
tion rate of compound (6) were reflected in
weak or no CNS-related activities. As might be
predicted, compound (3) showed relatively
weak peripheral muscarinic activity (saliva-
tion) whereas compound (6)was potent. Com-
pounds (4) and (5)were cited as meriting fur-
ther study.
McN-A-343 (203) is a selective M, agonist (206a) X = CH2; Y = +S(CH&
and it has been reported to exhibit antinoci- (206b) X = CO; Y = +S(CH&
ceptive effects (238). It was suggested that (206c) X = CH2; Y = c+SC4H8
postsynaptic M, receptors are involved in an- (206d) X = CO; Y = c+SC4H8
tinociception, and that presynaptic M, recep-
tors may also be involved, on the basis that
they participate in modulation of acetylcho- However, the sulfur compounds have lower
line release. intrinsic activities than their nitrogen ana-
Of a series of congeners of compound (2031, logs. The sulfur compounds also demonstrate
(2)-204 and (2)-205 were concluded to be potent affinity for rat cerebrocortical tissue in
muscarinic partial agonists, showing five- and a (-)-[3H]-N-methylscopolaminedisplace-
16-fold higher potency, respectively, than that ment assay. Sulfonium congeners (207) bear-
Cholinergics

ing chlorine or bromine at positions 3 or 4 of


the benzene ring retain selectivity for gangli-
onic muscarinic receptors, but they were con-
cluded to be partial agonists when compared
with the nitrogen system (203) (242). Nitro-
gen mustard congeners (208a and 208b) of
(203) demonstrate effects analogous to those
described previously for other oxotremorine-
based nitrogen mustards (243). (210) R = H; R' = morpholino
(211) R = NO2; R' = N(C2H5)2
4.6 Miscellaneous, Structurally Unique
Muscarinic Agonists
demonstrate analgesic activity. Shannon et al.
Several structurally unique muscarinic ago- (246), and references therein) presented a his-
nists have been identified. torical survey of muscarinic agonists that have
Compound (209) is claimed to be highly se- been reported to demonstrate antinociceptive
lective for the M, receptor (196); (210) and effects. These effects seem enigmatic, in that
(211) have been described as selective M, ago- the involvement of acetylcholine in excitation
nists devoid of classical muscarinic side effects of the pain sensation has been cited (247).
(196,244). Agonists at various G-protein-coupled musca-
Evidence was presented many years ago rinic receptors have potent analgesic activity,
(245) suggesting that some muscarinic agents but this is frequently accompanied by typical
muscarinic side effects (123). Analgesic prop-
erties of the arecoline congener (156) were
cited previously. Vedaclidine (212) appears to
be the most prominent of these agents, having
M, agonist and M,/M, antagonist activity
(123).
1,2,5-Thiadiazoleether analogs (213,214)
of vedaclidine (212) have also been viewed as
being analogs of the potent muscarinic agonist
aceclidine (149) (248).These ether analogs are
4 Cholinergics Not Closely Related Structurally to Acetylcholine

The R-enantiomer of (218) is highly selec-


tive for M, receptors over M, (252). The syn-
thetic route to (218) led to a 60:40 mixture of
Z:E oxime stereoisomers (253); this mixture,
on standing for 1 h at room temperature in

potent, efficaceous, and selective M, receptor


agonists. Replacement of the 3-oxyquinucli-
dine moiety of (213) or (214) by ethanolamine,
hydroxypyrrolidine, hydroxyazetidine,hydroxy-
isotropane, or hydroxyazanorbornane led to
compounds with high muscarinic receptor af-
finity adlor M, agonist efficacy. A concomitant
computational chemistry study led to the pro-
methanolic hydrogen chloride changed to an
posed description of an M, receptor pharma-
8515 equilibrium mixture of Z:E. Evaluation
cophore. No mention was made of testing of
of a series of azabicyclo[2.2. llheptane analogs.
this series of agents for antinociceptive effects.
of (218) revealed that with only a few excep-
Compound (215) inhibited jejunal contraction
tions, muscarinic activity resided in the
in the ferret, as well as demonstrating potent
Z-oximes, and that the E-isomers were inert
analgesic effects in the mouse writhing test
or very weakly active.
(249). An indole derivative, besipirdine (2191,dis-
plays some cholinomimetic effects, in addition
to prominent adrenergic actions. The mecha-
nism of the cholinergic effects was stated to be
unclear (254).

(215) 5 - R,6 - R,exo

A natural product, baogongteng-A (216)


was reported (250) to have agonist activity at
muscarinic receptors. A series of congeners
was prepared (2511, of which (2 17) was found
to be a potent muscarinic agonist with selec-
tivity toward M, receptors.
Cholinergics

5 CONFORMATION-ACTIVITY
RELATIONSHIPS OF SOME
CHOLINERCIC ACONISTS

Conclusions about pharmacologically signifi-


cant conformations of cholinergic agonists
have been largely based on X-ray diffraction
studies and NMR (chiefly 'H) studies. Casy
(255) noted that in the cholinergic field, NMR
evidence complements the results of X-ray
studies. Casy (256) proposed four questions to
which conformational studies of cholinergic apart, and the 7, angle commonly has a value
agonists must be addressed: of 73-94", so that the N and 0 functions are
approximately synclinal (gauche). Many com-
1. Does the "active" conformation of a cholin- pounds with the 0-C-C-N+ moiety, where the
ergic ligand correspond to its preferred ste- oxygen-containing function is hydroxy or ac-
reochemistry or is an energetically less fa- yloxy, prefer the T, synclinal (gauche) N/O dis-
vored form bound to the receptor? position in the solid state: L-(+)-muscarineio-
2. Is there a unique mode of ligand binding to dide (31, the (4R)-(+)-cis-dioxolane(107),and
cholinergic receptors or do multiple modes the furan derivative (106). NMR data sug-
exist? gested (260) that acetyl-P-methylcholine (31)
exists in solution in a T, synclinal conforma-
3. May the dual effects (nicotinic and musca-
tion. However, there are many exceptions: in
rinic) of acetylcholine be explained in terms
the crystal state the potent muscarinic ago-
of conformational isomerism?
nists carbamoyl choline (number (19)in Table
4. Do agonist and antagonist ligands occupy 2.1) and (+)-trans-ACTM (221) (259) prefer
the same or different binding sites (with the T, anticlinal T, antiplanar conformations,
one or more features common to both)? as do the weakly active thio and seleno analogs
of acetylcholine (24) and (25).
These challenging questions remain, some
25 years later, largely unanswered, despite a
large body of chemical and biological work and
a voluminous literature. Indeed, establish-
ment of the existence of multiple subpopula-
tions of both nicotinic and muscarinic recep-
tors renders question 3 even more formidable.
The three-dimensional steric disposition of
the flexible acetylcholine molecule and those
of its congeners can be defined on the basis of L-(+)-Muscarone (102) exhibits a T, angle
torsion angle T. Summations and definitions of that is antiplanar (261).
nomenclature incident to use of torsion angles The crystal structures of certain nicotinic
are found in refs. 257 and 258. Structure (220) agents, for example, acetyl a-methylcholine
defines relevant torsion angles in the acetyl- (32) and lactoylcholine (17 in Table 2.1), have
choline molecule. torsion angle (7, and 7,) features similar to
The torsion angles T, and T, usually fall most muscarinic agents (262). In contrast,
close to 180"; the values of 7, and T, are more some cyclic analogs of aryl choline ethers ex-
useful in defining pharmacologically signifi- hibit maximum nicotinic effects when the T, is
cant conformations for acetylcholine and re- antiplanar ("transoid") (98).
lated molecules. From X-ray studies (259) it However, there is no assurance that any of
was concluded that in most cases T, values fall the preferred conformations determined ex-
in the range 180 2 36" (antiplanar), placing perimentally by X-ray or solution NMR meth-
the quaternary head and the acetyl group far ods, or by molecular orbital calculations (263),
5 Conformation-Activity Relationships of Some Cholinergic Agonists

represent the geometry of the agonist at cho-


linergic receptors; barriers to rotation in mol-
ecules such as acetylcholine are low (264,265),
and there is considerable rotational freedom
in the muscarine and muscarone systems
(256). It is well established as a broadly appli-
cable working hypothesis that an agonist mol-
ecule may interact with its receptor(s) in other
that its (the agonist's) lowest energy confor-
mation. The energy expended by the agonist's
assuming a higher energy conformation is
compensated for by the energy advantage of
the agonist-receptor interaction itself.
An alternate strategy is the study of confor-
mationally restrained acetylcholine analogs in
which the presumed pharmacologically signif-
icant portions of the molecule (the quaternary
ammonium head and the ester function) are in
relatively "frozen" positions, so that the
The trans-sulfur isostere (224)of the 3-ace-
three-dimensional geometry of the pharma-
toxypiperidinium system (222) is weak mus-
cophoric moieties is known. This approach
carinic agonist (6-10%as potent as acetylcho-
presents the disadvantage of frequently re-
line); the cis-isomer (225) is inert (270).
quiring molecules that are larger and more
complex than the parent, with altered recep-
tor affinity and different solvent partition
characteristics a possible consequence. Casy
(266) has discussed this difficulty in more de-
tail.
Schueler (267) suggested that the musca-
rinic and nicotinic effects of acetylcholine are
mediated by different conformers of the flexi-
ble molecule, and he evaluated structures (t)-
(222) ("transoid") and (223) ("cisoid") as ex-
amples of analogs of conformational extremes
of acetylcholine.
Both (222) and (223) exhibited only feeble
cholinergic effects, and the difference in activ-
ity between the two was not great. Both of the
enantiomers of (222)were far less potent than
acetylcholine at muscarinic sites (2681, but
they have intrinsic activities (compared with
acetylcholine) approaching unity. The S-enan- Both the cis and trans isomers (224 and
tiomer was somewhat more effective than the 225) display prominent nicotinic action; the
R-, demonstrating an S:R eudismic ratio of cis-isomer is approximately 20% as potent as
13.4. However, because of the ability of the acetylcholine and is approximately seven
piperidine ring to undergo ring inversion (con- times as potent as the trans-isomer. In the
formational flip) with concomitant change in trans-compound (224), the T, angle (S-C-C-0)
the T~ torsion angle, the piperidine ring of is described as anticlinal-antiplanar on the as-
compound (222) is not an ideal template for sumption that the chair conformer has an ax-
acetylcholine conformational investigation. ial S-methyl and an equatorial acetoxy (270).
Casy (269) has summarized literature confor- However, the ability of the thianium ring to
mational studies on compound (222). undergo ring inversion (175) presents the
Cholinergics

same uncertainty of stereochemical interpre-


tation that was cited for the piperidinium ring
of compound (222).
The stereoisomeric tropyl acetates (226)
and (2271, in which a greater degree of molec-

A possibly serious defect in the design of


compounds such as the piperidinium (222),
the morpholinium (223), the tropines (226)
and (2271, and the decahydraquinoliniums
(228) is that these molecules do not bear the
trimethylammonium cation characteristic of
acetylcholine, but rather the quaternary head
is a part of a ring system. It was indicated
previously that incorporation of the nitrogen
atom of acetylcholine itself into a ring is detri-
mental to cholinergic activity and potency.
In a series of C-methylated trans-decalin
ular rigidity is imposed, are extremely weak congeners of (229), the 2,3-dimethyl com-
muscarinics, but both compounds exhibited pound (230) was the most potent muscarinic
potent nicotinic effects (271). in a guinea pig ileum assay [2% as active as
However, as demonstrated by Hardegger acetylcholine (274)l.
and Ott (272), some tropane ring systems can
assume a conformation in which the piperi-
dine ring is a boat. Therefore, the possibility of
ring inversion in (226) and (227) cannot be
precluded, and as with the piperidine and
thiane rings, conformational integrity is ques-
tionable.
Stereoisomers of the trans-decahydro-
quinoline (228) (273) and the trans-decalin
(229) (88) displayed extremely low orders of
muscarinic effect, with the 2,3-trans-diaxial
isomer of (229) being the most potent of the
four stereoisomers of this structure (0.06%the
potency of acetylcholine). The most potent members of all of these
series of decalin-derived molecules have anti-
planar 7, stereochemistry. In the series of cy-
clohexane-derived compounds (231), the
(1R,2R)-trans compound was an extremely
weak muscarinic and the (t)-cis-isomer was
completely inert (275). Casy (256) suggested
that an energetically unfavored trans-diaxial
conformer (antiplanar 7,) for structure (231)
may be the pharmacologically active form of
the molecule. However, introduction of a t-bu-
tyl group into the cyclohexane system to sta-
5 Conformation-Activity Relationships of Some Choline!rgic Agonists

+
N(CH3)3

0-C-CH3
II
0
(231) All stereoisomers of (221) and (233) are
feeble nicotinics. X-ray analysis of (+)-trans-
bilize the 1,2-trans-diaxial geometry did not ACTM (221) (282) established the 7, angle as
lead to greatly increased muscarinic effect 137" (which is within the anticlinal range),
and because of the rigidity of the cyclopropane
The cis- and trans-cyclopentane systems ring, this value probably closely approaches
(232)have been described (256)as feeble spas- the solution conformation. The (IS, 2s) abso-
mogenics with a T~ angle near anticlinal. lute configuration of (+)-trans-ACTM super-
imposes on the equivalent centers in the po-
tent muscarinic agonists (S)-(+)-acetyl-p-
methylcholine (31) (see Table 2.2) and
(2S,4R,5S)-( + )-muscarine (3) (283). A race-
mic cyclobutane analog (234) of trans-ACTM
is much less potent than (2)-trans-ACTM
0-C-CH3 (284).
II
0
(232)

Congeners of acetyl y-homocholine (29)


and 4-acetoxybutyltrimethylammonium (30),
in which the amino alcohol entity is a part of
cyclopropane or cyclobutane ring systems, ex-
hibited feeble muscarinic and appreciable nic-
otinic effects (277, 278), but these results pro-
vide little insight into active conformations for No conformational study on structure
acetylcholine. The low cholinergic potencies (234) has been reported, and inspection of mo-
and activities of all of these preceding com- lecular models did not reveal any convincing
pounds probably preclude their being used as structural or steric differences between the cy-
abasis for acetylcholine conformation-activity clopropane and cyclobutane systems. The ra-
hypotheses, because "almost any compound cemic cis-cyclobutane isomer (235) is equipo-
with a quaternary nitrogen has some stimu- tent to the racemic trans-isomer (234) as a
lant or inhibitory activity at cholinergic recep- muscarinic receptor stimulant (285). Chothia
and Pauling (282) defined the following molec-
The cyclopropane ring has been exploited ular parameters for muscarinic agonism in
as the smallest system capable of conferring acetylcholine congeners (cf. structure (220),
conformational rigidity on an acetylcholine based on conformational analysis of (+)-trans-
analog (280, 281); (+I-trans-ACTM (221)
equals or surpasses acetylcholine's muscarinic
potency in two test systems, and it is an excel-
lent substrate for acetylcholinesterase. The
(-)-trans-enantiomer is several hundred
times less potent, and the racemic cis-com-
pound (233) is almost inert.
Cholinergics

ACTM (221): r, = 180"; 7, = +73" to +1370; has increased greatly over the past several
r3 = 180 + 3 9 ; r4 = 180' or -1370. Inter- years, as a result of recognition of the poten-
atomic distances were defined as: N+-0' = tial value in therapy of Alzheimer's disease as
360; N+-C6= 450; Nt-C7 = 540 pm. Low po- well as of other defects in memory and learn-
tency or inactivity of certain acetylcholine de- ing. Giacobini (286) presented data confirm-
rivatives was attributed to deviation from one ing that a steady-state increase in acetylcho-
or more of these parameters. However, Casy line resulting from cholinesterase (sic)
(256) cited examples of deviations from these inhibition in the brain results in improvement
values in which high agonist activity is mani- of cognitive function and mild-to-moderate
fested. cases of Alzheimer's syndrome. Sussman and
It has not been possible to demonstrate un- coworkers (287) showed that the catalytic site
equivocally that acetylcholine assumes differ- of acetylcholinesterase is located at the bot-
ent conformations for interaction at nicotinic tom of a deep and narrow gorge surrounded by
and muscarinic receptors and/or at the sub- 14 aromatic amino acids. Moreover, these
populations of each major receptor subtype; workers presented evidence that the quater-
neither has this theory been disproved by the nary ammonium moiety of acetylcholine does
body of chemical and biological data. It must not interact with an anionic site on acetylcho-
be concluded that the relationship of acetyl- linesterase, but rather it binds with the ~ e l e c -
choline's molecular geometry to its physiolog- trons of Trp-84 (tryptophan). QSAR studies
ical roles is still not understood. (288) of a series of nicotine analogs and conge-
ners indicated that the cationic moieties of
various nicotinic receptor ligands interact
with aromatic groups on a,& and a, nicotinic
Symptoms resulting from an inadequate sup- receptors to an extent proportional to their
ply of acetylcholine may be relieved by block- receptor binding coefficients.
ing the body's acetylcholine-deactivating Figure 2.1 is a simplified representation of
mechanism. Interest in this category of agents the catalytic region of acetylcholinesterase

Figure 2.1.
6 Anticholinesterases

(289).Significant features are the Trp-84 aro- some or all of the methyl groups on the tetra-
matic center that anchors the quaternary methylammonium molecule tends to increase
head of the substrate; a serine residue, the potency (292). However, attempts to correlate
primary alcohol moiety of which participates biological test data with the calculated diame-
in a transesterification reaction with acetyl- ter of the unhydrated quaternary head led to
choline, resulting in acetylation of the en- inconclusive results.
zyme; and an imidazole ring (part of a histi- Belleau (293) calculated entropies and en-
dine residue) that, as a neighboring group, thalpies of binding to acetylcholinesterase for
participates in and facilitates the acetyl group a homologous series of alkyltrimethylammo-
transfer. The resulting acetylated serine moi- nium compounds RN+(CH,),, where R = CH,
ety is extremely labile and rapidly undergoes through n-C,,H,,. The observed relative po-
spontaneous hydrolytic cleavage to liberate tencies in the series were rationalized on the
acetate anion and to regenerate the active cat- basis of hydrophobic bonding phenomena cou-
alytic surface. pled with the ability of the alkyl chains to dis-
Taylor (290) described three classes of ace- place ordered water from the acetylcholines-
tylcholinesterase inhibitors, based on their terase surface.
mechanism of action: Edrophonium (236) combines a quater-
nary head for binding to the complimentary
1. Reversible inhibitors. site of the enzyme with a phenolic OH, which
2. Agents having a carbamate ester moiety presumably hydrogen bonds to a portion of the
that is hydrolyzed by acetylcholinesterase, esteratic area.
but much more slowly than acetylcholine.
3. Phosphoric acid- or phosphonic acid-de-
rived inhibitors, which are true hemisub-
strates for acetylcholinesterase.

Both the carbamates and the phosphorus


derivatives form a covalent (ester) bond with
the serine OH of the enzyme in essentially the
same manner as does acetylcholine. Taylor
(290)stated that the terms reversible and irre-
versible as they have been applied to the
carbamate and phosphorus-derived anticho- However, even this compound displays a
linesterase agents, respectively, reflect only rapidly reversible inhibition of the enzyme
quantitative differences in rates of cleavage of and its duration of action is short (290).
the esterified enzyme, and not an actual differ- Holmsted (294) tabulated an extended se-
ence in mechanism. ries of bis-quaternary ammonium compounds
that have been evaluated for anti-acetylcho-
6.1 Quaternary Ammonium Reversible linesterase activity; compound (237) is repre-
Inhibitors sentative of this category, which includes
some of the most effective enzyme inhibitors.
Simple quaternary compounds such as tetra-
methylammonium cation combine with the
substrate cation-binding site of the catalytic
surface of acetylcholinesterase and thus deny
acetylcholine's access to this site. These com-
pounds have a short duration of action due to
the facile reversibility of their binding and
rapid renal elimination (2901, and thus they
have minimal therapeutic utility. Cohen and
Oosterbaan (291) tabulated a comprehensive
list of tetraalkyl quaternary ammonium ace- Additional examples of anticholinesterase
tylcholinesterase inhibitors. Homologation of bis-quaternary ammonium compounds were
Cholinergics

reported by Fulton and Mogey (295) and by tion. Compound (240) is a somewhat less po-
Cavallito and Sandy (296), who noted that tent acetylcholinesterase inhibitor in vitro
there is a gradual increase in antiacetylcho- than THA. However, the two compounds are
linesterase activity as the chain joining the approximately equipotent in reversal of sco-
two quaternary heads increases. The optimum polamine-induced memory impairment in
connecting chain length was stated to be five mice, a putative predictive model of activity in
or six carbons. In addition, enzyme inhibitory Alzheimer's disease. These data suggest that,
activity was maximal in those molecules in in addition to acetylcholinesterase inhibition,
which the substituent(s) on the quaternary ni- there may be other biochemical components to
trogen~were decidedly lipophilic. Later stud- the mechanism of action of (240). This specu-
ies (297) demonstrated efficient bonding of
decamethonium (238) to Torpedo acetylcho-
linesterase, contradicting earlier (296) reports.

6.2 Reversible, Noncovalent inhibitors


Related to 1,2,3,4-Tetrahydro- lation, which may be applicable to THA itself
9-Aminoacridine and to others of its active analogs and conge-
1,2,3,4Tetrahydro-9-aminoacridine (2391, THA, ners, is supported by a summation (303) of
tacrine) was described in 1961 (298) as a re- reported pharmacological effects of THA:
versible inhibitor of acetylcholinesterase and blockade of potassium channels; inhibition of
an even more potent inhibitor of butyrylcho- neuronal uptake processes; and inhibition of
linesterase. On the basis of X-ray crystal stud- monoamineoxidase. In the design of THA-like
ies it was reported (299) that a tryptophan res- anti-Alzheimer drugs, it has been emphasized
idue (Trp-84) at the catalytic surface of that selectivity of inhibition of acetylcholines-
acetylcholinesterase is the binding site for the terase as compared with inhibitory effect on
aromatic ring of (239). This is the same do- butyrylcholinesterase is a highly desirable
main that is believed to bind the quaternary strategy for minimizing unwanted side effects.
head of acetylcholine. A structure-activity study (304) addressed
modifications of the THA molecule, illustrated
in structure (241): X = H, 6-Cl, 7-C1,6-F,or 6-

Clinical efficacy in relief of the symptoms of


Alzheimer's disease was claimed (300) for
THA, but this positive finding is tempered by
its tendency to produce hepatotoxicity (301). CF,; R = H, alkyl, benzyl, ring-substituted
It was speculated (302) that the hepatotoxicity benzyl, or w-phenoxyalkyl.
of (239) might be related to its lipophilic char- Most of the compounds were inferior to
acter, and a (+)-1-hydroxy derivative (240) (239) as inhibitors of acetylcholinesterase, but
was designed in the hope that the OH group some were decidedly less toxic, and a few
would serve as a metabolic "handle" for glucu- were equieffective or superior to (239) in an
ronidation and subsequent facilitated elimina- assay evaluating their ability to reverse sco-
6 Anticholinesterases

polamine-induced memory impairment. Re- linesterase and is approximately 1000 times


canatini et al.(305)reported a comprehensive more potent than THA in inhibition of rat ace-
structure-activity study of THA derivatives tylcholinesterase. This preference of(245)for
substituted on positions 6 and 7 of the ring acetylcholinesterase and the fact that THA-
system and bearing selected groups on the like agents may exhibit unwanted side effects
9-amino group. QSAR studies and compara- arising from peripheral actions accompanying
tive molecular field analysis (CoMFA) of the desired central actions led to studies of a series
THA analogs permitted some conclusions to of heterodimeric analogs(246)of (245)(297).
be drawn with respect to the applicability of
these analytical techniques to formulation of
descriptive and predictive structure-activity
relationships of THA derivatives.
Addition of a fourth ring to the THA system
sometimes leads to compounds such as (2421,
which have marked selectivity for inhibition of
acetylcholinesterase over butyrylcholinester-
ase(303).

Compound (243) was reported to be 100-


400 times more potent than THA in inhibition
of neuronal uptake of serotonin. A series of

compounds related to (244) was designed by


"molecular duplication" of the THA molecule
(306).Some members of the series showed in-
hibitory action against acetylcholinesterase,
but they were less potent than THA. One com-
pound reversed cognitive deficits in middle
aged rats. Compound(245)was designed tak-
ing into account that there are two binding
sites for THA on acetylcholinesterase (307).
The compound is 10,000times more selective
for acetylcholinesterase than for butyrylcho-
Cholinergics

Comparison of calculated desolvation free (310) to have memory enhancing effects in pa-
energies with IC,, values suggested the im- tients with Alzheimer's disease. However, for
portance of ligand hydrophobicity (low desol- clinical use it has a relatively short half- life,
vation free energy) for effective cation-n variable bioavailability, a low therapeutic in-
interaction of the homodimer (245) with pe- dex, and a multiplicity of unwanted cholin-
ripheral site(s). ergically related side effects.
(+)-Physostigmine, the enantiomer of the
6.3 Carbarnate-Derived Inhibitors naturally occurring alkaloid, has little effect
on acetylcholinesterase in vitro (311,312);it is
The prototype carbarnate-derived acetylcho-
linesterase inhibitor is physostigmine (247),
a weak centrally acting cholinergic agonist.
Eseroline (248), the ester cleavage product of
an alkaloid isolated from the seeds of the Cala-
bar bean, Physostigma venenosum. Physostig-
mine exhibits equal inhibitory activity against
acetylcholinesterase and butyrylcholinester-
ase (308).

physostigmine, is devoid of action toward


horse serum butyrylcholinesterase (313).
Rubreserine (249),an oxidation product of the

At the pH of the body fluids, a significant


proportion of physostigmine molecules is pro-
tonated at N1. This cationic species partici-
pates in binding of the molecule to the cata-
lytic domain of acetylcholinesterase, to permit
transfer of the N-methylcarbamyl moiety to
the OH of the serine residue, analogous to the
process described for the acetyl group of ace-
tylcholine. The resulting carbamylated en-
zyme is much more stable than the acetylated ester-cleaved physostigmine molecule, was re-
enzyme (t,,, for hydrolysis of the carbamy- ported to be approximately 11100 as potent as
lated enzyme is 15-30 min compared to <lms physostigmine as an inhibitor of horse serum
for the acetylated serine moiety) (290). Main- butyrylcholinesterase (314).
tenance of the enzyme in its carbamylated Eserine blue (250), formed from a reaction
form prevents its catalytic hydrolysis of ace- of rubreserine with ammonia (315), was re-
tylcholine for a prolonged time. In vivo, the ported to exhibit very low potency in a horse
duration of observable enzyme inhibition by serum butyrylcholinesterase assay (314). A
agents such as physostigmine is 3-4 h (290). later communication (316) suggests total inac-
Watts and Wilkinson (309)developed a kinetic tivity of these latter two physostigmine deriv-
scheme that was offered as a more adeauateA
atives.
explanation for carbamate-acetylcholinester- Brossi (317) prepared two short series of
ase reactions and provides an explanation for physostigmine homologs, one in which the
the observed catalysis of ester cleavage of car- substituent(s) on the nitrogen of the carba-
bamylated acetylcholinesterase by excess car- mate moiety was (were) varied, and one in
bamate. Physostigmine has been reported which the substituent on N1 was varied. Both
6 Anticholinesterases

C2H5,n-C3H7,or benzyl; and R" was a variety


of Cl-C, alkyl chains, phenyl, or benzyl. All
compounds were tested as their racemic mod-
ifications; selected ones were resolved, and
both enantiomers were studied. Two (-)-en-
antiomers, R = CH,, R' = C2H5, R" = n-
C7H15; and R = CH,, R' = C2H5, R" = n-
C,H,,, were more potent than physostigmine
or (251) in inhibition of acetylcholinesterase,
(+)- and (-)-enantiomers of the first series and they were six- to 10-fold more potent than
were prepared, but only the (-benantiomer of their respective (+)-enantiomers. These more
the second series was reported. Several of the active enantiomers had the same absolute con-
(-)-enantiomers (same absolute configura- figuration as physostigmine itself. Two bis-
tion as physostigmine) showed high potency in noreseroline derivatives (254a, 25413) showed
inhibition of acetylcholinesterase and of bu- marked antiacetylcholinesterase activity (316).
tyrylcholinesterase from a variety of sources.
Heptylphysostigmine (251) is a more li-
pophilic homolog and is reported (318) to be
less toxic than physostigmine, while retaining
its in vitro acetylcholinesterase inhibiting po-
tency.
Phenserine (2521, a selective inhibitor of
acetylcholinesterase with minimal effect on
butyrylcholinesterase, was cited as a possible
anti-Alzheimer drug (319).

Compound (254a) had relatively little ef-


fect on butyrylcholinesterase, whereas (254b)
was a potent inhibitor of both enzymes. The 3a
R enantiomers were less potent but they
showed the same selectivity as the 3a S com-
I pounds.
: It was postulated (320) that replacing the Studies aimed at incorporation of the car-
2
I N of the physostigmine molecule with a bamate ester moiety and the cationic site of
methylene group would increase the mole- physostigmine into simpler organic molecules
I
i ale's chemical and metabolic stability by con- have led to quaternary ammonium com-
; version of the potentially less stable aminal pounds based on structure (255).
i group to a more stable amino group. A series of The &substituted isomer of (255) is
&carbaphysostigmine congeners (253) was neostigmine. This compound is more stable
studied, in which R was H or CH,; R' was CH,, than physostigmine in aqueous solution, it
Cholinergics

does not penetrate the blood-brain barrier,


deviate from the proposed 4.7 A requirement;
and also (unlike physostigmine) the pharma-
their N+-to-C=O distance is considerably
cological effects of neostigmine are pH inde-
greater (on the order of 8-8.5 A).
pendent (321). Neostigmine is extremely po-
Compound (258) was reported to be 190
tent, and it has replaced physostigmine as the
times more potent than physostigmine
reference drug for carbamamate-derived in-
against acetylcholinesterase, and it was 60
hibitors of acetylcholinesterase.
times more selective for inhibition of acetyl-
The position 3-substituted isomers of (255)
cholinesterase than for butyrylcholinesterase
and (256) frequently exhibit prominent miotic
(323).
activity (which was taken as a reflection of an-
Most anti-Alzheimer drug design studies
ticholinesterase activity), whereas ortho- and
directed at enzyme inhibition have sought
para-substituted molecules are inert (313).
compounds that inhibit acetylcholinesterase,
Foldes and coworkers (322)concluded that the
but have little or no effect on butyrylcholines-
optimum N+-to-C=O interatomic distance
terase. However, based on cited literature sug-
for compounds of the type (255) is 4.7 A. The
gestions that "inappropriate" butyrylcho-
meta isomers of these compounds meet this
linesterase activity increases the risk and/or
requirement, as does pyridostigmine (256),
progression of Alzheimer's disease, Brossi et
which is used clinically. Molecular models
al. (324) described physostigmine congeners
(eseroline and N, noreseroline carbamates)
having a high level of selectivity for butyryl-
cholinesterase rather than acetylcholinester-
ase. Possible therapeutic utility for these
agents was proposed, but no test data were
presented.

6.4 Phosphorus-Derived Inhibitors


Among the most powerful anticholinesterases
(inactivating both acetylcholinesterase and
demonstrate that the active m-quaternary plasma butyrylcholinesterase) are phospho-
ammonium phenylcarbamate systems can as- rus-containing compounds, most commonly
sume reasonable conformations in which their derivatives of orthophosphoric acid or of phos-
cationic heads and C=O groups coincide with phonic acids. The entire category is frequently
analogous groups in acetylcholine. Long (313) collectively called organophosphorus com-
described the ortho-substituted compound pounds although, strictly speaking, this no-
(257) as a potent acetylcholinesterase inhibi- menclature is inaccurate. Certain of these or-
tor, whereas the meta- andpara-isomers were ganophosphorus compounds are extremely
much less active. Compound (257) conforms toxic, and much of the developmental work in
to the 4.7-A N+-to-C=O distance require- the area was done with the object of preparing
ment, but its other two positional isomers do chemical warfare agents ("nerve gases").
not. It is noteworthy that physostigmine and Compounds in this category are potent and
its congeners (e.g., compounds 251 and 253 useful insecticides, and have been used world-
6 Anticholinesterases

wide for this purpose. The reaction between potency of the organophosphorus compounds
acetylcholinesterase and most organophos- parallels the ease of nucleophilic attack on the
phorus inhibitors has been presumed to occur phosphorus atom. Compounds in this category
only at the esteratic site of the enzyme, and include ester and amide derivatives of or-
the reaction here is a transesterification, com- thophosphoryl halides, pyrophosphate esters
parable to that involving the carbamate esters and amides, alkyl and aryl phosphonic acid de-
and acetylcholine itself. The reaction at the rivatives, and thiophosphoric acid derivatives.
esteratic site of acetylcholinesterase is en- Representative compounds are shown in Ta-
hanced by the geometry of the tetrahedral ble 2.5.
phosphates, which resemble the transition Holmsted (294, 325) and Hayes (326) have
state for acetate ester hydrolysis. The result- tabulated and discussed a large number of or-
ing serine-phosphorylated or -phosphonylated ganophosphorus acetylcholinesterase inhibi-
enzyme is extremely stable; if the R groups tors. Tabun, sarin, and soman (2, 3, and 4 in
(structure 259) are methyl or ethyl, regenera- Table 2.5) are among the most toxic "nerve
gases" known. OMPA (6) is inert as such, but
it is metabolized to an N-oxide derivative that
is the biologically active entity (327). Para:
thion (8)is inactive in inhibition of acetylcho-
linesterase in vitro; mixed-function oxidases
(in human liver) convert parathion into its ox-
I I ygen bioisostere paraoxon (9), the pharmaco-
serine residue
logically active metabolite (328). Echothio-
phate (7) is representative of inhibitors that
bind initially to the agonist cation binding site
tion of the enzyme by hydrolytic cleavage re- of acetvlcholinesterase
" as well as to the ester-
quires several hours. atic area. This compound is used clinically in
If the R groups are isopropyl, essentially no the treatment of certain types of glaucoma.
hydrolysis occurs and reestablishment of en- The 1,3,2-dioxaphosphorinane(260) is rep-
zyme activity can occur only after de novo resentative of organophosphorus acetylcho-
synthesis of the enzyme. A characteristic
structural feature of the anticholinesterase
phosphorus compounds is the grouping P-Z,
where Z is an electronegative moiety, a good
leaving group, and the cleavage of the P-Z
bond is accompanied by liberation of a large
amount of energy. The P-Z bond is eminently
susceptible to attack by nucleophiles, such as
the serine OH of the esteratic site of acetylcho-
linesterase. In general, the enzyme inhibitory
92 Cholinergics

Table 2.5 Some Phosphorus-Containing Acetylcholinesterase Inhibitors


Number Structure Chemical, Proprietary, or Generic Narne(s)
DFP, diisopropyl fluorophosphate, diisopropyl
phosphofluoridate

Tabun, ethyl N-dimethyl


phosphoroaminocyanidate

Sarin (GB),isopropyl
methylphosphonofluoridate

Soman, pinacolyl methylphosphonofluoridate

Tetraethyl pyrophosphate (TEPP)

Octamethylpyrophosphoramide
6 Anticholinesterases 93

L Table 2.5 (Continued)


, Number Structure Chemical, Proprietary, or Generic Name(s)
i-
(7) CzH6-0 Echothiophate,
i' \ f0
D diethoxyphosphorylthiocholine

S Parathion

Paraoxon

linesterase inhibitors that were designed to


have a short duration of action (329). H , ~ ~ C H ~ - N ( C H ~ ) Z
This compound inactivates acetylcholines-
i terase by formation of "an unstable covalent
f
!
[
-
intermediate." The inhibited enzyme hydro-
lyzes spontaneously with t , , 10 min. Com-
pound (260) was proposed (329) to be a useful 0 0-
adjunct prophylactic agent against the insec-
ticide paraoxon and chemical warfare agents
such as soman.
A neurotoxic natural ~roduct.anatoxin-
a(s)(261),was isolated f r o i sever2 biological + 11
sources, including - a blue-green
- alga
- (330, (CH3)3N-CH2-CH2-O-C-S-R
331).
Its high toxicity (LD,, = 20-40 pgkg in
mice) has been ascribed to anticholinesterase
activity.

6.5 Miscellaneous Inhibitors


These compounds are not hydrolyzed by
Thiocarbonate derivatives of choline (262a, acetylcholinesterase. Possible utility in treat-
262b) competitively inhibit acetylcholinester- ment of Alzheimer's syndrome was suggested.
ase from various sources (332). An a-chloro-P-phenethylamine (263) irreve
Cholinergics

ibly inactivates acetylcholinesterase (333);the attachment of the ketonic carbon to position 8


active pharmacophoric species is the aziri- of the tetrahydrobenzazepine ring) demon-
dinium cation (264). strated potent in vitro inhibition of acetylcho-
The quaternary ion nature of the aziri- linesterase (337).It was active in a series of in
dinium cation allows for reversible complex vivo assays for CNS cholinergic effects, but it
formation with the cation binding site of the produced no significant peripheral cholinergic
enzyme, which precedes slow alkylation of the effects. Molecular modeling studies (docking
nucleophilic site (serine OH). Tetramethylam- analysis) of members of the series of com-
monium retards the irreversible inactivation pounds (266-268) indicated (338) that the N-
of the enzyme by this compound. benzyl group interacts with the same trypto-
Onchidal(265) is the principal constituent phan residue (Trp-84) as the aromatic ring of
of a secretion of glands of a mollusk (334). This THA (239). The other aromatic ring in these
inhibitors interacts with another tryptophan
residue (Trp-279) on the enzyme molecule,
and hydrogen bonding interaction between
the carbonyl group of the inhibitors
(266-268) and a tyrosine (Tyr-121) hydroxyl
on the enzyme seems to play an important
role. These data should be useful for the fu-
ture design of more potent, more specific,in-
hibitors.

compound is an irreversible inhibitor of ace-


tylcholinesterase. It is not a substrate for the
enzyme, and its mechanism of action appar-
ently does not involve acylation of the active
site serine hydroxyl. It was speculated (334)
that the a$-unsaturated aldehyde moiety
may be involved, through Michael addition, in
covalent bond formation with the enzyme.
Based on a molecular design strategy de-
rived from rationalizations concerning the to-
pography of the catalytic area of acetylcho-
linesterase, inhibitors based on compounds
(266) and (267) were identified (335, 336). Members of a series of 1-aroyl-3-[l-(benzyl-
Study of an extended series (structure 268 4-piperidiny1)ethyllthioureaderivatives (269)
and congeners of 266 and 267) revealed that are potent (submicromolar range) acetylcho-
one compound (268: R = H; Y = H; n = 3 and linesterase inhibitors (339).
6 Anticholinesterases 95

Comparable potency was retained by re-


placing the unsubstituted benzene ring with a
bioisosteric 2-pyridyl group. The guanidine
congener of (269) was almost inactive. In a
passive-avoidance test in rats, compound
(269) had maximal antiamnesiac activity at
0.03 mglkg with a therapeutic ratio greater
than 1000, and it displayed cholinergic side
effects only at high doses. Its potential use as
an antidementia agent was suggested (339).
The linear diamide (270) (caproctamine) was
described (340) as a more potent noncovalent
inhibitor of acetylcholinesterase than of bu-
tyrylcholinesterase.
It was reported to interact at both the ac-
tive site of the enzyme and at a second distal
site. It also showed prominent inhibitory ac-
tion at M, receptors, but it had only weak ef-
fect at M, and M, subtypes. In a search for less
flexible analogs of caproctamine (270),the tri-
cyclic system (271) was found to exhibit
"good" acetylcholinesterase inhibiting activ- (viewed as an analog of the physostigmine ring
ity (341). system), was almost as potent as physostig-
A carbamate derivative of the hexahydro- mine in vitro against human acetylcholinest-
chromenopyrrole moiety of (2711, ( +14272) erase and butyrylcholinesterase. Other ben-
Cholinergics

zene ring position isomers of the carbamate value in treatment of Alzheimer's syndrome
moiety were much less potent. The two enan- was suggested. Donepezil(276) is a reversible,
tiomers of (272) exhibited approximately the noncompetitive inhibitor of acetylcholinester-
same potency as the racemic material. ase (344). Its affinity for this enzyme is ap-
Of an extensive series of l-benzyl-442- proximately 1250 times greater than that for
(N-benzoylarnino)ethyl]piperidine derivatives, butyrylcholinesterase. The compound pro-
designed and evaluated as inhibitors of acetyl- -
duced a marked increase in the acetylcholine
cholinesterase, the sulfone derivative (273) content of rat; cerebral cortex. Introduction of
was the most potent (342). a fluorine atom at the 2-position of the in-
This compound showed an 18,000-fold danone ring of (276) resulted in a compound
preference for acetylcholinesterase over bu- with increased potency (345). Additionally,
tyrylcholinesterase. It was a reversible inhibi- there was a significant difference in the anti-
tor in a concentration-dependent manner. cholinesterase activity between the enantio-
Benzisoxazole derivatives (274) and (275) mers of 2-fluoro-(276) compared to that of the
showed threefold inhibitory selectivity for ace- nonfluorinated molecule. Docking simulations
tylcholinesterase over butyrylcholinesterase of fluorodonepezil with acetylcholinesterase
(343). have been reported (346). A "hypothetical
Compound (274) produced dose-dependent binding site" for (276) a t the acetylcholines-
elevation of acetylcholine in mouse forebrain terase catalytic region was proposed (344). Of
after oral administration. Possible palliative a series of aminopyridazines, (277) was the
7 Acetylcholine-Release Modulators

most potent inhibitor of electric eel acetylcho-


linesterase (IC,, = 0.12 mM)(347). It showed
less activity against butyrylcholinesterase.
Huperzine-A (2781, an alkaloid from Hu-
perzia serrata Trev. (or Lycopodium serratum
Thunb.) is three times as potent as physostig-

(27%
R1 = n- and branched chain alkyl, phenyl
Rz, R3 = H, F, CH3

tion of binding free energies of tacrine-


huperzine-A hybrids. Overall, the results were
concluded to support the validity of the puta-
mine against acetylcholinesterase, but it is tive binding model described in ref. 349. Ex-
less potent against butyrylcholinesterase tension of the series of compounds (279) pro-
(348). duced halogenated and/or alkylated congeners
Several members of a series of hybrid mol- that were tight binding but reversible inhibi-
ecules of THA and huperzine-A (279) were tors of mouse brain acetylcholinesterase
more active against acetylcholinesterase than (351). These compounds showed ability to
cross the blood-brain barrier. Molecular mod-
(-)-huperzine-A, but they were not as selec-
eling simulations provided a basis to explain
tive for the enzyme (compared with butyryl-
the differences in inhibitory activity in this
cholinesterase) as huperzine-A (349). Molecu-
series of compounds.
lar modeling of compounds in the series with
acetylcholinesterase from Torpedo californica
showed them to interact "as truly THA-huper- 7 ACETYLCHOLINE-RELEASE
zine-A hybrids." However, it was noted that MODULATORS
acetylcholinesterase from Torpedo is some-
what different from that of humans. A subse- Structure-activity studies (352) of 3,3-disub-
quent paper (350) reported a study of predic- stituted oxindoles led to DuP-996 (linopir-
Cholinergics

dine) (280); which enhances potassium- This newer compound is effective both in
evoked acetylcholine release in rat cortex, vivo and in vitro. Its mechanism of acetylcho-
hippocampus, and caudate nucleus, in vitro line release was not established, but it was
(353,354). suggested that the blockade of certain K'
This enhancement of acetylcholine release channels may be involved.
from nerve terminals occurs only when the Compound (282) stimulates the release of
release has been triggered (355). Compound acetylcholine (and also of dopamine and nor-
(280) is reported (355) to exert significant ef- epinephrine) in brain regions involved in
fects on the human central nervous system.
Dopamine and serotonin release are also en-
hanced by this agent, but release of glutamate,
GABA, and norepinephrine is unaffected. Fur-
ther structure-activity studies of 3,3-disubsti-
tuted oxindoles have been reported (3561, and
the potential utility of this category of com-
pounds in treatment of cognitive and neuro-
logical deficiencies was stressed. Compound
(281) was reported to be superior to (280) as
an acetylcholine-releasing agent (23).
memory and learning (37). This compound
was resolved, and it was reported that neither
the (R)nor the (5')enantiomer alone was as
active as the racemate in any of a series of
whole animal behavioral experiments.
One of the possible advantages to a thera-
peutic strategy for Alzheimer's disease or
other deficits in memory and learning using
acetylcholine-releasing agents is that such a
process would seem to permit stimulation of
both nicotinic and muscarinic receptors in the.
brain and to permit stimulation of all sub-
groups of acetylcholine receptors.

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CHAPTER THREE

Anticholinergic Drugs
B.V. RAMA SASTRY
School of Medicine
Vanderbilt University
Nashville, Tennessee

Contents
1 Introduction, 110
1.1Types and Selectivity of Antispasmodics, 111
1.2 Gastric Secretion, Peptic Ulcer, and
Anticholinergics as Antiulcer Agents, 111
1.3 Anticholinergics as Mydriatics
and Cycloplegics, 114
1.4 Anticholinergic Drugs in Prernedication
during Anesthesia, 115
1.5 Anticholinergic Activity as a Side Effect of
Drugs and Anticholinergic Syndrome, 115
1.6 Classification of Anticholinergic Agents
Based on Subtypes of Muscarinic Receptors,
115
2 Biocomparative Assay of Anticholinergics, 116
2.1 Antispasmodic Activity, 116
2.2 Antiulcer Activity, 118
2.3 Mydriatic and Cycloplegic Activities, 119
2.4 Miscellaneous Anticholinergic Activities, 120
3 Solanaceous Alkaloids, 120
3.1 History, 120
3.2 Chemical Structure, 120
3.3 Preparative Methods, 122
3.4 Molecular Factors in the Absorption, Fate,
and Excretion of Atropine and
Related Compounds, 122
3.5 Semisynthetic Derivatives
of Solanaceous Alkaloids, 124
4 Synthetic Anticholinergics, 126
4.1 Analogs of Atropine, 126
4.2 Receptor-Subtype-Selective Anticholinergics,
128
4.2.1 Tricyclic Benzodiazepines, 128
4.2.2 Benzothiazepines, 129
4.2.3 Quinuclidine-Based Antagonists, 129
4.2.4 Polymethylene Tetramines, 131
4.2.5 Indene Derivatives, 131
Burger's Medicinal Chemistry and Drug Discovery 4.2.6 Sila-difenidols, 132'
Sixth Edition, Volume 6: Nervous System Agents 4.2.7 Diphenylacetyloxy Derivatives, 132
Edited by Donald J. Abraham 4.2.8 Himbacine, 133
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 5 Structure-Activity Relationships, 133
109
Anticholinergic Drugs

5.1 Cationic Head, 133 6 Interaction of Anticholinergics at the Muscarinic


5.2 Cyclic Moieties, 141 Receptors, 151
5.3 Length of the Main Chain Connecting the 6.1 Kinetic Basis for the Mechanism of Action of
Cationic Head and the Cyclic Groups, 144 Anticholinergics, 152
5.4 Esteric Linkage, 146 6.2 Specificity of Antagonism, 152
5.5 Hydroxyl Group, 147 6.3 Molecular Basis for the Interaction of
5.6 Epoxy Group, 147 Acetylcholine and Anticholinergics at the
5.7 Stereoisomerism and Anticholinergic Muscarinic Receptors, 152
Activity, 147 7 Therapeutic Uses of Anticholinergics, 153
5.7.1 Opticalisomerism, 147 8 Molecular Basis for the Side Effects of
5.7.2 Derivatives of Tropine and Pseudo- Anticholinergics, 154
tropine, 149 9 Profile of Anticholinergic Activities of Various
5.7.3 Stereochemical Configuration, 150 Agents, 154
5.7.4 Dissociation Constants of Cholinergics 10 Nonanticholinergics as Antiulcer Agents, 155
and Anticholinergics, 150 11 Anticholinergics Developed for Specific Uses,
5.8 Compounds with Dual Action: Cholinergic 158
and Anticholinergic Activities, 150 12 Acknowledgments, 158

1 INTRODUCTION nerve transmission. These drugs do not pre-


vent acetylcholine from being released at
The role of acetylcholine as a parasympathetic nerve endings, although they may compete
neurotransmitter and its effects on smooth with the liberated neurohormone for cholin-
muscle and glands are reviewed elsewhere. ergic receptor sites. Acetylcholine is the chem-
Typical parasympathetic effects, in addition to ical transmitter at the postganglionic para-
cardiac inhibition and vasodilation in certain sympathetic nerve endings, as well as at
areas, are miosis and increased gastrointesti- autonomic ganglia and somatic neuromuscu-
nal motion and secretion. It is believed that lar junctions. Acetylcholine is also a chemical
acetylcholine is the common factor in many of transmitter at certain synapses in the central
these processes. Electrical stimulation of nervous system and drugs acting at central
parasympathetic nerves causes the appear- cholinergic sites are discussed elsewhere. Oif-
ance of acetylcholine at the neuromuscular ferent types of anticholinergic drugs antago-
junction; presumably, acetylcholine appears nize the actions of acetylcholine at the above-
regularly during the spontaneous functioning mentioned three types of peripheral synapses.
of the postganglionic fibers of the parasympa- Anticholinergic drugs that block somatic neu-
thetic nerves, and is regularly kept from accu- romuscular junction (curariform drugs) and
mulating by hydrolysis with acetylcholinester- autonomic ganglia (ganglionic blocking drugs)
ase. Spontaneous release of acetylcholine at are described elsewhere. The pharmacological
the parasympathetic nerve endings results in actions of anticholinergic drugs discussed in
the involuntary contraction or spasm of the this chapter mimic the effects of cutting the
muscle. Therefore, the contractions of the parasympathetic nerve supply to various or-
stomach, intestinal tract, heart, certain blood gans; therefore they are designated as para-
vessels, and many other structures in various sympatholytics. Muscarine mimics the actions
pathological situations are often attributed to of acetylcholine on the structures innervated
the amounts of acetylcholine in excess of nor- by parasympathetic nerves; it is relatively in-
mal requirements. Gastric secretion, saliva- active at autonomic ganglia and the somatic
tion, micturition, lacrimation, sweating, and neuromuscular junction. Parasympatholytics
miosis are influenced by acetylcholine. The that antagonize the actions of muscarine are
rates of these activities can be controlled by also known as antimuscarinic agents.
certain anticholinergic drugs. The classic parasympatholytic agent is at-
Anticholinergic drugs interfere with physi- ropine, and thus anticholinergic drugs used to
ological functions that depend on cholinergic be referred to as atropinic agents. Typical ef-
1 Introduction

fects produced by atropine are mydriasis, droxytryptamine spasm (lop7), histamine


tachycardia, decreased gastrointestinal peri- spasm and Ba2+ spasm Thus,
stalsis, and diminished secretions of gastric atropine is a highly specific anticholinergic
juice, saliva, and sweat. A large number of an- neurotropic spasmolytic.
ticholinergic agents have been synthesized The barium ion acts on all smooth muscles,
that have specific actions and uses. Although regardless of innervation, and is called a mus-
all anticholinergics could be considered as an- culotropic spasmogen. Drugs that relieve the
tispasmodics to different degrees, for conve- spasm produced by barium ions are called
nience they are divided into three categories: musculotropic spasmolytics. Papaverine and
(1)antispasmodics, which are specifically used nitrites are typical members of this class.
to relieve spasms of the bowel (e.g., irritable However, various drugs that resemble atro-
colon, spastic colitis); (2) antiulcer agents, pine manifest both kinds of spasmolytic action
which reduce gastric secretion; and (3) mydri- in widely varying situations.
atics and cycloplegics, which relax the sphinc- The ideal atropine-like antispasmodic
ter of the iris and the ciliary muscles. should be specific for the spasmogen, should
have selectivity for smooth muscles, and
1.1 Types and Selectivity of Antispasmodics
should abolish completely the spasm induced
Substances patterned on atropine are widely by the stimulation of the parasympathetic
used as antispasmodics of the gastrointestinal nerve to the organ. Further, the atropine-like
tract. Theoretically, any such substance that antagonist should be specific for the subtype of
relaxes the acetylcholine-induced spasm of the muscarinic receptor localized in the organ.
smooth muscles in suitable doses can be None of the available antispasmodics satisfies
termed an antispasmodic. In practice, not ev- all these requirements. However, a great
ery anticholinergic agent can be used as an many compounds have been synthesized with
antispasmodic. The reason is that in addition the hope of developing drugs that will exhibit
to their spasmolytic action, anticholinergics more selective antispasmodic action and have
influence the functions of other organs includ- fewer side effects than those of atropine.
ing heart, sweat and salivary glands, and iritic Some of these antispasmodics show rela-
and ciliary muscles, producing side effects. tive selectivity toward the subtype of musca-
Moreover, a number of them in small doses rinic receptor localized in smooth muscle cells.
cause undesirable disorders in the central ner-
1.2 Gastric Secretion, Peptic Ulcer, and
vous system (CNS). The same antispasmodic
Anticholinergics as Antiulcer Agents
is not suitable for the spastic states of all or-
gans. Further, there are differences in the in The pathophysiologyof peptic ulcer is not fully
vitro and in uivo efficacies of antispasmodics. known and, in the present state of knowledge,
Atropine abolishes the acetycholine-induced it is not possible to present the pertinent nor-
spasm of guinea pig ileum completely; how- mal physiology briefly. For a detailed discus-
ever, it is a familiar clinical experience that sion on the physiology and chemistry of gastric
atropine does not antagonize completely the secretion and the pathologic physiology of pep-
spasm caused by increased tone of the intesti- tic ulcer, reference should be made to reviews
nal vagus nerve. on the subject (1-5). The following is a brief
A number of agents cause spasm of the gas- summary of the gastric secretion and its rela-
trointestinal tract. The spasm may be induced tionship to peptic ulcer, a knowledge of which
not only by acetylcholine but also by hista- is necessary to understand the problems of de-
mine, 5-hydroxytryptamine, or barium chlo- veloping antiulcer agents.
ride. Atropine and other anticholinergics are Gastric juice contains a mixture of water,
effective mostly against acetylcholine-induced inorganic ions, hydrochloric acid, pepsino-
spasm, and less against the remaining three gens, mucus, various polypeptides, and the in-
spasmogens. Against a spasm induced by ace- trinsic factor. Pepsinogens are precursors of
tylcholine, atropine is effective at the lowest the proteolytic enzymes, pepsins. They are
concentrations (e.g., lop9 g/mL). Higher con- readily converted into the corresponding pep-
centrations are necessary to antagonize 5-hy- sins by either acid or pepsin itself. Conversion
Anticholinergic Drugs

by acid is instantaneous at pH 2.0. In humans, vous component, the intestinal phase includes
gastric juice contains hydrocholoric acid dur- humoral stimulation of secretion by unknown
ing the period of interdigestive secretion as agents. Gastrin released from the small intes-
well as during the period of digestive secre- tine may be involved. The response to what-
tion. Although the mechanisms of interdiges- ever humoral agent comes from the intestine
tive secretion are not known, they depend is greatly increased when subthreshold doses
partly on the tonic activity of the vagus. The of cholinergic drugs are given.
gastric secretory activity during the period of A number of humoral inhibitors of gastric
digestive secretion may be divided into three secretion arise in the small intestine. They are
phases, cephalic, gastric, and intestinal. Each termed enterogastrones. An enterogastrone is
phase is named to denote the region in which present in the jejunum and duodenal mucosa.
the stimuli act to induce gastric secretion. It is released in the presence of fat and inhibits
In the cephalic phase the stimuli are initi- gastric secretion and motility. The hormone
ated in the central nervous system. The stim- secretin, which stimulates pancreatic secre-
uli are the sight, smell, taste, and thought of tion, is an enterogastrone. It is produced in the
food, which act through conditioned and un- proximal duodenum and inhibits gastric se-
conditioned reflexes. The final efferent path is cretion in the presence of acids. Cholecystoki-
the vagus nerve. The impulses in the vagus nin, which is the same as pancreozymin, and
nerve stimulate the secretory cells in the gas- gastrin share the same terminal tetrapeptide.
tric glands. Acetylcholine, which is released Given alone, cholecystokinin is only a mild
from the postganglionic nerve endings, exerts stimulant of gastric acid secretion. It is a com-
a direct action on the secretory cells. Adminis- petitive inhibitor of the receptor for gastrin,
tration of atropine abolishes this phase. The which is a powerful stimulant of gastric acid
secretion is high in acid and pepsinogens, and secretion. Therefore, in the presence of gas-
its concentration of mucus is lower than that trin, cholecystokinin decreases the total out-
of the basal secretion; mucus output rises put of acid. Glucagon (and possibly enteroglu-
8-10 times as the volume increases. cagon) reduces the gastrin-induced acid
The gastric phase of secretion begins copi- secretion by noncompetitive inhibition of the
ously as soon as the food enters the stomach, receptors to gastrin. A gastric inhibitory
and it may continue 3-4 h, with a total volume polypeptide (GIP) that is present in duodenal
of 600 mL or more of strongly acid juice con- mucosa inhibits both histamine- and gastrin-
tain ng a high concentration of pepsinogens. induced acid secretion. A vasoactive intestinal
The gastric phase of secretion is caused by lo- peptide (VIP), which has been isolated from
cal and vagal responses to distension and by small intestinal mucosa, inhibits histamine-
the hormone gastrin, released by the musosa induced acid secretion. GIP and VIP are two
of the pyloric gland area. The local nerves of possible enterogastrones whose significance
the pyloric area are confined to the mucosa has yet to be established.
and are cholinergic. Irrigation of the pyloric Histamine, the exact role of which is not
gland area with acetylcholine releases gastrin, clearly understood, stimulates secretion of
and this liberation of gastrin is abolished by gastric juice that is rich in hydrochloric acid.
atropinization. There is a synergism between Recently, histamine receptors have been di-
gastrin and acetylcholine at the target cells; vided into three types, HI, H2, and H3. Stim-
the effect of injected gastrin on both acid and ulation of H2 receptors by histamine results in
pepsinogen secretion is increased two- to increased gastric acid secretion. H2 receptor
eightfold by subthreshold parasympathomec- antagonists (burinamide, metiamide, cimeti-
tic stimuli, and it is strongly inhibited by atro- dine) inhibit histamine-induced gastric acid
pinization. secretion in both humans and animals. In
The intestinal phase that begins when humans, H2 antagonists inhibit not only his-
chyme passes from the stomach to intestine, tamine- but also pentagastrin (a synthetic an-
contributes about 10% of the total response to alog of gastrin)-stimulated gastric acid secre-
a test meal. Protein and its digestion products, tion. This suggests that, at least in humans,
milk, dilute alcohol, and acid itself are effec- gastrin acts partially by histamine. Blockage
tive stimulants. Although there may be a ner- of acetylcholine receptors by atropine and his-
1 Introduction

Anticholinergics HPreceptor
(ACh) antagonists (H)
-Vagus nv
er, CP I Histamine

t
Antrum - Gastrin -
(-) Local hormones:
prostaglandins (G, H)
PGE, , PGA,

.- ,
Small
mtestine
Gastrin - (+) Parietal cell
- Mucus secretants
(carbenoxolone)

Enterogastrones 4 \ I

Secretin (G) I
~ntero~luca~on (G)
Cholicystokinin (G)
GIP (G, H)
VIP (H)
Fat (G, H)
Pepsinogen - Pepsin Pepsin inhibitors
(sulfated polysaccharides)
Figure 3.1. Interactions among neuronal and hormonal factors and pharmacological agents during
cephalic (Cp),gastric (Gp),and intestinal (Ip) phases of gastric acid secretion by parietal cell. ACh,
acetylcholine; GIP, gastric inhibitory peptide; VIP, vasoactive intestinal peptide; MI, muscarinic
receptor; HZ,histamine HZ receptor; GR, gastrin receptor; (+), stimulation of acid secretion; (-), ,

inhibition of acid secretion. In parentheses, next to the inhibitory agents, is indicated the blocked
stimulant agent (ACh, acetylcholine; H, histamine; G, gastrin).

tarnine receptors by H2 antagonists results in The interplay among various neuronal


reduction of the effectiveness of gastrin to in- and hormonal factors in the gastric acid se-
duce acid secretion. cretion by the parietal cell during cephalic,
Therefore, there seems to be a complex in- gastric, and intestinal phases are schemati-
teraction among the three receptors, acetyl- cally shown in Fig. 3.1. In addition to being
choline receptors, H2 receptors, and gastrin inhibited by atropine-like agents and entero-
receptors involved in the acid secretion by pa- gastrones shown in Fig. 3.1, the acid secretion
rietal cells. is inhibited by gastrone in the mucus of hu-
Among local hormones and messengers, man stomach, by urogastrone isolated from
prostaglandins (PGE,, PGA,) adenosine 3',5'- the urine of men and dogs, by strongly acid
monophosphate (cyclic AMP, CAMP) inhibit solutions in the duodenum, and by stimula-
both pentagastrin- and histamine-stimulated tion of the &mpathetic nervous system.
gastric secretion. According to present evi- Peptic ulcer occurs in the pyloric region of
dence, all hormones that reduce gastric acid the stomach or the first few centimeters of the
secretion increase both adenylcyclase and in- intestine. The gastroduodenal muscosa is ex-
tracellular CAMP activity. Conversely, all hor- posed constantly to mechanical, physical, and
mones that primarily stimulate gastric acid se- chemical insults, some of which have already
cretion reduce intracellular CAMP levels. been described. A peptic ulcer does not develop
Therefore, CAMPis involved in the final links without the presence of a pepsin-containing
of gastric acid secretion. juice of such low pH that it can exert a peptic
Anticholinergic Drugs

influence on the gastric wall itself. The extent completely for many hours (6). Its effect on
of this insult is determined by the number of secretion during the feeding of milk and cream
acid- and pepsinogen-producingcells, their ir- is significant (7, 8). However, anticholinergic
ritability, and/or the magnitude of the stimuli drugs do not effectively perform a "medical
that reach them. These stimuli are partly ner- vagotomy" and they do not effectively reduce
vous (vagal) and partly hormonal (gastrin, gastric acidity to the extent of achlorhydria
corticosteroids). when patients are fed (8, 9). The effective an-
The healthy stomach does not digest itself. ticholinergic agent as an antiulcer drug should
Counteracting the aggression are defensive be selective for the subtype of muscarinic re-
factors such as buffering and dilution by food, ceptors localized on the secretory cells of gas-
inhibition of the secretion of gastric juice, and tric glands as well as mucosa of the pyloric
drainage of gastric contents. In addition, how- gland area. Anticholinergics selective for mus-
ever, the local condition of the mucosa (the carinic receptors of M1 subtype are useful in
mucosal resistance) is also of importance. decreasing gastric acid secretion.
Some of the determinants of mucosal resis-
tance are the mucous barrier, the local circu-
1.3 Anticholinergics as Mydriatics
lation, and the healing capacity of the mucosa.
and Cycloplegics
A peptic ulcer forms when the insult is more
powerful than the defense. In the case of duo- The size of the pupil is determined by the bal-
denal ulcers, the powerful irritation is often ance of forces exerted by the dilator muscles
the important factor; in gastric ulcers it is the fibers (sympathetically innervated and radi-
insufficient defense. ally arranged) and the constrictor muscle fi-
The ideal agent for the treatment of the bers (parasympathetically innervated and cir-
peptic ulcer would be one that selectively inac- cularly arranged) of the iris. Normally both
tivates pepsin or inhibits the output of hydro- sets of muscle fibers have a constant degree of
chloric acid so as to maintain the pH of the tonus and act reciprocally to dilate or constrict
gastric contents at about 4.5 for long periods the pupil. Any substance that paralyzes the
after its oral ingestion. It should produce no, constrictor muscle fibers (parasympatholytic)
or only minimal, side effects, induce no toler- allows the unopposed tone of dilator muscle
ance, and be inexpensive. It should be effective fibers to widen the pupil.
during all periods and phases of gastric secre- Acetylcholine is the transmitter between
tion and prevent the formation of ulcers. the constrictor muscle fibers and the parasym-
Atropine-like anticholinergics do not sat- pathetic nerve that innervates them. There-
isfy all requirements of an antiulcer agent. fore, acetylcholine and its congeners stimulate
They block acetylcholine action at the neu- the constrictor muscle fibers of the iris and
roeffector junction of the vagus. They give re- constrict the pupil. Atropine and related com-
lief to patients with a peptic ulcer by their an- pounds paralyze the constrictor muscle fibers
tisecretory and antispasmodic effects. They and cause widening or dilatation of the pupil.
decrease the basal hydrochloric acid and pep- The ciliary muscle is innervated by the
sin secretion, thereby allowing the healing of parasympathetic nerve, and acts to decrease
ulcers. The antispasmodic effects of atropine- the tone on the supporting muscle fibers of the
like agents are as consistent as their antisecre- lens, and thus increases the accommodative
tory effects. Motor activity is closely related to power of the eye. Acetylcholine and its conge-
ulcer pain, and the pain-relieving action of an- ners constrict the ciliary muscle fibers, and
ticholinergic agents seems to be related to atropine and related compounds paralyze the
their effect on depressing motor activity (anti- ciliary muscle.
spasmodic effect). Mydriatics are drugs that dilate the pupil,
An "effective" atropine-like anticholinergic but have minimal effect on the ciliary muscle
drug is capable of favorably influencing the and thus on accommodation. Cycloplegics are
excessive gastric secretion under certain con- drugs that partially or completely paralyze ac-
ditions. It exerts a significant effect on acid commodation. Most of the anticholinergics
secretion during the basal and interdigestive have both properties to varying degrees. For
night secretion to the point of abolishing it mydriatics other than anticholinergics and for
1 introduction 115

drugs that constrict the pupil (miotics), the properties that disturb patient recovery be-
appropriate chapter should be consulted. cause of their anticholinergic effects on the
Mydriatics and cycloplegics are special CNS (11).These effects are termed central an-
types of antispasmodics. In clinical practice ticholinergic syndrome (CAS) and are dis-
mydriasis is produced by local instillation of cussed in different chapters on centrally act-
the chosen drug into the conjunctival sac. This ing drugs (volume 4). These effects can be
enables one to produce the desired effects on reversed with physostigrnine, the centrally ac-
the eye with minimal systemic effects. How- tive cholinesterase inhibitor, which has a spar-
ever, such compounds should possess proper- ing effect on acetylcholine molecules at mus-
ties that allow them to penetrate the cornea in carinic receptor sites. An increased number of
effective concentrations. There are no signifi- acetylcholine molecules displace the mole-
cant differences between the muscarinic re- cules of anticholinergic drug from the musca-
ceptors of the guinea pig ileum or the rabbit rinic receptor sites.
iris, as judged by the binding characteristics of
potent anticholinergic agents. Muscarinic re- 1.6 Classification of Anticholinergic Agents
ceptors in both tissues are possibly of the M3 Based on Subtypes of Muscarinic Receptors
subtype. If anticholinergic drugs are available Acetylcholine produces its parasyrnpathomi-
that are selective for muscarinic receptors on metic effects by binding at cholinergic recep-
constrictor muscles and ciliary muscles, myd- tors of the muscarinic type. The classical anti-
riatic and cycloplegic effects can be produced cholinergic agent, atropine, binds to the same
by different drugs. muscarinic receptors and prevents acetylcho-
line from binding to these receptors and elic-
1.4 Anticholinergic Drugs in premedication iting muscarinic responses. Based on modern
during Anesthesia developments in the design of relatively sensi-
Prevention of some undesirable side effects tive antagonists for muscarinic receptors in
during anesthesia has been considered a func- different tissues (12-15), muscarinic receptors
tion of premedication with anticholinergic have been subdivided into three (possibly five)
drugs. For example, atropine is a popular an- subtypes M1 to M5 (Table 3.1). All muscarinic
ticholinergic agent that has been used for its receptors are glycoproteins of molecular
antisialogogic, antibradicardia, and anti- weight of 80,000 and have seven membrane-
emetic effects (10). The emphasis of using an- spanning regions. All of the receptors have a
ticholinergic drugs during premedication has slow response time (100-250 ms) and are cou-
been changing over the years because of the pled to G-proteins (13, 14). They act directly
availability of inhalational anesthetic agents on ion channels or are linked to second-mes-
that are better than ether. An anticholinergic senger systems, attenuation CAMPformation
agent (e.g., atropine), although no longer re- (16, 17), and formation of inositol triphos-
garded as an essential premedicant under all phate and diglyceride (16, 18). The final effect
circumstances, does have specific applications of activation of these receptors can be to open
for injured patients and children. Atropine or close K' channels, Ca2+ channels, or C1-
(0.6 mg, i.v.1 blocks the muscarinic actions of channels. These multiple channel activities
suxamethonium (succinylcholine), bradycar- lead to either depolarization or hyperpolariza-
dia, and salivation during crash induction of tion of the cell membrane. The final responses
anesthesia in an injured patient (10). Admin- are either excitatory or inhibitory. Atropine
istration of an anticholinergic drug to prevent blocks all of these activities and does not dis-
bradycardia in children in response to suxam- tinguish subtypes. Selective muscarinic ago-
ethonium or tracheal intubation is desirable. nists and antagonists that will distinguish dif-
ferent subtvpes are needed. Further, it will be
" a

a major advance to obtain information to indi-


i 1.5 Anticholinergic Activity as a Side Effect
cate that each subtype performs a specific
f of Drugs and Anticholinergic Syndrome
function. Then it will be possible to develop
1 Many of the drugs used in current medical
practice, especially anesthetic drugs and other
specific anticholinergic drugs that are useful
only as (1)antispasmodic, (2)antisecretory, or
1
$
drugs used as adjuvants to anesthesia have (3) mydriatic agents. With certain anticholin-
11 6 Anticholinergic Drugs

Table 3.1 Provisional Division of Muscarinic Receptors (M), Their Agonists


and Antagonists into Five Subtypesa
M Subtype M1 M2 M3 M4 M5
Previous names M2, Mw
Cardiac M, Glandular M2
Tissue locationb Lower esophageal Heart Glands,
sphincter, smooth
gastric glands, muscle,
CNS ganglia CNS
Selective McN-A-343 - -
agonistsc
Selective Pirenzepine Methoctramine HHSID - -
antagonistsd (+)-Telenzepine AF-DX 116 p-F-HHSID Himbacine
Himbacine (High Affinity)
Effector J IP3DG CAMP J. IPJDG
pathway' Kf channel
Gene m2 m3
Amino acids 466 590
(human)
"Summarized from Refs. 12-18.
bCNS,central nervous system sites.
'Selective agonists for receptors M2-M5 are not available.
dHHSID, hexahydrosiladifenidol; p-F-HHSID: p-fluoro-hexahydrosiladifenidol.

ergic agents, some degree of selectivity (not 2.1 Antispasmodic Activity


specificity) has been attained to produce anti-
In studying drugs more or less like atropine, it
spasmodic, antisecretory, or mydriatic effects
is customary to test their antispasmodic ac-
(Table 3.2). No antagonist has a potency on
tion on smooth muscles, such as the isolated
one receptor subtype that is more than 10
guinea pig ileum, duodenum, or jejenum of
times higher than its potency on other sub-
rabbit, or rat intestine. Acetylcholine or any
types. All receptor subtypes have K, values for
one of the cholinergics may be used as a spas-
(-)-N-methylscopolamine (NMS) and (-1-3-
mogen, and the ability of the antispasmodic to
quinuclidinyl benzilate (QNB) of less than 1.0
inhibit or abolish the cholinergic-induced
nM (13). NMS and QNB are standard anticho-
spasm may be measured. Helical strips of
linergic agents in addition to atropine to com-
blood vessels with intact endothelium (e.g.,
pare anticholinergic potencies at muscarinic
strips of rat aorta) can also be used to evaluate
receptors.
the antispasmodic activity of anticholinergic
drugs (21). The antagonistic activities may be
2 BIOCOMPARATIVE ASSAY expressed as affinity constants or relative mo-
OF ANTICHOLINERCICS lar activities in relation to a standard antago-
nist. The selectivity of the antispasmodic ac-
Many of the methods of obtaining experimen- tivity may be determined by using different
tal evidence for the antispasmodic, antiulcer, spasmogens (e.g., histamine, 5-hydroxytryp-
and mydriatic activities do not measure pre- tamine, nicotine, and barium chloride).
cisely and selectively only one type of pharma- Thiry-Vella fistulas (19), prepared at vari-
cological activity. However, the techniques ous levels of the gastrointestinal tract, have
that are available (19,20), if used with an un- been used in the conscious dog for determin-
derstanding of their scope and limitations, can ing motility by (1)placing an indigestible bo-
provide useful information in the develop- lus in the oral end of the fistula and determin-
ment of anticholinergic agents and their struc- ing the traverse time before and after
ture-activity relationships. treatment with drugs; (2) placing a balloon
Table 3.2 Derivatives of Solanaceous Alkaloids and Their Semisynthetic
- Substitutes"
Advantage,
- . if any, of Molecular
Generic Name Trade Names Dose or Preparation ~odifi&ion Therapeutic Use
Atropine sulfate USP 0.5 mg (oral i.v or s.c.); Mydriatic with long recovery period;
0.5-1.0% ophthalmic preanesthetic medication to decrease
solution secretions, treatment of Parkinsonism,
and anti-ChE poisoning
Atropine tannate Atratran 1-2 mg (tablet) Slow absorption with sustained Antispasmodic in ureteral and renal colic
release of the alkaloid
Ipratropiumb bromide Atrovent Inhaler Low systemic absorption Bronchodilator in asthma
Atropine N-oxide X-tro 0.5-1.0 mg (capsule) Slow release of the alkaloid Same as atropine for oral use
hydrochloride Genatropine
Hyoscyamine hydrobromide 0.25-1.0 mg Possibly fewer central effects Same as atropine for oral use
.
than atro~ine because of
small doses administered
Methylatropine bromide Mydriasine 0.52% solution Mydriatic with short recovery Mydriatic
period
d Methylatropine nitrate Metropine 1-5% solution Same as above Mydriatic
4
v Scopolamine hydrobromide 0.6 mg (oral, (s.c.1; Central depressant ("twilight As a sedative during pre- or
USP 0.2% solution sleep") postoperative gynecologic care
Genescopolamine 1-2 mg Gradual release of alkaloid Same as above
hydrobromide
Methscopolamine bromide Pamine 2.55.0 mg (oral); 0.25- Parasppatholytic without Antisecretory and antispasmodic in
NF Lescopine 1.0 mg (s.c. or i.m.1 central effects peptic ulcer
Methscopolamine nitrate Skopolate 2-4 mg (oral) Same as above Same as above
NND Skopyl 0.25-0.5 mg (s.c. or
i.m.)
Homatropine hydrobromide 1-2% solution Mydriatic with recovery period Mydriatic
USP less than that of atropine
(see Table 3.18)
Homatropine methyl Novatropine 5 mg (oral) Parasppatholytic without Antisecretory and antispasmodic
bromide NF Mesopin central effects
Anisotropine Valpin 10 mg (oral) Parasppatholytic without Antisecretory and antispasmodic
methylbromidec Endo central effects
"For details of the preparations and their uses, standard references (97-99) in pharmacology should be consulted.
b8-Isopropylnoratropinemethobromide.
"8-Methy1-3-(2-propy1pentonoy1oxy) tropinium bromide odatropine bromide.
Anticholinergic Drugs

containing water and attached to a kymo- ligation and the stomach contents are col-
graphic recording system in the fistula and re- lected for examination. The stomach is opened
cording the pressure waves and their alter- along the greater curvature and the ulcers are
ations by the action of drugs; or (3) placing a examined and scored by a suitable scheme
French catheter in the aboral end of the fis- such as 0 = normal, 1 = scattered hemorrhagic
tula, connecting it to a suitable recording sys- spots, 2 = deeper hemorrhagic spots and some
tem, and thus making a record of normal pres- ulcers, 3 = hemorrhagic spots and ulcers, and 4
sures and those occurring after treatment. = perforation. Variable results have been re-
Other qualitative and quantitative meth- ported by investigators using this technique.
ods to study the antispasmodics have been de- Production of chronic experimental peptic
scribed (19). These include (1)the fluroscopic ulcers in dogs (or rats) by the Mann-William-
study of the gastrointestinal motility and (2) son procedure (36) is one of the standard
the use of an ingestible pressure-sensitive ra- methods. The gastric juice is diverted into the
dio-telemetering capsule (Transensor) for intestine some distance from the pancreatic
measuring the pressure in the gastrointesti- and biliary secretions. The objective is
nal tract. achieved by isolating the duodenum from the
The subtype of muscarinic receptor in the pylorus and the jejunum. The oral end of the
smooth muscle has been characterized as M3 duodenum is closed and its distal end is anas-
by use of selective anticholinergics and differ- tomosed with a loop of ileum, so as to dis-
ent smooth muscle preparations from differ- charge the pancreatic and biliary secretions
ent species. These smooth muscle tissues in- into the lower portion of the bowel. The cut
clude (1)trachea (22), ileum (23, 241, uterine end of the jejunum is then anastomosed to the
artery (25), and submucosal arterioles of pylorus. About 95% of dogs so prepared de-
guinea pig (26); (2) aorta (27) and coronary velop typical chronic peptic ulcers just distal to
artery of rabbit (28); and (3) trachea (291, the gastric anastomosis with the jejunum.
aorta (30), and iris (31) of rat. Human uterine With similar operative procedures 85% of rats
arteries (32),airways (331, and ciliary muscles develop gastric, marginal, or jejunal ulcers.
(34) have also been shown to contain the M3 The complete reversal of the duodenum in
type of muscarinic receptors. dogs produces chronic peptic ulcers in about 6
months (19). These animals maintain their
2.2 Antiulcer Activity
weight until the development of ulcerations
The problems encountered in testing drugs for and might become a useful preparation for de-
antiulcer activity result in part from a lack of tecting and comparing antiulcer activity.
complete understanding of the physiological Stress produces ulcers in the rats, which
and biochemical mechanisms involved in the could be used to test the antiulcer activity of
formation of ulcers, and in part from the test- drugs (37). Rats fasted for 48 h and immobilized
ing of drugs for activity on normal or quasi- in a galvanized screen cage under light ether
normal animal preparations, although they anesthesia develop ulcers in the glandular re-
are ultimately applied to abnormal or patho- gion of the stomach after 4 h of restraint. The
logical human states. The various methods estimate of severity can be all or none, or may be
differ in producing ulcers in experimental an- coded in the same way as the Shay preparation.
imals (19). One of the side effects of adrenocortico-
A preparation developed by Shay et al. (35) tropic hormone (ACTH)and corticoid therapy
has been used to test for antiulcer activity on in humans is the development or reactivation
an all-or-none basis. The ligation of the pylo- of gastroduodenal ulcers. Daily subcutaneous
rus of rats, previously fasted for 48-72 h, leads administration of cortisol or A'-cortisol to rats
to the accumulation of acid gastric contents for 4 days results in the regular development
and ulceration of the stomach 17-19 h after of gastric ulcers (38). This procedure has been
the operation. The antiulcer agents are given adapted to testing antiulcer activity (39).
subcutaneously or intraduodenally at the time There are certain differences between steroid
of ligation of the pylorus, or orally 1 h before. ulcers and "natural" ulcers in localization,
The animals are killed 17-19 h after pyloric rate of development, and severity (40).
2 Biocomparative Assay of Anticholinergics

The antisecretory activities of anticholin- jury and finally results in gastric metaplasia.
ergics are as important as their antiulcer ac- In the presence of antral H. pylori, the gastric
tivities for their therapeutic usefulness. The metaplasia becomes colonized and inflamed.
Pavlov gastric pouch (41) with intact vagal The inflammation and infection disrupts mu-
and sympathetic nerve supply and a modified cosal defense and regenerating mechanisms,
Heidenhain pouch (421, which is essentially resulting in ulceration. The combination of in-
denervated, are prepared from dog stomach flammation, protective deficiencies, and mod-
and have been used for determining the action erate amounts of acid and pepsin may be
of drugs on gastric secretion. Histamine or a enough to induce ulceration. Several groups of
test meal is usually used as a stimulus. Similar drugs including anticholinergic agents have
methods for the preparation and use of been developed to antagonize risk factors
chronic total gastric fistulas and chronic de- causing ulcer disease. A good animal model,
nervated gastric pouches have been described which incorporates all variable causes of ulcer
for determining drug action on gastric secre- disease, is yet to be developed.
tion in rats (43-45). The muscarinic receptors of the parietal
There are a significant number of reports cells are of the M1 subtype. The specific anti-
in which antisecretory and antimobility ef- cholinergic agents for M1 receptors are con-
fects of anticholinergic drugs have been eval- sidered to be effective for the treatment of ul-
uated in ulcer patients (9,46). The antisecre- cer disease (51). The muscarinic receptors on
tory potency can be measured best in the the duodenal smooth muscle are possibly of
duodenal ulcer patient in whom the acid out- the M3 subtype. Anticholinergics at M3 may
put is already high. Ability of the drug to abol- partially decrease pain of duodenal ulcers by
ish or diminish acid output under histamine decreasing the motility of the duodenum (52).
stimulation is a stringent test of activity, al-
though the test has limited physiological rele-
2.3 Mydriatic and Cycloplegic Activities
vance. The effect of the drug on the amount of
acid secreted under ordinary clinical condi- A simple and relatively accurate test for myd-
tions is the most pertinent of all tests in rela- riatic activity has been described (52). The
tion to therapeutic application. method requires mice and a binocular micro-
Despite extensive research, certain aspects scope, magnifying about 10 times and pro-
of ulcer disease are not clearly elucidated. Be- vided with a scale in the eyepiece with which
cause of the multiple processes that control to examine and measure the diameter of the
acid and pepsin secretion and defense and re- pupil of the mouse. A strong light shining into
pair of gastroduodenal mucosa, it is more the eye of the mouse must be attached to the
likely that causes of ulceration differ among microscope. The diameter of the pupil is mea-
individuals (Section 3.5). Two other factors sured at the peak effect after administration of
have been acknowledged as risk factors in the the anticholinergic agent by intraperitoneal
pathophysiology of peptic ulcers: nonsteroidal injection. The duration of the effect is also im-
anti-inflammatory drugs (NSAIDs) and Heli- portant, given that one of the most character-
cobacter pylori infection (47-50). NSAIDs in- istic and valuable properties of atropine and
duce a significant number of gastric and duo- analogous compounds is the prolonged effect
denal ulcers, possibly because of inhibition of that they produce in the eye.
prostaglandin synthesis with consequent loss Entopic pupillometry is an accurate and
of protective effects. H. pylori has been recog- practical method for measuring the size of the
nized as a risk factor in the ulcerative process, pupil in humans (53). With a Cogan entopic
similar to acid and pepsin. Duodenal ulcer is pupillometer, the normal size of the pupil and
typified by H. pylori infection and duodenitis the near and far points before and after instil-
&d possibly impaired duodenal bicarbonate lation of the drug in the conjunctival sac can
secretion in the face of moderate increases in be measured at different time intervals. The
acid and peptic activity. Increased peptic ac- amount of light entering the eye is quite small
tivity with decreased duodenal buffering ca- and the movements of the eye during the mea-
pacity possibly leads to enhanced mucosal in- surement do not interfere with the test.
Anticholinergic Drugs

2.4 Miscellaneous Anticholinergic Activities Apollo in his temple at Delphi. Here the priest-
ess of the god Pythia sat on a tripod uttering
A number of other methods are available for
incoherent words in a divine ecstacy, in reply
comparing the activities of anticholinergic
to the questions that were asked. Pythia was
agents, of which the antitremor and antisali-
intoxicated by the fumes from burning datura
vary effects are widely used. Arecoline or pilo-
leaves; her replies were interpreted by a priest
carpine may be used to induce tremor or sali-
in the form of a verse. The more common uses
vation in a suitable species that can be blocked
of datura were for robbery or conspiracy. In-
by an anticholinergic agent. There seems to be
dian courtesans were known to place datura in
good correlation between anticholinergic and
their visitors' wine, so that they could be
antitremor effects (54). Recovery of the sali-
robbed without interference. As recently as
vary gland from cholinergic block may con-
1908, there was a plan to poison the European
ceivably precede that of the gastric glands and
garrison in Hanoi in Vietnam using datura.
the two effects may therefore not necessarily
Those in the conspiracy intended to stupefy
parallel each other in duration (9).
the soldiers, and then to kill them.
The pharmacological actions of atropine
3 SOLANACEOUS ALKALOIDS and related alkaloids are intimately connected
with our knowledge of the organization and
The older anticholinergic drugs are the vari- function of the autonomic nervous system.
ous galenical preparations of belladonna, hyo- Schmiedeberg and Koppe (56) were the first in
scyamus, and stramonium, all of which are de- 1869 to focus attention on the similarity be-
rived from plants of the potato family, the tween a drug effect and electrical stimulation,
Solanaceae. The species used as drugs include when they pointed out that muscarine and va-
Atropa belladonna, one of several plants gus stimulation affected the heart in the same
known colloquially as "deadly nightshade"; fashion and the actions of both were antago-
Hyoscymus niger (black henbane); and Datura nized by atropine. Further, they recom-
stramonium (jimsonweed, jamestown weed, or mended atropine as an antidote for mushroom
thorn apple). The active principles in all these poisoning. As early as 1887, Kobert and Sohrt
plants consist mostly of (-)-hyoscyamine, with (57) provided experimental proof for both sim-
smaller variable amounts of (-)-scopolamine ilarities and dissimilarities between atropine,
(hyoscine).Atropine is (?)-hyoscyamine. and scopolamine.
Atropine was isolated by Mein in 1831 (58),
3.1 History and since then the synthesis of both atropine
The poisonous nature of solanaceous alkaloids and scopolamine has been achieved (59,60). A
has been known for many centuries (55). The biogenetic scheme for the synthesis of atro-
toxic properties of deadly nightshade were ev- pine-like alkaloids in datura species starting
ident when children ate the blackberries, from ornithine has been described (61).
which looked attractive in a fall hedgerow in
England. The children became delirious and 3.2 Chemical Structure
their eyes had widely dilated pupils. The
deadly nightshade was used by the poisoners All the solanaceous alkaloids are esters of the
of the Middle Ages to induce obscure and often dicyclic amino alcohol 3-tropanol (tropine, 1).
delayed poisoning. Therefore, Linn6, in 1753, Atropine is an ester of (+)-tropic acid and tro-
named the shrub Atropa belladonna after At- pine. In scopolamine the organic base is sco-
ropos, the oldest of the Three Fates, who cuts
the thread of life. "Belladonna" does not refer
to Atropos, who is considered as a grim and
-

awesome female. but to the Italian name


("handsome women") of the plant, which was
used by Venetian ladies to give them dilated
pupils ("sparkling eyes").
Datura has an ancient history, for it is said
to have been used a t the oracular shrine of
3 Solanaceous Alkaloids 121

pine. Scopine differs from tropine in having an In tropine, the axially oriented hydroxyl
oxygen bridge between C-6 and C-7. group, trans to the nitrogen bridge, is desig-
There are some other alkaloids that are nated as a! or anti, and the alternate, equato-
members of the solanaceous alkaloids (e.g., rially oriented hydroxyl group as P or syn. It is
apoatropine, noratropine, belladonnine) but generally considered that cycloheptane is fixed
they are not of sufficient therapeutic value to through an -N(CH3)-bridge in the struc-
be discussed in this context. tures of tropine and pseudotropine. Therefore,
The carbon cr to the carboxyl group of tropic a chair conformation is ascribed to the piperi-
acid is asymmetric and is easily racemized dine ring system in tropine and pseudotro-
during the isolation of the solanaceous alka- pine. However, there is only a seeming differ-
loids. Atropine and atroscine are racemic ence between the two conformations of
forms. The corresponding lev0 isomers, (-1- tropane derivatives (66). The tropane system
hyoscyamine and (-)-scopolamine (hyoscine), can be considered with equal justification as a
occur naturally in the solanaceous plants. piperidine twisted through the -CH2CH2-
The absolute configuration of (-)-tropic bridge or as a cycloheptane fixed through an
acid has been established by its correlation -N(CH3)-bridge. When the tropane system
with (-)-alanine (62). According to the Cahn- is structured by the chair form of piperidine, it
Ingold-Prelog convention (631, natural (- )- also represents the boat form of cycloheptane.
tropic acid possesses the (5')configuration. Ac- Similarly, the boat form of piperidine is at the
cordingly, (-)- hyoscyamine and (-)-hyocine same time a chair form of the cycloheptane
have an (S) configuration (64). ring. Therefore, it may be assumed that both
The piperidine ring system can exist in two forms are present in a state of equilibrium
principal conformations. Its chair form has (65a)65. Based on the conformations of the
the lowest energy requirement. However, the tropane system, the structure of atropine (4)
alternate boat form can also exist, because the can be represented by (5)and (61, of which (5)
energy barrier is not great. The formula of is more generally accepted.
3-hydroxytropine (1) indicates that, even
though there is no optical activity because of H
the plane of symmetry, two stereoisomeric H2C-C- CH2 CH20H
I I I
forms, tropine (2) and pseudotropine (31, can NCH3 CHOCOCH
exist because of the rigidity imparted to the I I I
molecule through the ethane chain across the H2C-C- CH2 C6H5
H
1,5 positions (65a).

(chair)

(2)
Anticholinergic Drugs

oq
I
H H
CH2 CHzOH
0
P - 7 - I I
NCH3 CHOCOCH -
- H, F6H5
\ c-c- I I
CH2
I
C6H5
C
1\
H H O--CI I CH20H

The amino alcohol derived from scopol- through its quinine salt and the separated en-
amine (7), that is, scopine (8), has the axial antiomorph~can be converted into (+)- and
orientation of the 3-OH group but in addition (-)-hyoscyamines.
has a P-oriented epoxy group bridged across (-)-Scopolamine (hyoscine) is isolated
the 6, 7 positions. from the mother liquor remaining after the
isolation of hyoscyamine, and is marketed as
H H its hydrobromide. Scopolamine is readily race-
CH2 mized to atroscine, when subjected to treat-
I
NCH3 CHOH ment with dilute alkali.
I 0
C-C-CH2 The synthesis of scopolamine differs from
H H OH that of atropine in the synthesis of the amino
alcohol, scopine portion of the molecule. Fod6r
and coworkers (60, 73, 74) have synthesized
scopine starting from 6-P-hydroxy-3-tropanone.
3.3 Preparative Methods Esterification of scopine with 0-acetyltropyl
Conventional methods of alkaloid isolation are chloride and mild hydrolysis of the acetylsco-
used to obtain a crude mixture of atropine and polamine give scopolamine.
(-)-hyoscyamine from the plant products.
This crude mixture of alkaloids is racemized to 3.4 Molecular Factors in the Absorption,
atropine by refluxing in chloroform or by Fate, and Excretion of Atropine and
treatment with cold dilute alkali (67). Related Compounds
Atropine can be synthesized from tropi-
none and tropic acid as starting materials. The belladonna alkaloids are absorbed rapidly
Tropinone can be prepared by Robinson's syn- after oral administration (75). They enter the
thesis (68) and reduced under proper condi- circulation when applied locally to the muco-
tions to tropine. (?)-Tropic acid can be pre- sal surfaces of the body. Atropine absorbed
pared from ethyl phenylacetate (69, 70) or from inhaled smoke of medicated cigarettes
acetophenone (71). The 0-acetyl derivative of can abolish the effects of intravenous infusion
tropyl chloride reacts with tropine to yield O- of methacholine in humans. The transcon-
acetyl of atropine hydrochloride, from which junctival absorption of atropine is consider-
the acetyl group hydrolyzes spontaneously in able. About 95% of radioactive atropine is ab-
aqueous solution (72). sorbed and excreted following subconjunctival
One of the commercial sources for (-)-hy- injection in the rabbit. The total absorption of
oscyamine is Egyptian henbane (Hyoscyamus quaternary ammonium derivatives (Section
muticus) in which it occurs to the extent of 3.5) of the alkaloids after an oral dose is only
0.5%. Another method for extraction of the about 25%. The liver, kidney, lung, and pan-
alkaloid uses Duboisia species. It is prepared creas are the most important organs that take
from the crude plant material in a manner up the labeled atropine. The liver probably ex-
similar to that used for atropine and is purified cretes metabolic products of atropine by way
as the oxalate. (?)-Tropic acid can be resolved of bile into the intestine (in mice and rats).
,
3 Solanaceous Alkaloids

Carbon dioxide
(+ noratropine 2%)

Atropanol
(aldehyde)
Rabbit liver
in vitro
1I Rabbit,
guinea pig

Rabbit
guinea pig
Tropine
tropic acid

Noratropine,
apoatropine
Rat liver
in vitro
Atropine
I
(25%) Man,
mouse
Tropine-modified
atropines (10%)
- Tropicacid %)

Mouse

p-Hydroxyatropine (2%) - m, p-Dihydro)

Figure 3.2. Metabolism of atropine and i t s variations in different species.

Because most of the synthetic antispas- At least four types of molecular modification6
modic and antiulcer agents are administered occur for the urinary excretion of atropine
orally, their absorption through the gastroin- (Fig. 3.2). Cleavage of the ester bond takes
testinal tract limits their therapeutic useful- place in the rabbit and the guinea pig (84),
ness. There are striking diferences in the ab- whereas para and meta hydroxylation of the
sorption of tertiary amines and quaternary benzene ring of tropic acid occurs in the mouse
ammonium compounds (76-78). The tertiary and the rat (80, 82). The tropine moiety of
amines (e.g., noroxyphenonium, mepiper- atropine is also chemically modified for excre-
phenidol; Section 4) are absorbed completely tion in man and mouse and, though unidenti-
from rat intestinal loops. The maximal ab- fied, "tropine-modified atropines" are ex-
sorption of the corresponding quaternary am- creted in humans and in mouse (83). Tropic
monium compounds is about one-fifth of the acid itself does not undergo metabolic alter-
total dose. The poor absorption of quaternary ation for urinary excretion in all species men-
ammonium compounds may be partly attrib- tioned above. The metabolic conversions of
utable to the positive charge that promotes tropine itself are not fully investigated. How-
the formation of a nonabsorbable complex ever, demethylation of atropine- N-14CH3(or
with mucin. The ready absorption of tertiary tropine- N-14CH3)has been reported in a num-
amines may be explained partly by their per- ber of species with exhalation of 14C0, (90).
meability through lipid membranes (79). The possible metabolic changes of atropine are
Considerable species variations have been schematically represented in Fig. 3.2.
reported for the metabolic detoxification of at- After intravenous injection of atropine, ap-
ropine in mammals (80-91). These differences proximately 25% of the dose is excreted in
seem to be more quantitative than qualitative. mouse urine as atropine, more than 50% as
Anticholinergic Drugs

conjugates with glucuronic acid, and the re- tropic acid. In this way a series of tropeines
maining 20-25% as intermediate oxidation have been synthesized, among which a num-
products (probably p-hydroxyatropine and ber of active compounds have been found (86-
3,4-dihydroxyatropine)and "tropine-modified 92). Of the tropeines, mandelyl tropeine (9,
atropines." Rats are known to metabolize at-
ropine in a manner similar to that in mice. In
humans, about 50% of the administered dose
of atropine is excreted unchanged in the urine
and about 33% as unknown metabolites that
are esters of tropic acid. Neither hydroxyla-
tion of the tropic acid moiety nor glucuronide
formation has been demonstrated in humans
(83). Only less than 2% appears as tropic acid
in urine. homatropine), has survived as a thrapeutic
It has been known for more than a centurv agent to the present.
"
that rabbits can tolerate large quantities of Methylatropine nitrate (10)(or bromide) is
atropine (84, 85). The cause of this observa- a synthetic quaternary derivative of atropine.
tion is the ability of the serum of some, but not Atropine oxide (atropine N-oxide) is known as
all, rabbits to hydrolyze atropine into tropic a genatropine (11)and may be prepared by oxi-
acid and tropine. The hydrolysis is attributed dation of the alkaloid with hydrogen peroxide.
to an enzyme, atropinesterase, which is found
in most other tissues as well as the serum of
these rabbits. The highest activities are found
in the liver and intestinal mucosa; only the
brain and aqueous humor of the eye contain
no enzyme. The enzyme is also found in the
liver of the guinea pig and accounts for the
appearance of tropic acid in the urine of the
rabbit or the guinea pig, but not other ani-
mals, following the administration of atro-
-pine.
The presence of atropinesterase in rabbits
is inherited through an incompletely domi-
nant gene (84). This gene is associated with
another gene that influences the color of the
fur, causing "extension of black pigment in the
The derivatives of scopolamine (7) pre-
fur."
pared by similar methods are available com-
Atropinesterase can also hydrolyze homat-
mercially. These include methscopolamine
ropine and scopolamine. This enzyme is ste-
bromide (121, methscopolamine nitrate, and
reospecific for (S)-(- )-hyoscamine, which is
genoscopolamine (scopolamine N-oxide, 13).
split; the more inert (R)-(+) isomer is not
readily hydrolyzed (84).
HC-CH CH2 CHzOH
3.5 Semisynthetic Derivatives / I I I
of Solanaceous Alkaloids 0 N+(CH3)2 CHOCOCHCsH5. Br-
\ I I
Early attempts to modfy the atropine mole- HC-CH CH2
cule (4) were aimed at converting the solana-
ceous alkaloids containing the tertiary nitro-
gen into quaternary ammonium compounds
and N-oxides. Later developments have been Homatropine (9) is prepared by evaporat-
to retain the tropine (or scopine) portion of the ing tropine with mandelic and hydrochloric
molecule and substitute various acids for acids. Homatropine methylbromide (14) may
3 Solanaceous Alkaloids

Br-

ment of bronchospasm associated with chronic


obstructive pulmonary disease. Because it is ad-
be prepared from homatropine by treating it ministered as an aerosolized preparation, its
with methyl bromide. droplets are deposited in upper airways and
Quaternization may or may not increase all produce bronchodilation within minutes.
types of anticholinergic activity significantly. Only less than 5% of the drug enters the
However, there are certain practical advan- systemic circulation. Ipratropium is an exam-
tages to quaternization. The quaternary am- ple of developing a useful drug for a specific
monium derivatives usually penetrate the purpose by minor molecular modification of
CNS less readily than the corresponding ter- atropine.
tiary amine analogs. Therefore, quaterniza- The N-oxides are converted to the corre-
tion serves as a useful technique to avoid or sponding tertiary bases in vivo. Atropine N-
minimize the side effects caused by the stimu- oxide and scopolamine N-oxide are slowly re-
lation of the central nervous system by the duced to atropine and scopolamine in the
tertiary amines, when the drugs are used for animal body. Therefore, N-oxidation is a con-
their peripheral actions. When a tertiary alka- venient technique for prolonging the duration
loidal base is converted to the quaternary of the action of the alkaloidal bases. The NL
form, the latter is also less readily absorbed oxides are said to be less toxic.
through the intestinal wall (93, 94; Section Solanaceous alkaloids have a wide and vari-
3.2). This is not a disadvantage when the drug able spectrum of anticholinergic activities and
is used for its effects in the gastrointestinal are widely used in therapeutics. The various
tract. However, if the drug is used for its sys- derivatives of atropine, scopolamine, and
temic or central actions, the effect becomes homatropine are listed in Table 3.2. Because
erratic and unpredictable because the absorp- of their chemical differences and the resulting
tion is poor after oral administration. The ter- biological interactions, different derivatives
tiary amines are preferred for ophthalmic use are preferred for antispasmodic, antisecre-
because they penetrate the cornea better than tory, mydriatic, or central effects. Scopol-
their quaternary ammonium derivatives. amine produces the same type of depression of
However, when a drug (e.g., atropine) has a the parasympathetic nervous system as do at-
long-lasting mydriatic effect, its recovery pe- ropine and homatropine, but it differs mark-
riod can be shortened by quaternization. edly from atropine in its action in the central
Therefore, the selection of the type of the de- nervous system. Whereas atropine stimulates
rivative (Table 3.2) depends on the specific the CNS, causing restlessness, scopolamine
purpose for which it is used, the mode of its can act dose dependently as a sedative. It also
administration, and the duration of the de- causes temporary amnesia ("twilight sleep")
sired effect. when used along with morphine in obstetric
Ipratropium bromide (15)is a useful qua- and gynecologic procedures. For a detailed dis-
ternary derivative of atropine (95, 96). It is cussion of the anticholinergic activities of so-
marketed as a metered-dose inhaler for treat- lanaceous alkaloids and their related com-
Anticholinergic Drugs

pounds, the standard textbooks or review simpler to synthesize a fairly complex mole-
in pharmacology should be consulted (75,97- cule from two halves by esterification than by
99). any other method. Therefore, many esters of
amino alcohols and carboxylic acids have been
synthesized as atropine substitutes, in which
4 SYNTHETIC ANTICHOLINERCICS
the structures of either one or both halves
have been changed. For example, in homatro-
Although atropine and its related alkaloids are
pine, the tropic acid moiety has been replaced
potent anticholinergics, they have a wide spec-
by mandelic acid. The amino alcohol moiety
trum of pharmacological activities. Therefore,
(tropine, 1)of atropine has afforded unusually
therapeutic administration of these alkaloids
rich opportunities for the synthesis of anticho-
to elicit a particular desired activity invariably
linergics (Fig. 3.3). Scission of its piperidine
results in some undesirable side effects. For
ring at point X gives the derivatives of hy-
this reason, the search for compounds possess-
droxyalkylpyrrolidines (16),and scission of its
ing one or another of the specific desirable ac-
pyrrolidine ring at point Y makes it possible to
tions has been an active field of investigation
proceed to derivatives of 4-hydroxypiperidine
in medicinal chemistry. The ideal specificity of
(17).The scission of both rings at Z leads to
action has not been attained in these at-
dialkylaminoalkanol derivatives (18). Fur-
tempts; perfect atropine substitutes with pre-
thermore, simplification and alteration of
dominant antispasmodic, antisecretory, or cy-
these three groups of amino alcohols has re-
cloplegic actions have yet to be synthesized.
sulted in the synthesis of esters containing
However, some progress has been made since
structural features more or less similar to
the discovery of multiple subtypes of func-
those of atropine.
tional muscarinic receptors (MI-M5) and the
Antagonists of acetylcholine often have
cloned muscarinic receptors (m,-m,) have
chemical structures resembling that of acetyl-
been identified (Table 3.1). Several antago-
choline, although they differ from it by greater
nists, which show selectivity to one subtype of
complexity of the molecule and higher molec-
muscarinic receptors over others, have been
ular weight. Acetylcholine is a quaternary am-
introduced and they have become useful in the
monium compound; atropine and tropine con-
delineation of subtypes of muscarinic recep-
tain a tertiary nitrogen. Therefore, a number
tors in various tissues. Some of these agents
of atropine-like compounds having quater-
may become useful as antiulcer agents, anti-
nary nitrogen atoms have been synthesized.
spasmodics, or mydriatics.
In some of them, the acetyl group of acetylcho-
line has been replaced by acid moieties con-
4.1 Analogs of Atropine
taining blocking groups (e.g., diphenylacetic
The synthetic anticholinergic drugs can be acid).
considered as analogs of atropine or antago- The principles used in the design of antime-
nists of acetylcholine. Most of these com- tabolites have been applied to synthesize atro-
pounds were designed using broad principles pine-like compounds. The ester group in atro-
of molecular modification such as (1)scission pine-like compounds has been replaced by a
of the atropine molecule into simpler mole- thioester, an amide, an ether group, or a chain
cules containing the essential pharmacophoric of methylene carbons (Table 3.3).
groups; (2) molecular modification by intro- All synthetic anticholinergic agents have
ducing "blocking" moieties into cholinergics; some structural features in common. In most,
and (3) changes in other anticholinergics us- the molecule has bulky "blocking moieties,"
ing principles of bioisosterism. often cyclic radicals, linked by a chain of atoms
The structure of atropine has been the ba- of limited length, to a positively charged
sis for a large number of synthetic anticholin- m i n e nitrogen (Fig. 3.4). The length and
ergic agents. However, no significant changes structure of the main chain have considerable
have been made to affect the "ester-complex" influence on the anticholinergic activity of the
grouping because of atropine-like properties. substance. At the same time the chemical na-
Another probable consideration is that it is far ture of the main chain determines the class of
4 Synthetic Anticholinergics

p H 3
HOCHR'CH2CHR"N
\
R"' Figure 3.3. "Scissions" of tropane
(18) ring.

organic substances to which a given substance However, several examples from drugs used as
belongs. Therefore, the classification of syn- therapeutic agents are discussed at appropri-
thetic anticholinergics in Table 3.3 is based on ate places in the following pages. These com-
the structure of the main chain of the mole- pounds may be classified differently, and the
e, taking into consideration wherever nec- same compound may be placed in more than
ary the presence or absence of any addi- one group. Each one of them may be consid-

It is beyond the scope of this text to consider ergic activities among a series of structurally
all compounds that belong to each group. related compounds whose structure-activity

Characteristic Group Atoms in the Pharmacophoric Groups


in the Main Chain Chain that May Be Present

II
C C - 0 - C -OH
0
I1
Thioester CC--S-C -OH
0
II H
Amide -C-N-€ -OH
0
II
Carbarnate )N-C--O--C
Alkane --C-C-C--
(a)Amino alcohols -OH
(b) Amides -4ONH,
Anticholinergic Drugs

Ester end Onium head sium channels. Acetylcholine opens potassium


channels in the heart and causes hyperpolar-
ization and a reduced rate of firing of the nodal
tissue. In many tissues, calcium channels are

-- -
opened and probably intracellular calcium is
mobilized and, like many other transmitters,
acetylcholine increases the turnover of phos-
H J
phoinositides. Therefore, there is much expec-
L V
tation that selective agents will be found
among muscarinic antagonists that will be
Acyl Ester Alkamine Quaternary
radical group chain amino function useful to block one particular physiological or
Acetylcholine (19) biochemical response to acetylcholine. Thus,

- -*
several agents have been synthesized that
Cyclic Esteratic Cationic have structural features similar to those of at-
radical group portion ropine-like agents, cyclic blocking moieties
linked by a chain of atoms of limited length to
,H a positively charged nitrogen atom.
Based on the cyclic-blocking moieties and
other substituent groups, subtype-selective
muscarinic antagonists can be classified into
eight groups: (1)tricyclic benzodiazepines, (2)
benzothiazepines, (3) quinuclidines, (4) poly-
methylene tetramines, (5) indenes, (6) sila-
difenidols, (7) diphenylacetyloxy derivatives,
~ a i chain
n and (8) himbacine akaloids.
Atropine (20)
Figure 3.4. Structural features of acetylcholine 4.2.1 Tricyclic Benzodiazepines. Sigdicant
and atropine. The asymmetric carbon in atropine is side effects of tricyclic antidepressants, like
marked with an asterisk (*). imipramine, are antimuscarinic effects. Ben-
zodiazepines also cause some antimuscarinic
effects like dry mouth at therapeutic concen-
relationships have been evaluated for differ-
trations. Some of the well-known anticholin-
ent types of pharmacological effects. Com-
ergic agents, Banthine, Probanthine, and
pounds with the same or similar structural
Trest, have tricyclic bulky moieties at the end
features may exhibit other pharmacological
of their molecules. Some molecular features of
effects as side effects. For example, a large
these three types of phamacological agents are
number of compounds have been synthesized
present in tricyclic pyrido-benzodiazepines.In
containing an ether link in the main chain.
these compounds, portions of benzene and
These compounds are useful as antiparkinso-
pyridine (or other rings) are fused to a seven-
nian drugs and antihistaminic agents.
membered diazepine ring in the middle. The
trycylic bulky moiety containing benzene, di-
4.2 Receptor-Subtype-Selective
azine, and pyridine rings (or other rings) at
Anticholinergics
the end of a molecule satisfies one of the re-
The muscarinic actions of acetylcholine can be quirements for an anticholinergic agent. Fur-
either stirnulatory or inhibitory. Acetylcholine ther substitutions on the imino-nitrogen atom
stimulates secretion and contraction of the have resulted in selective M1 receptor antag-
gut, but it inhibits the contraction of the heart onists that are useful as antiulcer agents.
and relaxes the smooth muscle of blood ves- Pirenzepine (21) was the first M1 receptor
sels. Acetylcholine can inhibit adenylate cy- antagonist shown to inhibit gastric secretion
clase and activate guanylate cyclase. In the (100, 101). This drug (100-150 mg/day) is
cortical neurones, muscarinic agents cause a used in several countries to decrease gastric
slow depolarization mediated by closing potas- secretion and achieve maximal rates of ulcer
4 Synthetic Anticholinergics 129

dNb 0 AX-RA 513 (24) is another analog of piren-


zepine and exhibits selectivity toward M2 re-
ceptors (104). The spatial orientation of the
protonated side-chain nitrogen atom in rela-
tion to the tricycle seems to be of major impor-
tance for Ml/M2 selectivity.

$'
AQ-RA 741 (25) is an analog of pirenzepine
0 that exhibits higher affinity to chimeric m2
and M4 receptors than for m5 receptors (105).
VH-AH-37 (26), a pirenzepine derivative, ex-
hibits higher affinity to chimeric m5 receptors
N than to m2 receptors.

4.2.2 Benzothiazepines. These are closely


related compounds to benzodiazepines. The
nitrogen atom in the diazepine ring is re-
placed by a sulfur atom (27). Among these
healing. At these doses, incidence of dry compounds BTM-1086 was found to be an
mouth and blurred vision are not significant. M1 receptor antagonist (106). It is cis(-)-
It has a low lipid solubility and limited perme- 2,3-dihydro-3-(4-methylpiperaziny1)-2-phe-
abilty into the CNS, so it does not cause any nyl-1,5-benzothiazepin-4(5H)-onemonohy-
CNS side effects. drochloride. It inhibits acetylcholine release
Telenzepine (22) is an analog of pirenz- from parasympathetic nerves and also gas-
epine and 4-10 times more potent for inhibi- tric secretion.
tion of gastric secretion.
4.2.3 Quinuclidine-Based Antagonists. A se-
ries of achiral3-heteroaryl substituted quinu-
clidin-2-ene derivatives (28-31) was synthe-
sized by Hacksell et al. (107), who determined
their dissociation constants (K,) at different
subtypes of muscarinic receptors. Among
these compounds 2-benzoforanyl quinuclin-2-
diene exhibits the highest affinity (K,, 9.6 nM)
at M1 receptors. Its affinity at M2 (K,, 31 nM)
or M3 (K,, 59 nM) receptor is lower than that
at M1 receptor. This antagonist is well accom-
modated within the defined model (108) of ml-
receptor. The quinuclidin-2-ene ring will be
located in an area of the receptor defined by
val102, ala 160, and val385, where the quinu-
clidine ring of potent agonists bind (108).Sub-
stitution of the benzofuranyl group (28) by
benzothienyl(29), benzoxzolyl(30), or benzo-
AF-DX-116 is an analog of pirenzepine that thia-zoylyl(31) group decreased the affinity at
differs markedly in its profile of muscarinic the M1 receptor (Table 3.4). There is a good
activities (102,103). It has greatest affinity for correlation between the magnitude of the elec-
cardiac M2 receptors. Its cardioselectivity is trostatic potential in the benzene nucleus and
also observed in humans and may become use- the M1 receptor affinity. Further, future work
ful in sinus bradycardia and AV block of vagal may yield more selective M1 antagonists that
origin. will be useful in the treatment of ulcers.
Anticholinergic Drugs

(21) (pirenzepine) (23) (AF-DX 116) (24) (AQ-RA 513)

(25) AQ-RA 741

(26) UH-AH 37 (29)


4 Synthetic Anticholinergics

Table 3.4 K , Values of 2-R-Quinuclidin- Table 3.5 Methoctramine-Related


2-emsat Muscarinic Receptors Tetramines and Their Selectivities at M2
and M3 Subtypes of Muscarinic Receptorsa
Ki (values)"
P& Selectivity
R Group MI M2 M3 Ratiob
-

Benzofuranyl 9.6 31 59 Antagonist M2 M3 M2M3


Benzottienyl 81 270 420 Methoctramine" 7.78 6.28 32"
Benzoxazolyl 100 400 720 Tripitramine" 9.69 6.50 1550"
Benzothiazoyl 170 600 1100 4-DAMP 8.53 9.19 0.22~
"Reciprocals of K , values give relative affinities at the "Test system for M2 receptors: guinea pig left atria.
receptors. Summarized from Hacksell et al. (107). Test system for M3 receptors: guinea pig ileum.
bThe selectivity ratio is the antilog of the difference
between pA, values on two different systems.
'Data from Melchiorre et al. (109).
dData from Tumialti et al. (110).

tetramine backbone. Among a series of tetra-


mines, tripitramine (33)is a potent and selec-
tive M2 receptor antagonist (Table 3.5).

4.2.5 lndene Derivatives. Dimethylpyrin-


dene (Dimethindene, 35) was first introduced
as an H1 receptor antagonist. Subsequently, it
was found to be an M2 receptor antagonist.
Because of the presence of asymmetric carbon
in the molecule, it occurs in two optical forms.
In general, (S)-dimethindene is more potent
than (R)-enantiomer at muscarinic receptor
subtypes MI, M2, and M3. However, the ste-
reoselectivity (31- to 41-fold) is greatest at M2
rece~tors(Table 3.6).
A . W-Dimethindene
. . is
4.2.4 Polymethylene Tetramines. Several more specific for muscarinic receptors than at
polymethylene tetramines were developed as receptors of other biogenic m i n e s (norepine-
antagonists of the M2 receptor (109, 110). pinephrine, dopamine, and 5-HT). It pene-
Among these, methoctramine is a prototype trates the blood-brain barrier in humans and
compound (32). The selectivity and affinity of
methoctramine-like compounds at M2 recep- Table 3.6 Activities of Enantiomers
of Dimethindene at Subtypes
-
of Muscarinic Receptors

4
-
0CH3
CH2-NH-(CH2)s-NH-

(32)
l2(CH&
Receptor
Subtype"
MI
M1
M2
M2
Test System
Rabbit vas deferensb
Rat duodenumb
Guinea pig atria
Rabbit vas deferens
pA, Values
of Isomers
(R)
5.81
5.49
6.25
6.22
(s)
6.83
6.36
7.86
7.74
tors are dependent on a tetramine backbone M3 Guinea pig ileum 5.61 6.92
and the nature of substituents on the terminal M3 Guinea pig trachea 5.59 6.96
nitrogens (33,34).This selectivity is improved
"Different selective agonists were used to stimulate the
by introduction of N-methyl groups into the receptors.
tetramine backbone and introduction of a tri- bSome test systems contain more than one subtype of
cyclic system on the terminal nitrogens of the muscarinic receptor.
Anticholinergic Drugs

(112, 113). HHSID shows a 15- to 30-fold


higher antimuscarinic potency at M3 recep-
therefore may become a valuable tool in Alz- tors of guinia pig ileum and urinary bladder
heimer's disease or evaluation of M2 receptors than at M2 receptors of the rat heart and vas-
of the CNS by PET studies. cular endothelium.

4.2.6 Sila-difenidols. Studies on antocho- 4.2.7 Diphenylacetyloxy Derivatives. Bar-


linergic agents of procyclidine (Kemadrin, low and his collaborators (114) synthesized
Table 3.3) and defenidol type have shown several muscarinic antagonists and tested
that substitution of the central carbon atom them at the muscarinic receptors in the heart
(R3--€-OH) by the silicon atom (R3-Si--OH) and the smooth muscle. One of these com-
leads to drugs with increased antimuscarinic pounds, 4-[(diphenylacetyl)oxy]-1'1-dimethyl-
potency and increased selectivity for M3 re- piperidium (CDAMP, 37) was about 10 times
ceptors (36).Hexahydrosiladifenidol (HHSID) more potent on M3 receptors of the smooth
and its p-fluoro-derivative have been used to muscle than on M2 receptors of the heart
characterize M3 receptors in smooth muscle (115).It has become very useful to identify M3
5 Structure-Activity Relationships 133

q €{I: CH-C-0
activity and higher Kd (181 nM).It appears
that himbacine is a potent muscerinic antago-
nist at M2 or M4 receptors compared to M1 or
M3 receptors (116,117).

d II

(37)
1-
5 STRUCTURE-ACTIVITY RELATIONSHIPS

Although atropine-like agents are antagonists


of acetylcholine at one type of cholinergic re-
ceptor (muscarinic receptor) that is specific for
activation by L(+)-muscarine,they may dem-
in several tissues, especially smooth muscles onstrate many other pharmacological proper-
of trachea, ileum, vascular tissue, and cilia of ties (ganglionic blocking; neuromuscular
different species. blocking; musculotropic, central stimulant, or
depressant activities). The following discus-
4.2.8 Himbacine. This akaloid has a tricy- sion of the relationships of structure to activ-
clic structure (38).It is considered to be selec- ity is limited to their inhibitory actions at the
tive for cardiac M2 receptor (116). However, it muscarinic receptors. Certain structural fea-
tures are common in many anticholinergic
0 agents that have been synthesized and evalu-
ated pharmacologically (Fig. 3.4). Some of
these features also appear in cholinergics (19).
A typical atropine-like anticholinergic agent
(20) contains a cationic head and a heavy
blocking moiety (cyclic groups), which are con-
nected by a chain of atoms of definite length
(118-124). Their molecules include essential
constituent groups (cationic head, cyclic radi-
cals) as well as nonessential but contributing
anchoring groups (e.g., hydroxyl). The steric
factors that are related to the essential groups
significantly influence the anticholinergic ac-
(38) Himbacine tivity. Several anticholinergic agents incorpo-
rating the above structural features are listed
in Table 3.7.
binds to all five cloned muscarinic receptor
subtypes in the following order of potencies
5.1 Cationic Head
(117):hM2 = hM4 > hM3 > hM1 > hM5. Its
K, values at these receptors are 4, 7, 59, 83, The cationic head is an essential group in a
and 296, respectively. It is a potent blocker of large number of anticholinergic and cholin-
oxotremorine-induced and muscarinic recep- ergic compounds. Ordinarily, this is a substi-
tor-mediated cyclic AMP inhibition in rat stri- tuted ammonium group or, less frequently, a
atum (K,,4.4 nM) and N1E-115 neuroblas- sulfonium or a phosphonium group. The
toma cells (Kd,10.6 nM) responses, which are mechanism of the cholinergic or anticholin-
considered to be mediated by M4 receptors. It ergic action of substances has long been linked
inhibits oxotremorine-induced acetylcholine to such cationic groups (118-124).It is reason-
release from rat hippocampal tissue (K,, 8.6 able to assume that the cationic head with its
nM). The subtype of muscarinic receptor in- positive charge is attracted by the negatively
volved in this response is possibly the M2 or charged field (anionic center) of the musca-
M4 type. At the postsynaptic putative M1 and rinic receptor. Thus, the cationic head seem-
M3 receptors involved in the phosphoinositide ingly starts the process of the adsorption of the
turnover in the rat cortex, himbacine has low substance at the receptor. Following the at-
Table 3.7 Synthetic Anticholinergics (Atropininic Agents)
Selected Reference
Nonproprietaqy Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures
Tertiary Amines-Characteristic Group in the Main Chain: Ester
Adiphenine Trasentine 2-Diethylaminoethyldiphenyl- (C6H5)2CHC02CH2CH2N(C2H,), 125,126
acetate hydrochloride
HOHzC CH3
Amprotropine Syntropan 3-Diethylamino-2,2-dimethyl-
propyl tropate phosphate

Pavatrine 2-Diethylaminoethyl-9-
fluorene-carboxylate
hydrochloride

Cyclopentolate USP Cyclogyl P-Dimethylaminoethyl


(1-hydroxycyclopenty1)-
phenylacetate hydrochloride

Dicyclomine NND Bentyl 2-Diethylaminoethylbicyclo-


hexyl-1-carboxylate
hydrochloride
*
If:I
0 d
If: If:
Table 3.7 (Continued)
Selected Reference
Nonproprietary Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures
Characteristic Group in the Main Chain: Alkene
Diphemanil NF Prantal 4-Diphenylmethylene-1,l- 166

Eucatropine Euphthalmine
di-methylpiperidinium
methylsulfate
4-(1,2,2,6-Tetramethyl-
(C6H5)2C
€ Nf(CH3)2

132,133
piperidyl) mandelate
hydrochloride
-.L C6H5CH(OH)C02
W
Q,

Oxyphencyclimine Dariwn, 1-Methyl-1,4,5,6-tetrahydro-


ND Vio-Thene 2-pyrimdylmethyl a-cyclo-
hexyl-a-phenylglycolate
hydrochloride

Piperidolate NND Dactil 1-Ethyl-3-piperidyl diphenyl-


acetate hydrochloride (CsHd2CHC03

\
C3H5
Pipethanate Sycotrol 2-(1-Piperidino)ethyl benzilate
hydrochloride (C6H5)2C(OH)C02CH2CH2N
Quaternary Ammonium Compoundsdharacteristic Group in the Main Chain: Ester
Glycopyrrolate ND Robinul 3-Hydroxy-1,l-dimethyl-
pyrrolidinium bromide
a-cyclopentylmandelate

Mepenzolate ND Cantil N-Methyl-3-piperidyl benzilate 138,139


methylbromide (CGH~)ZC(OH)C~Z

Methantheline NF Banthine P-Diethylaminoethyl 129


9-xanthenecarboxylate
methobromide

Oxyphenonium NND Antrenyl Diethyl(2-hydroxyethy1)-


methylammonium-a-phenyl-
a-cyclohexylglycolate
bromide

Penthienate NF Monodral 2-Diethylaminoethyl


a-cyclopentyl-2-thiophene-
glycolate methobromide
Table 3.7 (Continued)
Selected Reference
Nonproprietary Proprietary for Synthetic
Name Names Chemical Name of Salt Structure of Base Procedures
135

-0
Pipenzolate NND Piptal N-Ethyl-3-piperidyl benzilate
methobromide (CGH~)~C(OH)C~Z
Nt CH3
\

Poldine Nadon 2-Hydroxymethyl-1,l-di-


methylpyrrolidinium
methylsulfate benzilate

Propantheline USP Pro-Banthine p-Diisopropylmethylaminoethyl


9-xanthenecarboxylate
bromide
73H7

I
Valethamate ND Murel 2-Diethylaminoethyl-3-methyl- CH3CHCHC02(CHZ)
2N'(CzH5)zCH8
2-phenylvalerate 1
methobromide C6H5

Characteristic Groups in the Main Chain: Thioester, Amide, or Carbarnate


Thioesters
Thiphenamil Trocinate p-Diethylaminoethyldiphenyl- (C6H5)2CHCOSCH2CH2N(C2H,),
thiolacetate hydrochloride
Amides
Tropicamide ND Mydriacyl N-Ethyl-2-phenyl-N-
(4-pyridylmethyl) hydracryl-
amide
Carbarnates
C,H,
\
Dibutoline NND Dibuline Bis[dibutylcarbamate of NC02CH2N'(CH3),C2H5 151,152
ethyL(2-hydroxyethy1)- /
dimethylammoniumlsulfate C4H9

Characteristic Groups in the Main Chain: Alkane


Amino alcohols
containing
quaternary
nitrogen
Hexocyclium ND Tral N-(p-Cyclohexyl-p-hydroxy-p-
phenylethyl)-Nf-methyl-
piperazine methylsulfate

4
W
w Mepiperphenidol Darstine 5-Methyl-4-phenyl-141-
methy1piperidinium)-3-
hexanol bromide
Tricyclamol NND Elorine, l-Cyclohexyl-l-pheny1-3-
Tricoloid pyrrolidino-1-propanol
methochloride

Tridihexethyl NF Pathilon
1-cyclohexyl-1-propanol
ethiodide
140 Anticholinergic Drugs

Table 3.8 Basicity and Anticholinergic Activity of Substituted Aminoethyl


Esters of Benzilic Acid
+
(C,H&C(OH)COOCH2CH2N(CH,),R
Doseb Required to Eliminate the
Van der Effects of Arecoline in Mice,
Wads
v o w
Basicity, Radiusa of
R PK, N-R (A) Salivation Tremor
H 8.08 2.25 5.0 6.8 (6.7)
CH3 10.87 3.09 0.48 -
OH 4.68 3.01 94.8 284.5
0CH3 10.18 4.37 4.5 -
"The van der Wads' radius of N- R bond gives an estimate of the steric volume and, therefore, steric hindrance for the
interaction of the cationic head at the muscarinic receptor.
bDosesare calculated from the values reported by Kuznetsov and Golikov (65).

traction of the oppositely charged groups, the and partition between aqueous and organic
weaker dipole-dipole, hydrophobic, and van phases. Alkylation of the oxygen atom con-
der Valls forces go into action; if there are verts the N-oxides into typical quaternary am-
many of them, especially in the case of anti- monium compounds. By this procedure, both
cholinergics, they contribute to the stability of the basicity and anticholinergic activity (Ta-
the drug-receptor complex. In such an interac- ble 3.8) of the substance increase sharply.
tion not only the charge of the cation head but The influence of a steric factor is more evi-
also its size and shape are of vital importance. dent among compounds in which the size of
The basicity of different amino derivatives, the substituents at the nitrogen atom is varied
and consequently the degree of their ioniza- both in the series of anticholinergic and cho-
tion at physiological pH, varies over a broad linergic compounds. Progressive replacement
range. The more ions of the anticholinergic of the N-methyl groups of acetylcholine with
ammonium compound or amine in solution, ethyl groups leads to a stepwise reduction in
the greater the probability of their interaction muscarinic activity (167). Likewise, maximal
with the anionic center of the muscarinic re- anticholinergic or blocking activity (Table 3.9)
ceptor to form the drug-receptor complex. In is obtained by replacing the N-methyl groups
addition, the stability of the drug-receptor of P-dimethylaminoethyl benzilate methyl-
complex that has formed should depend on the chloride with ethyl groups (119). Further in-
basicity, given that the rate of hydrolysis of creases in size to butyl or larger alkyl groups
salts is inversely proportional to the base reduce or abolish the activity (119, 168-172).
strength. Therefore, it seems that for stimulant activity,
Thus, high basicity should favor the anti- the small cationic head must fit into a definite
cholinergic activity of a substance. Although space and must aid the neutralization of the
the logic of this conclusion is simple, its proof charge of the anionic site of the receptor. The
involves great difficulties. In a series of anti- inhibitory action is obtained when large
cholinergics, transition from one derivative to enough groups are substituted on the cationic
another is associated with stepwise changes in portion to prevent close contact with the re-
basicity, as well as steric factors. In this re- ceptor and hence the neutralization of the
spect the N-oxides, which are obtained charge (173,174). Thus, the cationic portion of
through the oxidation of the corresponding the blocking agents provides the electrostatic
tertiary amines, have lower basicities and also forces necessary to orient the molecules to-
lower anticholinergic activities (164-166). ward the receptor and hold them in place.
The N-oxides are closer to the corresponding The anticholinergic activity depends not
quaternary ammonium compounds than to only on the number and the molecular weight
the tertiary ammonium ions in steric respect of the alkyl radicals that are connected to the
5 Structure-Activity Relationships 141

Table 3.9 Influence of the Number, Size, and Structure of Alkyl Groups in the Cationic Head
on the Anticholinergic Activity

Name or Structure of Compounda Activity


Compound Ratiob
Pair Series A Series B Test System B/A Ref.
p~

1 RN(CH,), RN(C,H,), Cat: salivation 1.63 119


Cat: blood pressure 2.09
+ + Mouse: mydriasis 0.45
2 RN(CH3),nC3H7 RN(CH,),isoC,H, Cat: salivation 2.00 119
Cat: blood pressure 2.38
+ + Mouse: mydriasis 4.09
3 RN(CH3),nC3H7 RN(CH,),nC,H, Cat: salivation 0.49 119
Cat: blood pressure 0.52
+ + Mouse: mydriasis 0.63
4 RN(CH,),C,H, RNCH3(C,H5), Cat: salivation 1.06
(lachesine) Cat: blood pressure 1.31
+ + Mouse: mydriasis 0.60
5 RNCH,(C,H,), RN(CZHJ3 Cat: salivation 1.00 119
Cat: blood pressure 0.79
Mouse: mydriasis 1.33
6 Atropine ()NCH,) N-Ethylnoratropine Cat: blood pressure 0.04 179
7 Homatropine N-Isopropylnor- Cat: blood pressure 0.12 179
homatropine
8 Atropine N-Allylnoratropine Cat: blood pressure 0.04 180
Rat: mydriasis 0.13
aR = (CsH5)2C(OH)C02CHzCH2-.
*In Tables 3.93.11, 3.13, and 3.15 the influence of the molecular modification on the pharmacological activity is
expressed as activity ratios. An activity ratio represents the ratio of the relative molar activities of two substances, whose
activities are compared with a standard substance. A ratio of 1.0 indicates that the molecular modification that converts the
compound in series A to the corresponding compound in series B does not change the pharmacological activity. An activity
ratio of greater than unity indicates that the molecular modification has increased the activity; when it is less than unity the
molecular modification has decreased the activity.

nitrogen atom but also on their structure. In Besides the charge on the cationic head of
contrast to di-n-propylamino derivatives, di- anticholinergics (and cholinergics), other fac-
isopropylamino derivatives have an anticho- tors seem to contribute to the interaction be-
linergic activity close to or higher than the tween the muscarinic receptor and the anticho-
activity of diethylamino derivatives (136,175- linergics. The substituents at the nitrogen atom
178). The close correlation of the activities of apparently participate actively in the process.
the diethyl and diisopropyl derivatives could This is evident from the anticholinergic action of
be related with the equal linear lengths (from the 3,3-dimethylbutyi ester of benzilic acid,
the nitrogen atom) of these radicals. (C,H,),C(OH)C02CH,CH2C(CH3)3, which con-
In the case of cyclic amino alcohols where tains no nitrogen and consequently is not ion-
nitrogen enters into the composition of the cy- ized, but which has in the corresponding posi-
cle, the optimal anticholinergic effect is pro- tion a t-butyl radical that sterically imitates the
duced not by the N-ethyl, N-isopropyl, or N- trimethylammonium group (191). A similar re-
allyl, but by N-methyl radical, as is apparent placement of a trimethylammoniumgroup with
from a comparison of the esters of tropine (Ta- a t-butyl radical in acetylcholineleads to its "car-
bles 4-6). It may be that the elements of the bon analog," CH,CO,CH,CH,C(CH,),, which
cyclic structure occupy a sufficiently large is similar to acetylcholine in its behavior toward
space besides the nitrogen atom. cholinesterase (192).
As a general rule, quaternization with a 5.2 Cyclic Moieties
small alkyl group increases activity (Table
3.10),although a few exceptions have been re- The introduction of two phenyl groups into a
ported (181, 182). molecule of acetylcholine or a cholinergic
142 Anticholinergic Drugs

Table 3.10 Differences Between the Anticholinergic Activities of Tertiary and Quaternary
Ammonium Compounds and Atropine-like Agents
Series A: Tertiary Activity
Compound Ammonium Series B: Quaternary Ratio
Pair Compounds Ammonium Compounds Test System BIA Ref.
Atropine Methylatropine Guinea pig: ileum
Mouse: mydriasis
Mouse: mydriasis
Guinea pig: ileum
Mouse: mydriasis
Tertiary analog Rabbit: intestine
of methantheline
XN(C,H&
Tertiary analog Rabbit: ileum
of penthienate Rabbit: salivation
XN(C,H&
(5)-Procyclidine Guinea pig: ileum
Mouse: mydriasis
Methyl analog Guinea pig: ileum
+ of (?I-benzhexol Mouse: mydriasis
RN(CH& Cat: salivation
Cat: blood pressure
Mouse: mydriasis
Cat: Salivation
Cat: blood pressure
Mouse: mydriasis
"For complete structures see Table 3.7.
*For complete structures see Table 3.7.
'1-Piperidino-3-pheny1-3-cyc1ohexy1-propan-1-o1.
dR = (C6H5)2C(OH)C02CH2CH2-.

substance [i.e., CH3C02(CH2)2+N(CH3)3or stituents as blocking groups at the same car-


CH3(CH2),+N(CH3),] changes the compound bon atom (Table 3.11) but a third cyclic sub-
to an anticholinergic agent [ (C6H5)2CHC02(CHJ stituent lowers the anticholinergic activity
+N(CH3I3 and (C6H5)2CH(CH2),+N(CH,),, re- (193). When these cyclic groups are too large,
spectively]. such as biphenyl and naphthyl, the com-
Anticholinergics contain varied cyclic pounds have low anticholinergic activities. A
structures, the phenyl group being the most sufficiently large number of anticholinergics
common (65c). Very often one encounters cy- that contain only one cyclic group on carbon
clohexyl and cyclopentyl radicals and the cor- are known; however, there is usually also an
responding unsaturated groups (cyclohexenyl, aliphatic group or, even better, a hydroxyl
cyclopentenyl). Substances containing a-,or, group present in such a case. Examples of such
less frequently, P-thienyl radicals may possess compounds are the esters of tropic acid. The
high anticholinergic activity. Often un- introduction of a second benzene ring into the
branched (methyl, ethyl) or branched (isobu- a-carbon of tropic acid lowers the anticholin-
tyl, isoamyl) groups are located at the same ergic activity of its aminoalkyl esters ( 6 5 ~ ) .
carbon atom together with one or two cyclic It is difficult to assess which cyclic substitu-
groups. The anticholinergic activities of sub- ents contribute the most for the anticholin-
stances that contain only aliphatic radicals are ergic activity. It could be that the effect of one
lower than those of the corresponding co- or another moiety depends on the substituents
mounds with cyclic substituents. already present and on other characteristics of
The most common and, as a rule, the most the substance. An overwhelming majority of
active anticholinergics contain two cyclic sub- the therapeutically most active anticholin-
5 Structure-Activity Relationships

Table 3.11 Influence of Cyclic Radicals on Anticholinergic Activity


(Test System: Rabbit Intestine)

Name or Structure of Compounda Activity


Compound Ratio
Pair Series A Series B B/A Ref.
1 C6H5CH2R (C6H5),CHR 6.7 193
(adiphenine)
2 C6H5CH2R (C&J&R 0.7 193
3 CH2(OH)R C6H,CH(OH)R 23.3 193
4 C6H5CH(OH)R (CJ&)&(OH)R 114 193
5 Adiphenine (C6H5)CH(C6Hll)R 3.3 194,195
(transentine) (transentine-H)
6 Adiphenine Dicyclomine 10.0 196

ergics contain at least one phenyl group (Table


3.7). The second cyclic group, where there is
one, need not be a phenyl. It is even better if,
for example, it is a cyclohexyl, cyclopentyl, or
any other cyclic structure. Such unsyrnmetri-
cal doubly substituted compounds have higher
anticholinergic activities and lower toxicities
(65, 194, 195). This is a situation similar to
that in 5,5-disubstituted barbituric acid hyp-
notics and anticonvulsants.
A question might arise whether the aro-
matic (flat surface) nature of one of the cyclic
radicals is essential for anticholinergic activ-
ity, because such a large number of anticholin-
ergics contain a phenyl group. The sufficiently
high activity of compounds in which both sub-
stituents are alicyclic (e.g., cyclohexyl or cyclo-
pentyl) provides a basis for asserting that the H-C-H
aromatic nature of the substituents is not es- I
COOR
sential in anticholinergics (651365.
Not just the number and the character of
the cyclic group but also the mode of linking of
the substituents are important for anticholin-
ergic activity. Two benzene rings are linked The importance of the cyclic nature of the
differently in 2-diethylaminoethyl esters of di- substituent and not simply of its mass is evi-
phenylacetic acid (391, fluorene-9-carboxylic dent from the comparison of the anticholin-
acid (40) and p-biphenylacetic acid (41). Of ergic activities of 1-cyclohexyl-1-phenyl-3-pip-
these, the diphenylacetic acid derivatives have eridino-1-propanol (42) and 1-(n-hexy1)-1-
the highest anticholinergic activity (193). phenyl-3-piperdino-1-propanol (43), of which
(42) is an active anticholinergic, whereas (43)
is not effective (174).
As far as the contribution of cyclic struc-
tures to anticholinergic activity is concerned,
the introduction of cyclic groups into acetyl-
choline or a cholinergic compound leads to a
change in the pharmacological properties
that, without lowering and possibly even
Anticholinergic Drugs

ments for a chain of atoms that connects the


cationic head and the cyclic moieties; these ap-
ply to the length and form of the chain, lateral
branching, and functional groups in the chain,
if any.
A considerable number of the anticholin-
ergics belong to the group of aminoalkyl esters
of substituted acetic acids. In an overwhelm-
ing majority of cases, the substituted esters of
p-aminoethanol are more active as anticholin-
ergics than are the corresponding derivatives
of y-aminopropanol(119, 170, 175, 198). Fur-
ther increase of the chain length of the amino
alcohol leads to a decrease or disappearance of
the anticholinergic activity. The arninoalkyl
esters of diphenylacetic acid are more active
anticholinergics than the corresponding ami-
noalkyl esters of p,p-diphenylpropionic acid
(199). Therefore, in all these esters with high
anticholinergic activity the main chain con-
necting the cyclic moieties and the cationic
head contains five atoms (Table 3.12, series
1-3). In an homologous series of compounds in
which the ester group is replaced by a chain of
carbon atoms (Table 3.12, series 4-9), there
are three atoms in the main chain in com-
strengthening its affinity for the muscarinic
pounds with maximal anticholinergic activity.
receptor, abolishes or blocks the action of the
To explain the differences in the anticholin-
chemical transmitter. This phenomenon is
ergic activities of different series of com-
similar to the transition from a metabolite to
pounds, the ability of their structures to exist
an antimetabolite. It has been suggested that
in different spatial conformations has to be
the cyclic groups of the anticholinergic agent
taken into account.
form an additional contact with the musca-
Acetylcholine and related esters can exist
rinic receptor by hydrophobic or van der Walls
in two conformations (Fig. 3.5), the skewed
forces; as a result, this contact is strengthened
and extended forms (200) (e.g., 44 and 45, re-
and the muscarinic receptors are protected
spectively, for acetylcholine). The skewed
from approaching molecules of acetylcholine
form (44) of acetylcholine is closely related to
(174, 197). Cyclic groups of substantial size
the structure of muscarine (46) (200). Simi-
can create a kind of protective screen that
larly the substituted aminoethyl esters, which
sterically hinders the approach of molecules of
are anticholinergics, may exist in two confor-
acetylcholine, not only to the given active site
mations. The skewed forms of acetylcholine
but also to the vicinity of the active sites of the
(441, muscarine (461, the skewed form of ami-
receptor. Tricyclic anticholinergic agents may
noethyl esters (47), and the extended form of
fall under this category.
aminopropane derivatives (48) all interact at
the same muscarinic receptors. In the former
5.3 Length of the Main Chain Connecting
two compounds the interatomic distance be-
the Cationic Head and the Cyclic Croups
tween the quaternary nitrogen and the ether
The presence of the cationic head and of cyclic oxygen atom is nearly the same, and both of
groups is not sufficient for optimal anticholin- them are agonists. In (48) the interatomic dis-
ergic activity of a compound. The activity de- tance between the quaternary nitrogen and
pends on the mutual distribution of these the carbon atom to which the cyclic radicals
groups. This establishes the basic require are attached is the same, and both of them are
Table 3.12 Chain Length Between Cationic Head and Cyclic Radicals Among Anticholinergics
Value of n for High Total Number
Anticholinergic of Atoms in
No. Series Activity the Chain Test System Ref.
Rabbit: mydriasis 198

Rabbit: mydriasis 198

Mouse: mydriasis 119


Rabbit: ileum 158
Rabbit: ileum 158
Rabbit: ileum 158
Mouse: salivation
Mouse: salivation
Mouse: tremor
Mouse: salivation
"No exact values are available for esters with n = 1
Anticholinergic Drugs

Figure 3.5. Conformations of cholinergics and anticholinergics.

antagonists (65d)65. Thus, anticholinergic ac- ciently. A great importance was attached to
tivity depends not only on the length of the the complex
- esters in the initial period
- of the
main chain of the molecule but also on its abil- search for atropine-like substances, when ac-
ity to adopt a certain conformation that is fa- tive compounds were known only among the
vorable for the interaction of the substance esters of amino alcohols and carbowlic - acids.
with the receptor. However, the presence of this grouping is not
There is some information about the influ- necessary - for the manifestation of anticholin-
ence of branching of the main chain on the ergic activity. Presently, a large number of
anticholinergic activity. Esters with a methyl substances are known that belong- to different
group CY to the ester oxygen in the amino chemical structures and that possess high an-
alcohol part are less active than compounds ticholinergic activity (Table 7).
without the methyl group (175, 198, 201). The influence of an ester link can be as-
Similarly, the derivatives of 1,3-aminopropanol, sessed by comparing similar compounds that
aminopropane, and y-arninobutyronitrile (201, do not contain pharmacophoric groups other
203),which contain a branch at the carbon atom than the anchoring groups (amino nitrogen,
p to the nitrogen, are less active anticholinergics cyclic radicals). Comparative data on the
than the compounds without the branching. anticholinergic activities of the 2-diethyl-
The negative influence of such a side chain has aminoethyl ester of diphenylacetic acid
been explained by steric hindrance at the recep- [(C6H5),CHC0,CH,CH,N(C2H5)2] and 1,l-
tor (174). diphenyl-5-diethylaminopentane [(C6H5),-
The inclusion in the main chain of opti- CHCH,CH,CH,CH,N(C,H5),] indicate that
mum length of other atoms such as oxygen, they are equally active (65d). Thus, the com-
sulfur, nitrogen, and other functional groups plex ester group is not essential for anticholin-
changes any anticholinergic activity (65). ergic activity; however, it may contribute to
However, such compounds are considerably optimal activity when it is present in atropine-
potent (see Section 5.4). like compounds (123). It may influence the
conformation of a molecule that in turn deter-
5.4 Esteric Linkage
mines the effectiveness of the interaction of
The question of the importance of complex es- the essential anchoring groups, the cationic
ter grouping in anticholinergics, and even head and the cyclic radicals (65d), with the
more of its role, has not been cleared up suffi- muscarinic receptor.
5 Structure-Activity Relationships

5.5 Hydroxyl Croup tion decreases the original muscarinic activity


to about 113, whereas the introduction of both
The anticholinergic compounds that contain a a- and P-OH functions decreases the musca-
hydroxyl group in a certain position of a mol- rinic activitv" to about one-tenth.
ecule possess considerably higher activity The introduction of a hydroxyl group into
than similar compounds without the hydroxyl. 2-diethylaminoethyl phenylacetate approxi-
That position is of great importance. For es- mately doubles its activity (Table 3.13),
ters of amino alcohols and hydroxycarboxylic whereas the same structural change - in the
acids, maximum activity is achieved if the hy- corresponding ester of diphenylacetic acid in-
droxyl is p to the carboxyl group. Atropine is creases its activity about 140 times. The posi-
about 10 times more active than homatropine. tive influence of the hydroxyl group has been
However, esters with an a-hydroxyl also pos- observed in a large number of anticholinergics
sess considerable anticholinergic activity. In (Table 3.7). The exceptions are those cases in
anticholinergic amino alcohols the hydroxyl which the cyclic groups are too large or are
on the third carbon atom from the nitrogen connected in such a way that they can steri-
gives optimal activity (Table 3.7). The location cally prevent the interaction of the hydroxyl
of the hydroxyl group in relation to the cyclic with the surface of the muscarinic receptor.
radicals is also of vital importance. In the
great majority of anticholinergics they are lo- 5.6 Epoxy Group
cated at the same carbon atom or at adjacent
carbons. The presence of an epoxy group seems to in-
The hydroxyl group in anticholinergics can crease the mydriatic activity (Table 3.13).
be replaced by CN- and CONH,- groups However, scopolamine (7), which contains an
while preserving some degree of activity. How- epoxy group, is a central depressant, as indi-
ever, replacement of the hydroxyl by methoxy cated by drowsiness, euphoria, amnesia, and
or an acetoxy group lowers the activity (204, dreamless sleep. Atropine (4), which does not
205). contain an epoxy group, stimulates the me-
The hydroxyl group may interact by hydro- dulla and higher cerebral centers. In clinical
gen bonding with a site on the muscarinic re- doses (0.5-1.0 mg), this effect is usually con-
ceptor, which is rich in electrons. In support of fined to mild vagal excitation. Toxic doses of
this statement (65e), hydroxylated anticholin- atropine cause restlessness, disorientation, '

ergics form complexes in solution with sub- hallucinations, and delirium.


stances such as amines that contain electron-
donor atoms. In a series of structurally related 5.7 Stereoisomerism and Anticholinergic
compounds the anticholinergic activity was
-
Activity
proportional to their capacity for molecular
association by way of the hydroxyl group. 5.7.1 Opticalisomerism. Atropine (4-6) is
There is a direct relationship between the an- the racemic form of hyoscyamine, which is the
ticholinergic activity and the mobility of the (S)-(-)-tropyl ester of 3a-tropanol (2). The
hydrogen atom of the hydroxyl group as deter- carbon a to the carbonyl group is asymmetric.
mined by the rate of acetylation. The contri- (S)-(-)-Hyoscyamine is more active than (R)-
bution of the hydroxyl group to the free energy (+)-hyoscyamineas an anticholinergic (Table
of adsorption is quite high, of the order of 2 3.11). The alkaloid scopolamine (7) is the (S)-
kcal; it is apparently independent of the num- (-)-tropyl ester of scopine (8);again the (S)-
ber of methyl groups attached to the cationic (-) isomer is more active than (R)-(+) isomer
head (206). in its anticholinergic activities.
Although a hydroxyl group increases the A considerable number of synthetic anti-
activity of an anticholinergic, it does not con- cholinergic agents patterned after the struc-
vert a cholinergic substance into an anticho- ture of atropine contain an asymmetric carbon
linergic. Propionyl-, a-hydroxypropionyl-,and atom corresponding to the position of the
or$-dihydroxypropionylcholines possess cho- asymmetric carbon in atropine. In all com-
linergic properties (207). a-Hydroxy substitu- pounds examined, the asymmetric carbon is
Table 3.13 Muence of the Hydroxyl and Epoxy Groups on Anticholinergic Activity
Activity
Name or Structure of Compound
Ratio
Group Series A Series B Test System B/A Ref.
Hydroxyl CJ-15CH2C02CH2N(C2H& C6H5CH(OH)C02CH2CH2N(C2H5)2 Rabbit: intestine 2.3 193
(C,H5)2CHC0,CH2CH2N(C2H5)2 (C6H5),C(OH)C02CH2CH2N(C2H5)2 Rabbit: intestine 143 193
Epoxy (- )-Hyoscyamine (-)-Scopolamine Guinea pig: ileum 0.24 208
Mouse: eye 2.70
Cat: eye 5.80
Cat: blood pressure 0.64
Cat: salivation 0.77
(-)-Methylhyoscamine (- )-Methylscopolamine Mouse: eye 1.00 208
Cat: eye 3.33
Cat: blood pressure 0.80
Cat: salivation 0.80
5 Structure-Activity Relationships 149

Table 3.14 Optical Isomerism and Anticholinergic Activity


Compounds Whose (+) Position of the
and (-1 Isomers Are Asymmetric Active Isomeric
No. Tested Test System Carbon Isomer Ratioa Ref.
Hyoscyamine Dog: salivation
Cat: salivation a-carbon to the
Cat: bloodpressure carbonyl
Guinea pig: ileum group
Rabbit: ileum
Scopolamine Dog: salivation a-carbon to the
Rabbit: intestine carbonyl
POUP
Tricyclamol Guinea pig: ileum Carbon with
cyclic radical
Benzhexol Guinea pig: ileum Carbon with
Rabbit: intestine cyclic radical
Mice: mydriasis
Procyclidine Guinea pig: ileum Carbon with
Mice: mydriasis cyclic radical
1,l-Diphenyl-3- Rabbit: intestine a to N
piperidino-1-butanol
hydrochloride
Methiodide of no. 6 Rabbit: intestine a to N

Diphenylacetate of 3- Rabbit: intestine p to N


auinuclidinol
"Activity ratio between the enantiomers.

located in the acyl moiety and is connected 3-quinuclidinyl diphenylacetate, the carbon
with the cyclic and the hydroxyl groups (di- atom p to the nitrogen is asymmetric; the (-)
rectly or through a methylene group). The (-1 isomer has more atropine-like activity than
isomers are often more active than (+) iso- does the (+) isomer.
mers (Table 3.14), indicating some apparent
stereospecificity with respect to the carbon 5.7.2 Derivatives of Tropine and Pseudo-
atom a to the carbonyl group of atropine. tropine. The configuration of the 3-OH group
The atropine-like activities of some com- in the tropine part of the molecule has signif-
pounds in which the asymmetric carbon atom icant influence on the activity at the musca-
is considerably closer to the amino group have rink receptor (Table 3.15). The derivatives of
been described. In 1,l-diphenyl-3-piperidino- +-tropine (pseudotropine, 3) are less active;
1-butanol, the carbon a to the nitrogen is +
the activity ratio for the compound relative
asymmetric. In this case the (+) isomer seems to the isomeric tropine varies from 2 to 13, but
to be more active than the (-) isomer. In more information is needed on this point.

Table 3.15 Relative Anticholinergic Activities of the Esters of Tropine and Pseudotropine

Pair of Structural Isomers Activity


Isomer Ratio
Pair A B Test System A/B Ref.
1 Atropine Tropyl-$-tropine Cat (?): blood pressure 2 213
2 Benzoyl-tropine HC1 Benzoyl-Jr-tropine Rabbit or Guinea pig: 3 214
intestine
3 CHJ of no. 2 CHJ of no. 2 Guinea pig: intestine 13 214
4 C,H,Br of no. 2 C,H,Br of no. 2 Guinea pig: intestine 4 214
Anticholinergic Drugs

5.7.3 Stereochemical Configuration. The constant of agonists (KA)and antagonists (K,)


acetylcholine-like cholinergics and atropine- acting at the same receptors, (2)the absolute
like anticholinergics contain similar pharma- configuration of the compounds, and (3) the
codynamic groups. In various hypotheses, it interrelationships between the configurations
has been assumed that both stimulant and of agonists and antagonists acting at the same
blocking drugs interact with the muscarinic receptors.
receptor through the essential pharmacody- The dissociation constants of some cholin-
namic groups. The tropic acid portion of atro- ergic agonists and antagonists have been de-
pine contains an asymmetric carbon, and the termined (Table 3.16). D(+)-and L(-)-lactoyl-
muscarinic receptor is stereospecific for the cholines are agonists at muscarinic receptors
carbon a to the carbonyl group in anticholin- and there is no significant difference in their
ergics. Acetylcholine does not contain such an intrinsic efficacies. The KAof D(+)-lactoylcho-
asymmetric carbon atom. Lactoylcholine is an line is lower than the KAof the L(-) isomer at
agonist that contains an asymmetric carbon the muscarinic receptor. Therefore, the D(+)
(2071, and the muscarinic receptor is ste- isomer has a higher affinity to the muscarinic
reospecific for the carbon a to the carbonyl receptor than that of the L(-) isomer (219).
group among lactoylcholine-like cholinergics Mandeloyl- and tropinoylcholines are compet-
(215). Because of the structural similarities in itive antagonists of acetylcholine and lactoyl-
tropic and lactic acids, it has even been sug- choline at the muscarinic receptors (220-222).
gested that a lactoylcholine-like parasympa- Among these anticholinergics, the D isomer
thetic neurohormone may occur in animal tis- has a higher affinity (l/K,) than that of the
sues (207, 216). However, this has not been corresponding L isomer. The above anticholin-
corroborated. ergics did not exhibit significant intrinsic effi-
cacies at the muscarinic receptors. The carbon
5.7.4 Dissociation Constants of Cholin- a to the carbonyl carbon of the ester group is
ergics and Anticholinergics. The absolute con- asymmetric in agonists (lactoylcholines) and
figuration [ ( R )and (S)] is self-consistent for a their competitive antagonists (mandeloylcho-
molecule in question and cannot be used to lines and tropinoylcholines). Therefore, the D
relate a series of compounds. The configura- isomers have the preferred relative configura-
tion in relation to a standard substance (D and tion that comes into definite spatial position
L) is very useful to compare a series of com- with the muscarinic receptor. Similarly, D(-)-
pounds. For example, the pharmacological pa- hyoscamine has a higher affinity to the mus-
rameters of all D compounds in a series can be carinic receptor than does the L(+)isomer and
compared with those of the L compounds, pro- has the preferred configuration (223).
vided each one of the compounds contains a
5.8 Compounds with Dual Action:
single asymmetric carbon (217).
Cholinergic and Anticholinergic Activities
In a number of studies on structure-activ-
ity relationships, the pharmacological activi- In several groups of atropine-like agents, de-
ties are expressed in terms of potencies or rel- rived from acetylcholine-like compounds, ago-
ative molar activities, which are derivatives of nist activity is replaced by partial agonist ac-
their ED,, values. The reciprocals of ED,, val- tivity and eventually antagonist activity with
ues do not give exact measures of affinities increasing substitution (224-227). For exam-
(218), which are required to make valid con- ple, a transition between cholinergic and anti-
clusions on the stereoisomer-receptor interac- cholinergic properties occurs when the acyl
tions and the nature of receptor surfaces. The group of acetylcholine is progressively length-
differences in the potencies of a pair of stereo- ened. Cholinergic activity decreases from
isomers may be attributed to the differences in formylcholine to butyrylcholine, and the
their affinities or intrinsic efficacies. For these higher members of the series are anticholin-
reasons, the following information is neces- ergics (Table 3.17). It has been demonstrated
sary to make definite conclusions for delineat- that hyoscyamine and atropine at small dose
ing receptor surfaces using stereoisomer-re- levels exhibit cholinergic properties (228,
ceptor interactions (217): (1)the dissociation 229).
6 Interaction of Anticholinergics at the Muscarinic Receptors

Table 3.16 Dissociation Constants and Intrinsic Efficacies of Cholinergic


and Anticholinergic Agents
Activity
Type of Dissociation Relative
Cholinergic or Anticholinergic ReceptoP Constantb Intrinsic
and Configuration (Test System) (KA or KB) Efficacy Ref.
Acetylcholine Muscarinic 1.08 X 1.00 219
Nicotinic 2.17 x 1.00 219
(R)-D-(+)-Lactoylcholine Muscarinic 7.3 x lo-5 0.52 219
Nicotinic 1.85 x 1.07 219
(S)-L-(-)-Lactoylcholine Muscarinic 3.02 X 0.30 219
Nicotinic 8.08 X 1.15 219
(R)-D-(-)-Acetyl-P-methylcholine Muscarinic Inactive - 224
(S)-L-(+)-Acetyl-P-methylcholine Muscarinic 1.24 X - 224
(active isomer)
(R)-D-(-)-Mandeloylcholine Muscarinic 3.00 X lop6 NSc 220,221
(S)-L-(+)-Mandeloylcholine Muscarinic 5.22 X NS 220,221
(S)-D-(-)-Tropinoylcholine Muscarinic 2.15 X lo-' NS 220,222
(R)-L-(+)-Tropinoylcholine Muscarinic 3.26 x NS 220,222
(S)-D-(-)-Hyoscyamine Muscarinic 4.47 X 10-lo NS 223
(R)-L-(+)-Hyoscyamine Muscarinic 1.41 X lo-' NS 223
"Muscarinic activities are tested on the guinea pig longitudinal ileal muscle in all cases except acetyl-p-methylcholine,
which is tested on the circular muscle from fundus of rabbit stomach. Nicotinic activities are tested on the frog rectus
abdominis muscle.
bMoles/liter.
"Not significant.

6 INTERACTION OF ANTICHOLINERGICS line stimulates these receptors, atropine


AT THE MUSCARINK RECEPTORS blocks them. Although considerable progress
has been made in understanding these inter-
It is generally accepted that acetylcholine and actions of stimulant and blocking drugs, some
atropine interact with the same postgangli- aspects of drug-receptor interaction are not
onic muscarinic receptors. Whereas acetylcho- clear. For detailed discussions of cholinergic

Table 3.17 Cholinergic and Anticholinergic Activities of Choline Esters

Intrinsic
Activity
a P& Test System Ref.
Rat: intestine 225
Rat: intestine
Rat: intestine
Rat: intestine
Rat: intestine
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Guinea pig: ileum
Rat: intestine 225
Anticholinergic Drugs

and anticholinergic drugs at the muscarinic istence on the receptor of two active sites sep-
receptors see original papers and reviews on arated by a distance 3.2 + 0.2 A (219, 237-
the subject (230-236). 239). One of them is an anionic site with which
6.1 Kinetic Basis for the Mechanism of the quaternary ammonium group interacts to
Action of Anticholinergics induce stimulant or blocking actions. The
ether oxygen of muscarine and the ester oxy-
The major action of a number of anticholin- gen of acetylcholine interact with the second
ergics is a competitive antagonism to acetyl- site. There are some similarities between the
choline and other cholinergic agents. The an- active sites on acetylcholinesterase and the
tagonism can therefore be overcome by muscarinic receptor. The amine portion of an-
increasing the concentration of acetylcholine ticholinergics interacts at the same anionic
at receptor sites of the effector organs. Thus site as the quaternary group of acetylcholine
anticholinesterases partially reverse the an- and atropine. Several facets of acetylcholine-
tagonism of anticholinergics by sparing acetyl- atropine antagonism are well known:
choline at the receptor sites. The anticholin-
ergics can inhibit all muscarinic actions of 1. One molecule of atropine blocks one mole-
acetylcholine and other choline esters. Re- cule of acetylcholine. Atropine is a larger
sponses to postganglionic cholinergic nerve molecule than acetylcholine and either me-
stimulation may also be inhibited, but less chanically or electrostatically inactivates
readily than responses to administered cho- receptors engaged by it.
line esters. The differences in the ability of
2. Atropine has greater affinity than acetyl-
anticholinergics to block the effects of exoge-
choline for the receptor. Its intrinsic activ-
nous choline esters and the effects of endoge-
ity is not significant, whereas acetylcholine
nous acetylcholine liberated by the postgangli-
has high intrinsic activity. Substances with
onic parasympathetic nerves may result from
intermediate intrinsic activities behave ei-
the release of the chemical transmitter by the
ther as cholinergics or as anticholinergics,
nerve at the receptors in relatively inaccessi-
depending on the nature of their influence
ble sites where diffusion limits the concentra-
on the receptor. Among such substances
tion of the antagonist.
are partial agonists with "dual action";
6.2 Specificity of Antagonism cholinergic activity precedes the anticho-
linergic activity. The partial agonists can
Atropine is a highly selective antagonist of
be detected in a homologous series by grad-
acetylcholine, muscarine, and other cholin-
ually proceeding from agonists to antago-
ergic agents on the smooth and cardiac mus-
nists with increasing molecular weight.
cles and glands. This antagonism is so selec-
tive for cholinergic agents that atropine 3. Besides the cationic head, bulky cyclic
blockade of the actions of other types of drugs groups are essential constituents of com-
has been taken as evidence for their actions pounds with anticholinergic activity. It
through cholinergic mechanisms. For exam- seems clear that the van der Wads or hy-
ple, the smooth muscle of guinea pig ileum is drophobid binding of the planar cyclic
stimulated by muscarine, 5-hydroxytrypta- groups together with the binding of the
mine, histamine, and barium chloride. Atro- amine group produce a strong drug-recep-
pine is more specific in blocking the stimulant tor complex, which effectively blocks the
effects of muscarine and acetylcholine at lower close approach of acetylcholine to the
dose levels than those of the other three stim- receptor.
ulant agents. 4. Acetylcholine increases potassium efflux
and causes depolarization of the mem-
6.3 Molecular Basis for the Interaction of brane, both of which effects are blocked by
Acetylcholine and Anticholinergics at the atropine.
Muscarinic Receptors
5. The receptor proteins on the membrane
Structure-activity relationships among mus- may undergo molecular disorientation dur-
carinic agents (or cholinergics) indicate the ex- ing the interaction of acetylcholine with
7 Therapeutic Uses of Anticholinergics

Table 3.18 Mydriatic and Cycloplegic Activities of Anticholinergics in Man"


Mydriasis Cycloplegia
Strength of Maximal, Recovery, Maximal, Recovery,
D~gb Solution, % min days h days
1 Atropine sulfate 1.0 30-40 7-10 13 8-12
2 Owhenonium bromide 1.0 3040 7-10 13 8-12
3 Scopolamine hydrobromide 0.5 20-30 3-5 -12 -1 1-2
4 Atropine methyl nitrate 1.0-5 30 2 1 2
5 Homatropine bromide 1.0 1030 -4 - 4
1 1
--I,
2
1 1
-2 -2
6 Cyclopentolate 0.5-1.0 30-60 1 -21 -1 1
hydrochloride
Dibutoline sulfate 5.0-7.5 60 1-
4
- -12 1 ---
1 1
4 2
8 Tropicamide c
1.0 20-35 -1
4
-12 2-6 h
9 Eucatropine hydrochloride 5-10 30 ---
1 1
4 2
None -
"For details see Refs. 241-243. The values should be considered approximate.
*Oneinstillation of one drop unless otherwise specified.
"Two drops at 5-min intervals.

the cholinergic receptor, and this change in The mydriatic and cycloplegic activities of
the receptor proteins may be prevented by anticholinergics in humans are listed in Table
a suitable blocking agent (240). Given that 3.18. Atropine is recommended in situations
five subtypes of muscarinic receptors have requiring complete and prolonged relaxation
been isolated and their amino acid se- of the sphincter of iris and the ciliary muscle.
quences have been determined, future in- Mydriatics, like cyclopentolate, eucatropine,
vestigations may reveal the molecular na- and homatropine bromide, with a shorter du-
ture of interactions of anticholinergics ration of action, are usually preferred for mea-
with muscarinic receptors. suring refractive errors because of the relative
rapidity with which their cycloplegic effects
7 THERAPEUTIC USES OF are terminated.
ANTlCHOLlNERGlCS Atropine and scopolamine are used for pre-
medication before the administration of some
The chief use of most of the antispasmodic inhalation anesthetics, to reduce excessive sal-
agents is as an adjunct in the management of ivary and bronchial secretions. Atropine and
the peptic ulcer; this group of drugs includes related agents have been used in the treat-
adiphenine, aminopentamide, amprotropine, ment of renal colic and hyperhidrosis, and to
dibutoline, diphemanil, glycopyrrolate, hexo- control sweating that may aggravate certain
cyclium, homoatropine methylbromide, meth- dermatologic disorders. Atropine also may be
scopolamine bromide, methscopolamine nitrate, used to counteract the toxicity of certain cho-
oxphencyclimine, oxphenonium, penthienate, linergic drugs and anticholinesterase agents.
pipenzolate, piperidolate, pipethonate, propan- Certain drugs with anticholinergic effects
thelin, tricyclamol, and trihexethyl (241). To are used for the symptomatic treatment of
this group of several M1 receptor antagonists Parkinson's disease (paralysis agitans) and re-
that decrease acid secretion should be added lated syndromes of the extrapyramidal tracts.
pyrenzipine, which is a leading compound in this (Of the presently available drugs, none is use-
group of agents. The anticholinergic agents that ful in all cases of Parkinsonism.) Despite
are useful as adjuvants in the management of claims of superiority for newly introduced syn-
the functional disorders of the bowel (e.g., irri- thetic agents, none possesses outstanding effi-
table colon, spastic colitis, ulcerative colitis, and cacy and freedom from adverse side effects
diverticulitis) include dicyclomine, hexocyclium, when compared clinically with atropine and
mepenzolate, and valethamate. scopolamine (241).
Anticholinergic Drugs

8 MOLECULAR BASIS FOR THE SIDE of euphoria, dizziness, and delirium may be
EFFECTS OF ANTlCHOLlNERClCS observed because the drugs can cross the
blood-brain barrier.
The most widely used mode of approach in the Many synthetic quaternary ammonium
design of anticholinergics is based on the use compounds may block acetylcholine at ganglia
of tropine alkaloids as models of prototypes, at high doses. Ganglionic-blocking agents
from which congeners or homologs or analogs cause impotence as a side effect. High doses of
have been designed. Tropine alkaloids have methantheline may also cause impotence, an
many pharmacological activities and interact effect rarely produced by pure antimuscarinic
at many cholinergic sites. In drug design the drugs and indicating ganglionic blockade.
main purpose is to increase one pharmacolog- Toxic doses of quaternary ammonium com-
pounds (e.g., menthantheline, propantheline,
ical action at one particular site of action while
and oxyphenonium) block acetylcholine at the
concomitantly suppressing other pharmaco-
somatic neuromuscular junction and paralyze
logical activities at other sites. It is not always respiration.
possible to abolish all pharmacological effects Adiphenine and amprotropine have local
other than the desired activity by molecular anesthetic activities, and anesthesia of the
modification. Though the desired activity is oral mucosa results when tablets of these
useful in its therapeutic applications, other drugs are chewed. It should be remembered
pharmacological activities manifest them- that local anesthetic esters and amides exert
selves as side effects. For example, atropine, their action by anticholinergic mechanisms,
scopolamine, and cocaine are structurally re- probably essentially at the nodes of Ranvier.
lated, each having atropine nucleus. They dif- The central side effects have appeared
fer in some of their pharmacological activities. among children even when cyclopentolate,
Atropine stimulates the CNS, scopolamine de- tropicamide, and other anticholinergics are
presses the CNS, and cocaine is a local anes- used as mydriatics. All anticholinergics in-
thetic and CNS stimulant. crease intraocular pressure in most patients
By molecular modification, it has been pos- with simple glaucoma.
sible to produce a series of anticholinergics Some of the cyclic groups in anticholin-
having qualitative effects resembling those ergics are pharmacophoric moieties for other
produced by parasympathectomy to a particu- types of activities. For example, the com-
lar organ. Although these drugs exert specific pounds containing a phenothiazine nucleus
therapeutic effects at one organ, they exert exhibit central depressing and antihistaminic
side effects at other organs. Recent develop- side effects. These side effects are of advan-
ments on the design of anticholinergics selec- tage in the treatment of Parkinson's syn-
tive for subtypes of muscarinic receptors and drome. The side effects of certain drugs that
identification of subtypes of muscarinic recep- result from their anticholinergic activities are
tors in a number of organs has partially pro- prominent among some analgesics (e.g., me-
vided a solution for this problem. peridine), antihistamines (e.g., prometha-
The untoward effects associated with the zine), psychosedatives (e.g., benactizine), and
use of anticholinergics are manifestations of psychotomimetics (e.g., dexoxodrol).
their pharmacological actions, and usually oc-
cur on excessive dosage. The effects include 9 PROFILE O F ANTlCHOLlNERClC
dryness of mouth, blurred vision, difficulty in ACTIVITIES OF VARIOUS AGENTS
urination, increased intraocular tension,
tachycardia, and constipation. Most of these The relative anticholinergic activities of the
side effects are lessened when the quaternary well-known therapeutic compounds are listed
anticholinergics are administered orally in the in Table 3.19. Although it is very difficult to
treatment of peptic ulcer because of low ab- justify collecting the results of a wide variety
sorption into the systemic circulation. In the of experiments, it seems likely that the table
case of tertiary amines the central side effects gives some idea of their relative antisecretory,
10 Nonanticholinergics as Antiulcer Agents 155

antispasmodic, and mydriatic activities rela- Studies on the effectiveness of anticholin-


tive to atropine. Ratios less than unity indi- ergic agents in the ulcer disease complicated
cate that they are more active than atropine. by Helicobacter pylori infection are hampered
Atropine itself is a very active substance in by the lack of suitable animal models (262).
all three types of activities. (-)-Methscopol- Marchetti et al(263) have developed a mouse
arnine seems to be the most active of all com- model of H. pylori infection that mimics hu-
pounds; it is about five times as active as atro- man disease. The pathogenesis of H. pylori in-
pine. None of the synthetic compounds is more fection in vivo was investigated using fresh
active than (-)-methscopolamine, and very clinical isolates of bacteria to colonize the
few of them are more active than atropine. stomachs of mice. The gastric pathology re-
The compounds with high antisecretory activ- sembling human disease was observed with
ities also exhibit some degree of antispasmodic cytotoxin-producingstrains but not with non-
and mydriatic activities. Therefore, there is no cytotoxin strains. Oral immunization with pu-
complete dissociation between the three types rified H. pylori antigens protected mice from
of anticholinergic activities. Compounds with bacterial infection. This model will be useful
only one type of anticholinergic activity have for the development of therapeutic regimens
yet to be synthesized. Only among very weak involving vaccines against H. pylori and anti-
compounds is there any dissociation between cholinergic agents.
the antispasmodic and the mydriatic activities
(e.g., propivane). However, this difference
may be related to the mode of administration. 10 NONANTICHOLINERGICS AS
Mydriatic activities are measured after instil- ANTIULCER AGENTS
lation into the eye, whereas antispasmodic
and antisecretory activities are measured af- The interplay of various neuronal, hormonal,
ter parenteral administration to the animal or and other factors in gastric acid secretion are
on in vitro preparations. To establish a claim shown in Fig. 3.1. Pharmacological agents can
that one compound has only one type of anti- be used to decrease gastric acid secretion by
cholinergic activity, two types of data should their action at different sites. So far, the prin-
be available: (1)all types of activities should be cipal medications other than anticholinergics
measured in the same animal after the drug is and antiacids to treat peptic ulcer are limited.
Experimental and clinical investigations are
administered by the same route; (2) the exact
in progress on a number of agents that can
concentrations of the drugs at the sites of their
decrease the volume and acidity of gastric
action should be known. Such information is secretion through mechanisms other than
not available for most compounds in published blockade of the cholinergic nervous system
literature. (264-267). These include (1) histamine H2-
For their antispasmodic and antisecretory receptor antagonists (2661, (2) gastrin inhibi-
activities in humans, the drugs are adminis- tors (265), (3) pepsin inactivators (2651, (4)
tered orally. A comparison of their oral doses mucus producers (69), (5)prostaglandin ana-
(micromoles) indicates that atropine is the - (69). (6) enteromstone
logs - and its analogs-
most active compound. In clinical experience (265, 267), (7) noncholinergic antispasmodics
all three types of anticholinergic activities are (69, 264), and (8) gastric Hf/Kt-ATPase in-
exhibited by all compounds. The principal ad- hibitors.
vantage of the available quaternary ammo- Histamine HZ receptor antagonists are
nium compounds lies in the fact that they are popular for the treatment of peptic ulcer (266).
elatively free of any of the CNS effects that A single dose of cimitidine, an HZ receptor an-
may be seen with atropine. This may permit tagonist, has a maximum effect on nocturnal
the administration of sufficient quantities of acid output in humans, and no further effect is
the compounds to achieve a more fully effec- obtained by adding poldine, an anticholinergic
tive peripheral anticholinergic action. agent, to cimitidine (266~).Cimitidine is also
Table 3.19 Relative Activities of Anticholinereicsa
Total Dose Per Day in
c
Equipotent Molar Ratios Relative to Atropine Humans f

No. Antisecretoryd Antispasmodice Mydriatic mg pmol Ref.


Solanaceous Alkaloids and Semisynthetic Substitutes
Atropine sulfate
Methylatropine

Synthetic Anticholinergics: Esters, Quaternary


Glycopyrrolate
Lachesine
Mepenzolate
Methantheline
Methyleucatropine
Oxyphenonium

Penthionate
Pipenzolate
Poldine methyl sulfate
Propantheline
Valethamate
Esters, Tertiary
Adiphenine
Amprotropine phosphate
Benactyzine
Carbofluorene
Cyclopentolate
Dicyclomine
Eucatropine
Oxyphencyclimine
Piperidolate
Propivane

Thioesters, Tertiary
Triphenamil 6.0rb

Carbamates, Quaternary
Dibutoline sulfate

Main Chain: Alkane, Quaternary


Hexocyclium methyl
sulfate
Isopropamide iodide 0.85rb
Mepiperphenidol 0.48g
Tricyclamol chloride 1.2g 2.3m
Trihexethyl chloride 2.17rb
Main Chain: Alkane, Tertiary
Aminopentamide 2.lrb
Benzhexol 3.7g 16m
Procyclidine 2% 31m
Methixene

Main Chain: Alkene, Quaternary


Diphemanil methyl 8.0g
sulfate
"No comparative studies of all anticholinergics in the same animal species or on the same test system are available. The above data were assembled or cross-calculated from
information reported in a number of sources; therefore the activities are relative and approximate. However, the information is useful to compare the available anticholinergic agents.
bAll quaternary salts are bromides, and all tertiary m i n e s are listed as hydrochlorides unless otherwise specified.
'The compounds were tested in different species. The following abbreviations are used to indicate the species: c, cat; d, dog; h, human; g, guinea pig; m, mouse; r, rat; rb, rabbit.
Values less than unity indicate that they are more active than atropine.
dAntisecretory activities are on salivation unless otherwise indicated. "a" after the species indicates inhibition of acid secretion.
'All antispasmodic activities are inhibition of the contraction of intestine using cholinomimetic as spasmogen.
fThe total dose includes the initial dose, as well as maintenance dose used orally (except dibutoline, which is administered subcutaneously) in man.
Anticholinergic Drugs

an effective drug in healing gastric and duode- 11 ANTICHOLINERGICS DEVELOPED FOR


nal ulcers. Anticholinergic drugs and antacids SPECIFIC USES
help to control symptoms, but they do not ac-
celerate healing. Promethazine, an antihista- Ipratropium (Atrovent) was first developed
minic inhibits the release of gastrin in the dog for the symptomatic treatment of obstructive
and humans (265). (bronchospastic) disease (268). It is a deriva-
Pepsin inhibitors, sulfated amylopectin tive of atropine. Two chemical features distin-
(Depepsin),and carrageenin decrease acid se- guish it from atropine: ( I ) an isopropyl group
cretion in experimental animals and protect replaces the N-methyl group of the atropine
animals against histamine-induced ulcers component; (2)the methyl quaternary group
(265). They have to be studied further ade- (as the second substituent on the N-atom)
points toward the pyrrolidine part of the ring
quately to ascertain their therapeutic useful-
system and occupies an equatorial position.
ness.
These structural features allow the Ipra-
Carbenoxolone and cimetidine are comple- tropium molecule to attain a relatively selec-
mentary in their contribution to the healing of tive bronchodilator effect on the cholinergi-
peptic ulcers, and the use of both may be bet- cally innervated airways. By the inhalation
ter than either singly for some patients. Car- route of application, this poorly absorbable
benoxolone accelerates healing by helping the quaternary ammonium derivative becomes se-
defense mechanisms of the body. It stimulates lective to primarily affect the airway smooth
extramucus secretion and prolongs cell life in muscle. Another advantage of ipratropium
the gastric epithelium. Cimetidine reduces over atropine is that, in contract to the latter,
gastric acid secretion. It would be interesting it does not suppress mucociliary function.
to know whether anticholinergic drugs are A novel series of N,N1-disubstituted6,7-di-
more effective for the treatment of peptic ul- azabicyclo-(3,2,2)-nonane derivatives were
cer in the presence of carbenoxolone. synthesized and pharmacologically tested
Carbenoxolone (Biogastrone, Duogas- (268). Compounds belonging to the 3-(uconfig-
trone) is the disodium salt of glycyrrhetinic uration were more potent than those of the
acid hemisuccinate. It is prepared by hydroly- 3-P configuration. The quaternary ammonium
sis of glycyrrhizic acid, a glycoside in licorice derivatives were also more potent than the
root. It increases the secretion of mucus and tertiary amines in this series. Ba 679 Br,
accelerates the healing of gastric ulcers. This tiotropium bromide, a new azoniatricyclo non-
drug is now under clinical investigation in the are derivative has shown potent bronchodila-
United States. tor activity that significantly outlasts that of
ipratropium (269-271). This special feature
Pharmacological doses of several prosta-
and its selectivity can be explained by its
glandins and their analongs inhibit gastric
slower dissociation rate from M1 and M3 than
acid secretion. 15-(R)-Methyl-PGE,, in small
from M2 muscarinic receptors. In patients
doses (100-200 pg, oral), reduces gastric acid with chronic obstructive pulmonary disease
secretion and output in humans and animals, (COPD) tiotropium is significantly more effec-
and it is currently being studied in the treat- tive than ipratropium. Several studies indi-
ment of peptic ulcer. cate that tiotropium is very useful for long-
Among the nonanticholinergic antispas- term maintenance treatment of patients with
modics, alverine citrate (Spacolin) and iso- airflow obstruction resulting from COPD.
metheptene (octin) hydrocholoride or mu-
cate are available on the market. They relax
smooth muscle by nonspecific actions. They 12 ACKNOWLEDGMENTS
exert little effect on gastric acid secretion.
They are most useful in the symptomatic The author is supported by USHHS-NIH Re-
treatment of gastrointestinal disorders char- search Grant DA-06207; The Council for To-
acterized by hypermotility and spasm. bacco Research, USA, Inc.; The Smokeless To-
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CHAPTER FOUR

CNS Stimulants
DAVID E. NICHOLS
Department of Medicinal Chemistry and
Molecular Pharmacology
School of Pharmacy and Pharmacal Sciences
Purdue University
West Lafayette, Indiana

Contents
1 Introduction, 168
1.1 Ephedra and Khat, 168
1.2 Caffeine, 169
2 History, 172
3 Clinical Use of Agents, 172
3.1 Therapeutic Applications, 172
3.1.1 Attention Deficit Hyperactivity
Disorder (ADHD), 172
3.1.2 Narcolepsy, 173
3.1.3 Use for Depression in Terminal Illness,
173
3.1.4 Use in Obesity, 173
3.1.5 Apnea in Premature Infants, 173
3.2 Side Effects, Adverse Effects,
and Drug Interactions, 174
3.2.1 Methylphenidate, 174
3.2.2 Pemoline, 174
3.2.3 Cocaine, 175
3.2.4 Caffeine, 176
3.3 Absorption, Distribution, Metabolism, and
Elimination, 176
3.3.1 Amphetamine Metabolism, 176
3.3.2 Methylphenidate Metabolism, 177
3.3.3 Cocaine Metabolism, 177
3.3.4 Diethylpropion Metabolism, 177
4 Physiology and Pharmacology, 179
4.1 Where and How These Drugs Work, 179
4.2 Biochemical Pharmacology: Receptor Types
and Actions, 180
4.2.1 A Role for Serotonin, 182
4.2.2 A Role for Norepinephrine, 183
5 Structure-Activity Relationships, 184
5.1 Amphetamine, 184
Burger's Medicinal Chemistry and Drug Discovery 5.1.1 Length of the Side-Chain, 185
Sixth Edition, Volume 6: Nervous System Agents 5.1.2 Nitrogen Substituents, 185
Edited by Donald J . Abraham 5.1.3 Stereochemistry a t the a! Carbon, 186
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 5.1.4 The a!-alkyl Substituent, 186
167
CNS Stimulants

5.1.5 Other Side-Chain Substitutions, 186 5.3.5 Substitutions on the Aromatic Ring at
5.1.6 Aromatic Ring Substitution, 187 Position 3, 191
5.2 Methylphenidate, 187 5.3.6 Requirement for the Intact Tropane
5.3 Cocaine, 188 Ring System, 192
5.3.1 N-substituents, 188 6 Recent and Future Developments, 192
5.3.2 Basic Nitrogen Atom, 189 6.1 Web Site Addresses and Recommended
5.3.3 Substituent at C(2),189 Reading, 194
5.3.4 The Ester Linkage at C(3),191

1 INTRODUCTION prescribed for appetite control, but they lose


efficacy rather quickly through the develop-
Natural products that have stimulant proper- ment of tolerance. Thus, it was not uncommon
ties have been known for millennia, and their for patients to become dependent on them,
active species (including ephedrine and co- with symptoms of withdrawal upon abrupt
caine) are now well known. Stimulants, also cessation. The increased awareness of the ad-
called psychostimulants, are drugs that lead to dictive potential of stimulants, coupled with
increased arousal, improved performance on their widespread abuse, has led to much more
tasks of vigilance and alertness, and a sense of extensive restrictions over their availability.
self-confidence and well-being. High doses can These drugs are much more carefully con-
produce feelings of elation or euphoria. Be- trolled today, and are rarely used for weight
cause of their ability to produce elation and control except in a few special instances.
euphoria, the stimulants have reinforcing There remain some important medical uses
properties and can lead to dependency. That for this class of drug, yet as noted later, the
is, because they make users feel "good," they therapeutic actions of psychostimulants must
are sometimes taken for extended periods of be balanced against their undesirable actions.
time in an attempt to maintain an elevated Issues of dependency, tolerance, and potential
mood. abuse must be considered when deciding
Tolerance develops to the mood-elevating whether treatment with a psychostimulant is
properties of psychostimulants, however, and an appropriate therapy. On the other hand,
more and more of the drug must be taken to new generations of drugs that have sprung
maintain the effect. Increased doses also pre- from an understanding of the classic stimu-
vent sleep, and continued use can result in lants may open important therapeutic hori-
symptoms of psychosis. Cessation of the drug zons for the future. Table 4.1 catalogs various
after one of these binges may lead to an emo- data on psychostimulant and anorexigenic
tional and physical "crash" (the result of poor preparations.
nutrition, lack of sleep, and increased physical
activity), and severely depressed mood. In de-
1.1 Ephedra and Khat
pendent individuals, craving for the drug oc-
curs, resulting in another period of extensive The Chinese drug ma huang (Ephedra sinica
drug use with the subsequent crash. This cycle Stapf) has been used in China for more than
is repeated in chronic psychostimulant depen- 5000 years. The alkaloid that is responsible for
dency. the CNS stimulant effects is ephedrine. The
Many central nervous system (CNS) stim- levorotatory erythro isomer (1)is the most ac-
ulants also have appetite-suppressant effects tive of the four possible stereoisomers with
that led to their use in treating obesity. In that structural formula. Khat (kat, or qat) or
short-term studies, amphetamine-like drugs Abyssinian tea (Catha edulis Forskal) is the
have been shown to be more effective than product from a small tree or shrub indigenous
placebo in promoting weight loss. Long-term to tropical East Africa. Khat leaves are chewed
(>20 weeks) weight loss has not been shown, habitually by peoples in East Africa and cer-
however, unless the drug is taken continu- tain other Arabian countries, and produce a
ously (1).At one time, stimulants were widely mild CNS stimulant effect (2). The principal
1 Introduction

active component in Khat is a substituted where it occurs to the extent of about 3.5%, by
phenethylamine derivative known as (-)- weight), of coffee beans (Coffea arabica, where
cathinone (2) (3). it constitutes about 1-2% by weight), and tea
(Camellia sinesis, where it makes up 1-4% of
the mass of dried leaves). The annual con-
sumption of caffeine has been estimated at
120 million kilograms, the approximate equiv-
alent of one caffeine-containing beverage per
day for each of the world's six billion plus in-
habitants. As a beverage, the worldwide con-
sumption of tea is surpassed only by water.
The structurally related dimethylxanthines,
theophylline (5) and theobromine (61, have
less of a CNS stimulant effect, and are princi-
pally important for their ability to relax
smooth muscle. Cocoa and chocolate have lit-
tle caffeine, but do contain theobromine.

Both of these compounds possess a p-phen-


ethylamine framework, a common structural
theme that occurs in many related CNS stim-
ulants. In general, these compounds have sim-
ilar mechanisms of action.
(-)-Cocaine (3) has a completely different
structure and, as we shall see later, its mech-
anism of action is also somewhat different
from the structurally simpler (1)and (2). Nev-
ertheless, all of these natural prototype CNS
stimulants have the common action of exert-
ing powerful effects on brain pathways that
utilize dopamine as the neurotransmitter.

1.2 Caffeine
From an economic standpoint, the most im-
portant CNS stimulant is caffeine (1,3,7-tri- A regular cup of coffee contains between 40
methylxanthine, 4). It occurs naturally and is and 176 mgof caffeine, with a mean content of
a product of kola (cola) nuts (Cola nitida, about 85 mg. Tea contains less caffeine, with
Table 4.1 Psychostimulant and Anorexigenic Preparations
Generic Name Dosea
(structure) Trade Name Originator Chemical Class (mgtday)
Psychostimulants
Cocaine HCl(3) Cocaine HCl powder Mallinckrodt Ecgonine methyl ester NA
benzoate
Amphetamine (7) Adderall Shire Richwood Phenethylamine 5-30 mg
Amphetamine Amphetamine sulfate Lannett 5 mg
sulfate (7)
Dextroamphetamine Dextroamphetamine sulfate Various 5-10 mg
sulfate (10)
d
4'
Dexedrine SmithKline-Beecham
0 Richwood
Dextrostat
Methamphetamine Desoxyn Abbott 5 mg
HCl(11)
Desoxyn Gradumet Abbott 5-10 mg
Methylphenidate Methylphenidate HC1 Various a-Phenyl-2-piperidineacetic 5-20 mg
HCl(8) acid methyl ester
Ritalin Ciba-Geigy
Methylin Mallinckrodt
Metadate ER Medeva 10 mg, ER
Concerta Alza 18 mg, ER
Modafinil(44) Provigil Cephalon Diphenylmethyl-sulfinyl-2- 100-200 mg
acetamide
Pemoline (9) Pemoline 2-Amino-5-phenyl- 18.75-75 mg
4(5H)oxazolone
Cylert Abbott
PemADD Mallinckrodt
Caffeine (4) Quick Pep; Caffedrine; NoDoz; Thompson; Thompson; Bristol-Myers; Trimethylxanthine 75-200 mg
Stay Awake; Vivarin; Stay Major; SK-Beecham; Apothecary;
Alert; Enerjets; Starbucks Chilton
Anorexiants
Benzphetamine (22) Didrex Upjohn Phenethylamine 25-50 mg
Diethylpropion (16) Diethylpropion various Phenethylamine 25-75 mg
Tenuate Aventis Phenethylamine
Phendimetrazine Phendimetrazine various Phenethylamine 35 mg
(21)
Bontril PDM Carnrick
Plegine Wyeth-Ayerst
Phendimetrazine various 105 mg, SR
Adipost Jones
Bontril Slow-Release Carnrick
Dital UAD
Dyrexan-OD Trimen
Melfiat-105 Unicelles Numark
Prelu-2 Boehringer-Ingelheim
Rexigen Forte ION Labs
Phentermine (19) Phentermine Various Phenethylamine
Ionamin Medeva
-.L Fastin SmithKline-Beecham
V Ion
d zantqd
Adipex-P Lemmon
Obe-Nix 30-P Holloway
Decongestants and
Bronchodilators
Ephedrine sulfate Pretz-D 0.25% spray Parnell Phenethylamine NA
(1)
Ephedrine sulfate West-Ward Phenethylamine 25 mg
Ephedrine sulfate Various Phenethylamine 50 mg/mL
aAdministered orally unless otherwise noted.
CNS Stimulants

an average of about 27 mg per cup, and an narcolepsy (7) and, by 1936, orally active
ounce of sweet chocolate typically contains be- Benzedrine tablets were available without
tween 75 and 150 mg of combined methylxan- prescription (8). By 1937 it was being used
thines (4). recreationally by the general population,
The reader should be aware that the use of with particular popularity among American
the term CNS stimulation encompasses sev- college students (9).
eral physiological mechanisms of action and It is not clear when or by whom metham-
many different types of biologically active phetamine was first synthesized. Various ac-
substances. A number of different agents, in- counts indicate its first preparation some-
cluding caffeine (see below), affect these phar- where between 1888 and 1934 (5). In any case,
macological mechanisms and cause CNS stim- Hauschild (10) published the first studies of
ulation. Other diverse examples include the pharmacology of methamphetamine in
strychnine (causing CNS stimulation by 1938, characterized its stimulant effects in an-
blockade of inhibitory glycine receptors) and imals, and also carried out a self-experiment.
benzodiazepine inverse agonists (causing CNS
stimulation by decreasing the inhibitory ef-
3 CLINICAL USE OF AGENTS
fects of GABA on inhibitory chloride chan-
nels). It is not the intent of this chapter to
3.1 Therapeutic Applications
provide an encyclopedic treatment of all the
possible substances that can cause "CNS stim- Psychostimulants generally increase the level
ulation," but rather to focus primarily on the of activity, alleviate fatigue, increase alert-
psychostimulants (i.e., drugs that affect brain ness, and elevate mood (or cause euphoria in
monoaminergic systems). high doses). Unfortunately, the ability to pro-
duce euphoria leads these compounds to have
a high potential for abuse and dependency.
2 HISTORY The principal clinical indications for psycho-
stimulants are in the treatment of attention
The historical development of amphetamine deficit hyperactivity disorder (ADHD) and the
and methamphetamine is described in inter- sleep disorder known as narcolepsy. A less
esting detail by Angrist and Sudilovsky (5). commonly recognized use, but one that' is
The discovery of psychostimulants differs gaining importance, is in the treatment of de-
somewhat from the usual drug discovery pro- pression in terminal patients or the chroni-
cess because there was a long folkloric history cally ill (11-13). There is also need for psycho-
of the use of khat, coca leaves, and ma huang stimulants in certain occupations (e.g., in the
(ephedra). Although there may not have been military), as a countermeasure to fatigue from
a formal pharmacologicalclassification of CNS irregular or prolonged work hours, where a
stimulants at that time, the ability " of these high level of vigilance and alertness must be
agents to alleviate fatigue was well recog- maintained (14, 15). Some specific clinical ap-
nized. plications include the following.
Amphetamine itself was synthesized in
1887 and first studied as early as 1910, but its 3.1 .I Attention Deficit Hyperactivity Disor-
stimulant effects were not discovered until der (ADHD). ADHD is a diagnosis applied
about 1930. Amphetamine was independently mostly to children, but one that persists into
resynthesized in 1927 by the noted psycho- adulthood for many people. It is reflected in a
pharmacologist Gordon Alles in a program to persistent pattern of inattention and/or hy-
develop synthetic substitutes for ephedrine, a peractivity-impulsivity that is more frequent
drug then being used as a bronchodilator for and severe than typically observed in individ-
the treatment of asthma (6).
. . The central stim- uals at a comparable level of development (16).
ulant effects of amphetamine were probably Inattention prevents ADHD patients from
noted about 1930, when it appeared in nasal keeping their mind on one thing and focusing
inhalers in Germany. The first medical use their attention; they are easily bored with a
for amphetamine was in the treatment of task after only a short while. They have no
3 Clinical Use of Agents

difficulty devoting attention to activities that that may occur without warning and are often
they enjoy, but find it hard to focus conscious irresistible. Another hallmark symptom of
attention to organizing or completing a task, narcolepsy is cataplexy, which is a sudden loss
or learning something new. They may forget of voluntary muscle control, often triggered by
to plan ahead and tasks are rarely completed, emotions such as laughter or surprise. Cata-
or are filled with errors. plexy occurs more frequently during stress or
Children with ADHD (particularly of fatigue. The attack may involve only a feeling
school age) have great difficulty being still, of weakness and limp muscles or it may result
they may be in and out of their seats, and talk in total muscular collapse, during which the
incessantly. The inability to focus makes person can appear unconscious, but actually
learning tasks boring, and exacerbates the de- remains awake and alert. Attacks may be very
sire to move around and become involved in brief or may last for tens of minutes. Another
distractions. ADHD children may squirm, characteristic symptom of narcolepsy is hyp-
shake their legs, touch everything, or make nagogic hallucinations. These are vivid, realis-
distracting noises. Hyperactive teens and tic, and often frightening, reminiscent of
adults may feel intensely restless, and may try nightmares, and are usually accompanied by
to do several things at once, going from one sleep paralysis, a temporary inability to move.
activity to the next. Impulsivity is another Whereas the psychostimulants can have a
characteristic of ADHD, with patients often beneficial effect, they are likely to be sup-
acting without thinking about the conse- planted by newer drugs that are more specific
quences. They may have difficulty curbing and have fewer side effects.
their immediate reactions to situations, mak-
ing inappropriate remarks without thinking 3.1.3 Use for Depression in Terminal 111-
what they are saying. They find it hard to wait ness. Although this indication for psycho-
for things they want or to wait to take their stimulants is not as widely recognized, agents
turn. such as amphetamine and methylphenidate
In normal subjects, psychostimulants can are preferred because they do not suffer from
increase activity and talkativeness, especially the weeks-long delay in onset of action that is
at higher doses. Paradoxically, in ADHD suf- characteristic of traditional antidepressant
ferers, stimulants appear to have a calming medications. Thus, a rapid antidepressant re-
effect, and allow an increased focus and atten- sponse can be achieved in severely ill patients,
tion to tasks. Although appearing paradoxical, who in some cases may not survive long
it is now believed that the decreases in activity enough for a traditional antidepressant medi-
in ADHD are secondary to improvements in cation to begin to have an effect (11, 17-19).
attention. This beneficial effect of low doses of
the stimulants has led to a large number of 3.1.4 Use in Obesity. As noted earlier,
children being prescribed methylphenidate many of the psychostimulants have also been
(Ritalin) or various amphetamine prepara- used as anorectics (anorexics; anorexigenics),
tions for the treatment of ADHD. This, in that is, as appetite suppressants. A few of
turn, led to great concern about the fact that them are still useful in this regard, but the
these drugs were overprescribed for ADHD, high abuse potential of psychostimulants, cou-
and that children who are merely highly ener- pled with the development of tolerance to
getic were routinely being given them for be- their anorectic effects, has meant that pre-
havior management. The reader should be scribing psychostimulants for weight control
aware of this social issue, but it requires no has generally fallen into disfavor.
further comment in the context of this chap-
ter. 3.1.5 Apnea in Premature Infants. Apnea of
prematurity (AOP) occurs in about 90% of
3.1.2 Narcolepsy. Narcolepsy is a condi- premature neonates weighing less than 1 kg
tion that includes as its predominant symp- at birth, and in 25% of infants with a weight of
tom, excessive daytime sleepiness (EDS), per- less than 2.5 kg (20). The first-line pharmaco-
sistent drowsiness, and daytime sleep attacks logical therapies for the management of AOP,
CNS Stimulants

to stimulate respiration, are the methylxan- been recently discussed extensively by Angrist
thines, with theophylline (5) presently being (27). Interestingly, psychostimulants can in-
most extensively used. Recent studies suggest, duce a psychotogenic response in schizophren-
however, that caffeine (4) should be consid- ics, in doses that are subpsychotogenic in nor-
ered the drug of choice because of similar effi- mal subjects, and methylphenidate was found
cacy, longer half-life, fewer adverse effects, to have greater potency in this regard (28).
and better brain penetration than that of the- Activation of psychotic symptoms by methyl-
ophylline (21). phenidate was found to be a predictor of risk of
relapse (29). These, and other studies, are all
3.2 Side Effects, Adverse Effects, consistent with the dopamine hypothesis of
and Drug Interactions schizophrenia.
Generally, psychostimulants like amphet-
3.2.1 Methylphenidate. Methylphenidate
amine (7) and methylphenidate (8) can be
(Ritalin, 8) is widely prescribed for the treat-
used safely with most classes of medications
ment of ADHD. Approximately 90% of chil-
and with few contraindications (22). The
dren treated for ADHD are given methyl-
acute adverse reactions to stimulants can gen-
phenidate (30), representing about 2.8% of all
erally be understood from the perspective of
U.S. children aged 5-18 years (31). It is both
their pharmacology. Psychostimulants act as
well tolerated and efficacious in the treatment
indirect sympathomimetic agents; they either
of attention deficit hyperactivity disorder, and
directly release stored catecholamines, includ-
is associated with few serious adverse effects
ing those in peripheral adrenergic neurons re-
(32). Although there are rare reports of drug
sponsible for vascular tone, or else block their
interactions between methylphenidate and
reuptake. These actions affect the cardiovas-
certain other drugs, they are so infrequent
cular system in fairly predictable ways. In ad-
that there is no consistent pattern that can be
dition, cocaine produces a local anesthetic ef-
identified. Toxic concerns with methylpheni-
fect by the blockade of sodium channels (23).
date would principally revolve around the
Although this would normally be the pharma-
abuse of this drug to obtain a stimulant high,
cological basis for a class I antiarrhythmic
and the consequent possibility of developing
drug, it paradoxically induces proarrhythmia
dependency. A further concern with the long-
(24). term use of methylphenidate is the possibility
that patients may be at increased risk for psy-
chostimulant abuse. Although when taken
orally methylphenidate has a low euphori-
genic potential (33), when used intravenously
it has an abuse pattern and symptoms of tox-
icity similar to those of cocaine and amphet-
amine (34).
. . Recent studies in rats have also
In addition to acute effects, however, pro- shown that animals treated with methyl-
longed usage of amphetamines (and other psy- phenidate develop behavioral sensitization,
chostimulants) can produce an "amphetamine suggesting that human users may have in-
psychosis." This syndrome was first clearly creased susceptibility to psychostimulant
documented by Connell(25)and is regarded as abuse (35).
very similar to paranoid schizophrenia, char-
acterized by "paranoid psychosis with ideas of 3.2.2 Pemoline. Pemoline (91, an agent
reference, delusions of persecution, auditory used in treatment of ADHD, has been associ-
and visual hallucinations in a setting of clear ated with hepatotoxicity, with the majority of
consciousness" (25). The psychosis clears cases occurring in pediatric patients. From its
quickly after the drug is withdrawn. Psychosis marketing in 1975 up to 1989, 12 cases of
has been induced experimentally in normal acute hepatic failure and six deaths associated
subjects by continuous amphetamine admin- with pemoline hepatotoxicity had been re-
istration (26). Amphetamine psychosis has ported to the FDA (36). Death generally oc-
3 Clinical Use of Agents

(41, respectively, serve as the raw material for


the production of (-)-cocaine (3). The latter
was first isolated in 1860 and became medi-
cally important as an excellent local anes-
thetic agent, but one that is a potent and
highly addictive CNS stimulant. The acute
toxicity of cocaine derives primarily from its
intense sympathomimetic actions. In 1991 an
attempt was made to assess the intrinsic tox-
icity of cocaine by computing the incidence of
curred within 4 weeks of the onset of signs and adverse health outcomes per population of
symptoms of liver failure. In two recent cases, drug abusers. The rates of emergency depart-
pemoline-induced liver failure required liver ment visits and deaths were estimated at 15.1
transplantation (37). and 0.5, respectively, per 1000 persons using
drugs (40).
Cocaine can have marked effects on the
heart and cardiovascular system. Adverse ac-
tions may include myocardial ischemia, car-
diac arrhythmias, cardiotoxicity, hypertensive
effects, cerebrovascular events, and a hyperco-
agulable state (24,40). By 1997 more than 250
cases of mvocardial
" infarction related to the
recreational use of cocaine had been docu-
mented in the literature (41). Although less
common, aortic dissection related to use of co-
Although the absolute number of reported caine-free base ("crack cocaine") has also been
cases is not large, the rate of reporting is 4-17 documented (42). Seizures also can be associ-
times higher than that expected in the general ated with cocaine use (43).
population. This estimate may be conservative Acutely, cocaine can cause anxiety or panic
because of underreporting and because the reactions. Used chronically, cocaine can in:
long latency between initiation of pemoline duce a psychosis that closely resembles that
treatment and the occurrence of hepatic fail- produced by amphetamine. It is generally con-
ure may limit recognition of the association. If sidered that amphetamine psychosis predom-
only a portion of actual cases was recognized inantly mimics the positive symptoms of
and reported, the risk could be substantially schizophrenia, but in fact stimulant-induced
higher. By contrast, a meta-analysis of the lit- psychosis can mimic a broad range of symp-
erature by Shevell and Schreiber (38)suggests toms, including negative and bizarre symp-
that the risk of acute hepatic failure may be an toms (44). Paranoid behavior has been pro-
overestimate. Nevertheless, because of its as- duced in experienced cocaine users by
sociation with life-threatening hepatic failure, continuous (4 h) cocaine infusion (45).
pemoline should not ordinarily be considered In addition to these physiological toxicities,
as a first-line therapy for ADHD. In fact, cocaine addicts suffer from a variety of social
pemoline has been withdrawn from the Cana- and economic problems that result in tremen-
dian market as a result of this toxicity (39). dous costs to society. Many of the estimated
1.5 million cocaine addicts in the United
3.2.3 Cocaine. The coca plant is a small States (see http://www.nida.nih.gov), are un-
shrub or tree that is indigenous to South deremployed, and if they are employed at all,
America, where for centuries the leaves have they are likely to be involved in drug distribu-
been chewed by the local native populations. tion activities, and typically perform marginal
The dried leaves of Eythroxylum coca roles in the legal economic system (46, 47).
Lamarck, or E. truxillense Rusby, commer- Adults in such drug-using households rarely
cially known as Huanuco coca, or Truxillo coca engage in conventional behaviors, and often
CNS Stimulants

parent children by using conduct norms that correspond to functional antagonism of this
are structured to produce individuals who receptor, similar to the effects of caffeine (57).
have reduced chances to become conventional 3.3 Absorption, Distribution, Metabolism,
adults (48). and Elimination
3.2.4 Caffeine. The psychostimulant ac- All substituted amphetamines are strong or-
tion of caffeine generally is accepted as well ganic bases, with pKa values ranging from 9.5
established. Caffeine quickens reaction time to 10 (58). The pKa of both cocaine and phen-
and enhances vigilance, increases self-rated metrazine is somewhat lower, at 8.5, and
alertness, and improves mood. There is, how- methylphenidate has a pK, of 8.8 (58). Thus,
ever, little unequivocal evidence to show that these bases are all significantly protonated at
physiological pH. Binding to their biological
regular caffeine use is likely to benefit sub-
targets also probably occurs with the proton-
stantially either mood or performance. In-
ated species [e.g., (5911. These drugs are all
deed, one of the significant factors motivating
administered as their water-soluble salts, usu-
caffeine consumption appears to be "with- ally as hydrochlorides or sulfates. At physio-
drawal relief" (49). logical pH, of course, these bases exist in an
Caffeine can produce adverse and unpleas- equilibrium between the protonated ionized
ant effects if doses are increased. Caffeine has form and the unprotonated un-ionized spe-
weak reinforcing properties, but with little or cies. The latter free bases are relatively lipid
no evidence for upward dose adjustment, pos- soluble and readily penetrate the brain, where
sibly because of the adverse effects of higher they exert their CNS stimulant effects. Many
doses. Withdrawal symptoms, although rela- of these drugs are eliminated in the urine un-
tively limited with respect to severity, do oc- changed because acidic urine leads to a higher
cur, and may contribute to continued caffeine fraction of protonated species, thus decreasing
consumption (50). Health hazards are small if reabsorption of the unchanged drug in the re-
any, and caffeine use is not associated with nal tubules. Decreasing urinary pH by, for ex-
incapacitation (51). Acute intake of caffeine ample, administering ammonium chloride
increases blood pressure, with the strongest leads to the anticipated increased urinary ex-
pressor response in hypertensive subjects. cretion and reduced duration of action (60). A.
Some studies with repeated administration of comparison has been reported of the urinary
caffeine have shown a persistent pressor ef- excretion pattern of methamphetamine in hu-
fect, whereas in others chronic caffeine inges- mans, guinea pig, and rat (61). In humans,
tion did not increase blood pressure (52). 23% of the dose was excreted unchanged.
Epidemiologic studies have produced contra- Ring-hydroxylated and N-demethylated me-
dictory findings regarding the association be- tabolites were excreted as 18 and 14%of the
tween blood pressure and coffee consumption. dose, respectively.
Duringregular use, tolerance to the cardiovas-
cular responses develops in some people, and 3.3.1 Amphetamine Metabolism. The me-
therefore no systematic elevation of blood tabolism of (+)-amphetamine (10)is variable,
pressure can be shown either in long-term or depending on the species studied. Possible
in population studies. Thus, regular caffeine metabolic transformations involve hydroxyl-
consumption may be harmful to some hyper- ation at the a or p side-chain carbon atoms,
tension-prone subjects (52). The hemody- the nitrogen atom, and thepara position ofthe
namic effects of chronic coffee and caffeine aromatic ring. These metabolites would then
consumption have not been sufficiently be further oxidized, or conjugated and ex-
studied. creted. One or more of these pathways pre-
Finally, caffeine may provoke a panic at- dominates, depending on which animal spe-
tack in individuals who suffer from panic or cies is being studied. In humans, the half-life
anxiety disorders (5356). Recently, an aden- of (+)-amphetamine has been reported as 7 h
osine &, receptor knockout mouse has been (62). About 30% of the dose of racemic am-
developed that has behavioral symptoms that phetamine is excreted unchanged, and acidifi-
3 Clinical Use of Agents

cation of the urine can decrease the half-life methylphenidate to between 10% and 50%
significantly (63,641.In humans, the principal (68). Ritalinic acid is not pharmacologically ac-
metabolite is benzoic acid (65). The details of tive. A ring-hydroxylated ritalinic acid metab-
the sequences of metabolic reactions of am- olite (2%) has also been identified. Other mi-
phetamine that lead to benzoic acid have not nor pathways involving oxidation of the
been elucidated (62), but the P-hydroxylated piperidine ring (0x0-ritalin) and conjugation
metabolite, norephedrine, has also been iden- reactions represent less than about 1%of the
tified as a metabolite in humans (66). administered dose (30).
The metabolism of methamphetamine (11)
involves both N-demethylation and ring hy- 3.3.3 Cocaine Metabolism. Because co-
droxylation. Caldwell et al. (61) reported that caine (3)has two ester functions, both can be
23% of the administered dose was excreted as hydrolyzed in vivo to generate metabolites.
unchanged drug, 18% as the 4-hydroxylated Hydrolysis of the methyl ester leads to benzo-
compound, and 14% as the N-demethylated ylecgonine (12), and hydrolysis of the benzoyl
amphetamine. ester leads to ecgonine methyl ester (13). Tro-
pan-3P-01-2P-carboxylicacid is known as ecgo-
3.3.2 Methylphenidate Metabolism. The me- nine (14). In cocaine users who also consume
tabolism and pharmacokinetics of methyl- significant amounts of ethanol, a transesteri-
phenidate have been studied extensively. fication product (cocaethylene, 15) is also de-
Methylphenidate (8)is administered as the ra- tected. Cocaethylene is also a potent psycho-
cemic threo isomer, but the (-)-threo enantio- stimulant, with about four times higher
mer is more rapidly metabolized. potency as a local anesthetic than that of co-
Methylphenidate is an ester, and the caine itself (69),and can enhance the cardio-
methyl ester is rapidly cleaved. The ester hy- toxicity associated with cocaine use.
drolysis product, called ritalinic acid, com-
prises about 80% of the urinary metabolites 3.3.4 Diethylpropion Metabolism. Diethyl-
after an orally administered dose (67). The la- propion (16) is used most extensively as an
bility of the ester function is probably the ma- appetite suppressant. It possesses the core
jor factor limiting the oral bioavailability of phenethylamine structure characteristic of
CNS Stimulants

many psychostimulants, but is a tertiary arni- apparently N-dealkylated readily and, thus,
noketone. It is extensively metabolized in hu- the principal metabolite is the N-deethylated
mans, with only about 3-4% of the drug ex- compound (17),constituting about 35%of the
creted unchanged. a-Alkylaminoketones are administered dose. Reduction of the carbonyl
4 Physiology and Pharmacology

is less important, with about 20% of the dose begun to focus attention on glutamate sys-
going that route, to afford N,N-diethyl- tems as potential key components of the ac-
norephedrine. About 30% of the dose cannot tions of psychostimulants. For example,
be accounted for as an amine product in the Swanson et al. (79) have shown that re-
urine and is probably a deaminated metabolite peated cocaine administration leads to long-
(70).Studies by Yu et al. (71) found that the term attenuation of group I metabotropic
N-deethylated metabolite (17) was probably glutamate receptor function in the nucleus
responsible for the pharmacological effects of accumbens. In particular, this functional re-
diethylpropion (16). These workers reported duction was related to significantly reduced
that the N-monoethyl metabolite (17) was a mGluR5 immunoreactivity in the medial nu-
substrate at the norepinephrine and serotonin
cleus accumbens. Even more exciting is the
transporters and an inhibitor at the dopamine
recent report that mGluR5 knockout mice
uptake transporter, whereas (1R,2S) and
(1S,2R)-N,N-diethylnorephedrine as well as do not display the reinforcing and locomotor
diethylpropion itself were inactive in those as- effects of cocaine, in spite of the fact that
says. cocaine administration increases extracellu-
lar dopamine in the nucleus accumbens of
these mice to levels that do not differ from
4 PHYSIOLOGY A N D PHARMACOLOGY those of wild-type animals (80).In the near
future, the role of glutamate systems in the
4.1 Where and How These Drugs Work
actions of psychostimulants will no doubt be
Neurons in the central nervous system com- more fully elucidated, resulting in new ap-
municate by chemical transmission. Of rele- proaches to the treatment of conditions that
vance to the present discussion are mono- now respond to classical stimulants.
amine neurons that release dopamine, There are two principal mechanisms for in-
norepinephrine, or serotonin as one of their creasing synaptic monoamine levels. One is to
transmitters in response to an action poten- block the reuptake of neurotransmitter after
tial. Reuptake transporter proteins embedded its excitation-coupled release from the neuro-
in the neuronal plasma membrane then clear nal terminal. Thus, blocking the action of the
the synapse of monoarnines, typically taking uptake carrier protein prevents clearance of
up 70-80% of the released transmitter. This the neurotransmitter from the synapse, leav-
reuptake is thought to be the major termina- ing high concentrations in the synaptic cleft
tion mechanism for the monoamine chemical that can continue to exert a signaling effect.
signaling process. This mechanism is the one invoked to explain
All psychostimulants appear to elevate the action of cocaine, a potent inhibitor of
synaptic levels of dopamine and norepineph- monoamine reuptake at the dopamine, seroto-
rine. In addition, cocaine and, to a lesser ex- nin, and norepinephrine transporters, and of
tent, some of the other agents also raise syn- methylphenidate, which is a reuptake inhibi-
aptic levels of serotonin. It is the current tor at the dopamine and norepinephrine
consensus that elevated dopamine levels transporters (81).It should be noted, however,
lead to CNS stimulation and are responsible that methylphenidate also has the ability to
for the reinforcing properties of stimulants induce the release of catecholamines stored in
(72-78). Nevertheless, recent studies have neuronal vesicles (82,83).
180 CNS Stimulants

Figure 4.1. Amphetamine interacts with the dopamine transporter protein (1)and is transported
inside. Na+ and C1- are cotransported, and Kf is countertransported in the process. After being
transported inside the terminal, high concentrations of amphetamine can displace dopamine from
vesicular storage sites (2),leading to elevated cytoplasmic levels of dopamine (3).After amphetamine
dissociates on the intraneuronal surface, dopamine binds to the carrier (4). The carrier then trans-
ports dopamine to the extracellular face (5), driven by the favorable concentration gradient, where
the dopamine dissociates and leaves the carrier available for another cycle.

The second mechanism is the one more rel- uptake. Not surprisingly, cocaine and amphet-
evant to the action of amphetamine and re- amines have effects on the cardiovascular
lated agents. This mechanism is illustrated in system, by virtue of their ability to enhance
Fig. 4.1. Amphetamine, and other small mo- indirect adrenergic transmission at peripheral
lecular weight compounds with similar struc- sites. Knowledge of the physiology of the sym-
tures, are substrates at the monoamine up- pathetic nervous system and the functions of
take carriers and are transported into the peripheral adrenergic nerve terminals allows
neuron. The uptake carrier has an extracellu- a relatively straightforward prediction of the
lar and intracellular face, and after transport- types of drug effects possessed by monoamine
ing a substrate (amphetamine, etc.) into the uptake inhibitors or releasing agents.
neuron, the intracellular carrier face can bind
to dopamine and transport it back to the ex- 4.2 Biochemical Pharmacology: Receptor
tracellular face. This exchange diffusion Types and Actions
mechanism is calcium independent, and is ca-
pable of robustly increasing synaptic trans- The monoamine reuptake carrier proteins
mitter levels. This process is often described (targets of the psychostimulants) are mem-
as a "reversal" of the normal uptake carrier bers of a larger Nat/C1- transporter family
process. that includes a number of other proteins, in-
Whereas the CNS stimulant effects of these cluding the GABA transporters, amino acid
molecules depend on an action in the brain, transporters, and orphan transporters (84).
uptake inhibitors and substrates at peripheral The primary amino acid sequence of the
monoamine carrier sites can obviously exert monoamine transporters is highly conserved,
other physiological effects. Cocaine is an excel- with several regions of these proteins having
lent local anesthetic agent. Furthermore, its high homology. It is presently believed that all
potent inhibition of norepinephrine reuptake of the members of this family possess a mem-
leads to stimulation of a-adrenergic receptors, brane-spanning 12 a-helix motif, with a single
causing local vasoconstriction that delays the large loop containing glycosylation sites on the
diffusion of the anesthetic agent out of the tis- external face of the membrane (Fig. 4.2).
sue. Similarly, users who chronically insuf- Members of this family of proteins have been
flate cocaine into their nasal passages often identified not only in mammalian species, but
develop necrotic lesions as a result of the local also in eubacteria and archaebacteria, indicat-
vasoconstricting effect of cocaine, again aris- ing their very early emergence in the evolution
ing from the blockade of norepinephrine re- of life.
gy and Pharmacology 181

Inside
-e 4.2. Representation of the 12-helix transmembrane transporter protein family. Both the
I- and the carboxyl-terminus are intracellular, with the second extracellular loop being larger,

messing glycosylation sites. [Adapted from Nelson (84).1

uman norepinephrine uptake trans- stimulant drug of interest. The imaging tech-
1s first sequenced and then expressed nique then is used to determine how much of
cells in 1991 (85) and found to have the labeled ligand has been displaced from its
IS identical to those of the native receptors by competition from increased ex-
ber. The cloning and sequencing of tracellular endogenous dopamine. Based on
nine transporter (86-88) and the se- the known affinity of the labeled ligand for its
ransporter (89, 90) were reported in dopamine receptor, calculations can be used to
year. There are a number of excel- determine the increased concentration of do-
!w articles written about monoamine pamine that must have been available at the
;ers (84, 91-93). receptors. These definitive studies have
lacological studies of the mechanism clearly established a role for dopamine in the
For psychostimulants in animals have effects of stimulants in humans (72, 74).
liformly pointed to the importance of This type of approach has recently been ap-
pathways for the increases of loco- plied to the study of methylphenidate. For ex-
tivity and reinforcing properties (94, ample, Booij et al. (96) used SPECT imaging
:onclusions of those studies have gen- and an [1231]benzamidedopamine D, receptor
!n extrapolated to humans, with little ligand antagonist ([123111BZM)to measure sig-
vidence until recently to clearly sup- nificant displacement of the ligand by endoge-
e ideas. In the past several years how- nous dopamine that had been released in re-
ical studies of several stimulants, us- sponse to administration of methylphenidate.
yo brain imaging either with single In related work, Volkow et al. (74) used [llC]-
lission computed tomography (SPECT), (+I-threo-methylphenidateto show that greater
)n emission tomography (PET) tech- than 80% occupancy of the dopamine trans-
lave provided evidence for elevated porter was required to produce the stimulant
~ l adopamine
r in response to psycho- "high." With the dopamine D, receptor antag-
t administration. In essence, these onist [llClraclopride, Volkow et al. (97, 98)
!mploy either a single photon- or showed that the intensity of the methylpheni-
emitting dopamine receptor antago- date "high" was quantitatively correlated
labeled antagonist is administered with the levels of released dopamine and dopa-
ie absence and in the presence of the mine D, receptor occupancy. Subjects who
CNS Stimulants

perceived the most intense high had the high- postsynaptic receptor isoforms that are impor-
est increases in extracellular dopamine. Con- tant in the various actions of psychostimu-
versely, no high was experienced by subjects lants.
when methylphenidate did not increase dopa-
mine levels. In a second study, using the same 4.2.1 A Role for Serotonin. Although the
methodology, this same group (99) found that conventional wisdom is that stimulants ele-
subjects who "liked" the effects of methyl- vate synaptic dopamine, it is not at all clear
phenidate had significantly lower dopamine that this sole mechanism is responsible for the
D, receptor levels than those of subjects who spectrum of effects seen with the psycho-
disliked its effects. The authors speculated stimulants. In addition, it is becoming evident
that lower D, receptor density might be a fac- that animal models used to understand the
stimulants must consider mechanisms under-
tor contributing to psychostimulant abuse, by
lying effects on locomotor activity somewhat
providing a more pleasurable response. These
differently from those that govern either re-
imaging studies illustrate how data from ani-
ward or drug discrimination phenomena (101,
mal research can now be validated in humans. 102). The use of mice genetically deficient for
Because the stimulants cause increased the serotonin or dopamine transporter
synaptic levels of dopamine, and other mono- ("knockout mice") has produced some partic-
amine neurotransmitters, they indirectly lead ularly interesting findings. For example,
to stimulation of various postsynaptic recep- knockout mice lacking the DA transporter
tors, through the increased concentrations of have high levels of extracellular dopamine, a
neurotransmitter. A large number of animal condition that would presumably mimic the
studies have been reported that used various pharmacological action of cocaine and display
agonists and antagonists to elucidate the role spontaneous hyperlocomotion (103). Surpris-
of different dopamine receptor isoforms. Until ingly, these mice still self-administered co-
recently, however, only nonspecific ligands caine (104). Further experiments in these
(i.e., with effects on both the Dl-like and D,- mice indicated the probable involvement of
like families) were available. In drug discrim- the serotonin transporter. In addition, condi-
ination studies, rats have been trained to rec- tioned place preference, another animal model
ognize and discriminate the interoceptive cue of the reinforcing quality of a drug, could be
produced by injection of amphetamine or co- established for cocaine in mice lacking either
caine (100). Administration of a partial but the dopamine transporter or the serotonin
selective Dl-receptor agonist SKF 38393 was transporter (105). Place preference could also
partially recognized by these cocaine-trained be established for methylphenidate, another
stimulant that is thought to work through do-
rats, but not by amphetamine-trained ani-
pamine mechanisms, in mice lacking the dopa-
mals. Yet, both amphetamine- and cocaine-
mine transporter.
trained rats discriminated the cue produced
Experiments with knockout mice often
by a dopamine D, agonist bromocriptine as produce unexpected results. It must be kept in
being similar to their training drugs. A dopa- mind, however, that when a key protein is
mine D,-selective agonist produced cocaine re- missing during neural development, the off-
sponses, but was only partially recognized by spring often have some type of adaptation that
amphetamine-trained rats. Following addi- is not seen in the wild-type organism. Some
tional experiments with dopamine receptor caution, therefore, must be exercised in inter-
subtype selective antagonists, the authors preting the results. For example, Belzung et
concluded that the dopamine D, receptor al. (106) found that mice lacking the serotonin
played an essential role, but that both the Dl 5-HT,, receptor failed to display conditioned
and D, receptors might have some less impor- place preference. However, when these knock-
tant function. There is an extensive present out mice were compared in studies using clas-
research effort under way in many labora- sical pharmacological antagonists of the
tories that is attempting to elucidate both 5-HT,, receptor, divergent results were ob-
the anatomical substrates and the specific tained. The 5-HT,, receptor knockout mice
4 Physiology and Pharmacology

had an increased locomotor response and in- their ability to release NE, and not DA. Fur-
creased propensity to self-administer cocaine ther, their ranking in subjective effects did not
(107). By contrast, a 5-HT,, receptor antago- correlate with decreased plasma prolactin, a
nist attenuated cocaine-induced locomotor ef- response that is mediated by dopamine recep-
fects but had no effect on cocaine self-admin- tor stimulation. These authors suggested that
istration (108). The authors point out that NE might contribute to the amphetamine-like
compensatory changes during development of psychopharmacology of stimulants, at least in
the knockout mice may have rendered them humans.
more vulnerable to the effects of cocaine. In a related vein, the subjective psycho-
Nonetheless, there is a vast body of litera- stimulant effects of amphetamine were atten-
ture documenting interactions between dopa- uated following a 2-h pretreatment with a ty-
mine and serotonin pathways in the brain rosine- and phenylalanine-free amino acid
(109-111). Clearly, however, if a drug (e.g., mixture (118).These amino acids are biosyn-
cocaine) releases multiple transmitters, then a thetic precursors of the catecholamines, and
behavioral interaction is not surprising. Inhi- deprivation would be expected to produce
bition of presynaptic reuptake of serotonin, transient reductions in endogenous dopamine
for example, could lead to postsynaptic activa- and norepinephrine. The authors concluded
tion of a variety of other receptors, some of that tyrosine depletion attenuates the release
which could modulate dopamine function. In of dopamine required for the psychostimulant
addition to potential effects on 5-HT,, recep- effect. Interestingly, the pretreatment did not
tors, other studies have implicated serotonin reduce the subjective appetite-suppressant
5-HT, receptors (112), 5-HT,, receptors (anorectic) effect of amphetamine. The study
(113),and 5-HT,, receptors (114). 5-HT,, re- authors attributed this latter finding to a con-
ceptors can also modulate the locomotor ef- tinued release of norepinephrine by amphet-
fects of cocaine (115). amine. Tyrosine depletion, however, would
also attenuate norepinephrine biosynthesis
4.2.2 A Role for Norepinephrine. Although and it may be more reasonable to conclude
the vast majority of studies of psychostimu- that the anorectic effect might be related to
lants have focused on the role of dopamine the often-overlooked ability of amphetamine
andlor serotonin, the importance of norepi- to release neuronal serotonin.
nephrine (thought to be paramount 30 years This chapter makes no attempt to review
ago) is generally now overlooked. Details of all the literature that focuses on the role of
the mechanism of action of psychostimulants norepinephrine and serotonin in the actions of
have been developed primarily through the psychostimulants. At the time of this writing,
use of animal models, in which dopamine the general consensus seems to be that effects
seems to be the key player, and these results on dopamine systems are necessary, but per-
then have been extrapolated to humans. Yet, haps not sufficient, conditions to explain all
cocaine also is a potent NE uptake inhibitor, the different actions of stimulants. There ap-
and the potency of amphetamine for norepi- pears to be increasing awareness, spurred ini-
nephrine release is similar to that for dopa- tially by studies of cocaine, that serotonin may
mine release. Indeed, in the rat prefrontal cor- be a much more important player than was
tex, amphetamine and cocaine increased heretofore recognized. In the next few years
extracellular norepinephrine to an extent that this role likely will be studied and elucidated
was quantitatively similar to that of dopamine in much greater detail.
(116).Further, it appeared that the increase in The role of norepinephrine in the actions of
prefrontal cortical norepinephrine was actu- stimulants has largely been overlooked, al-
ally attributable to the blockade of the norepi- though a few studies suggest that this trans-
nephrine transporter by both drugs. Recently, mitter may be of major significance. On the
Rothman et al. (117) reported that the oral other hand, until clinical studies are carried
doses of several stimulants required to pro- out using receptor blockers and specific nor-
duce amphetamine-like subjective effects in epinephrine transporter inhibitors, this area
humans were most closely correlated with will remain muddy, at best. In virtually every
CNS Stimulants

example, from amphetamine to cocaine, the of locomotor activity in animal models, studies
compounds have significant effects at the nor- have implicated the dopamine D, receptor
epinephrine transporter, in some cases equal (129, 130). It has not been clear, however,
to, or even greater than, those at the dopamine whether effects mediated by striatal adeno-
transporter. When behavioral or mood changes sine &, receptors absolutely depend on the
are correlated with levels of extracellular do- presence of dopamine D, receptors. To study
pamine, and dopamine is highly correlated this problem, Chen et al. (131) employed ge-
with changes in extracellular norepinephrine, netic knockout mice deficient either in dopa-
one cannot be certain which underlying phar- mine D, receptors or adenosine &, receptors,
macology is ultimately more important with- or a double knockout mouse deficient in both
out experiments using specific blockers of both types of receptors. These studies found that
dopamine and norepinephrine transporters A, receptors may affect neuronal activity in a
and receptors. It may be that effects on dopa- manner that is partially independent of the
mine are necessary, but not sufficient, and presence of dopamine D, receptors, such that
that both norepinephrine and serotonin play endogenous adenosine may be most accu-
modulatory roles. Because the stimulants rately viewed as a facilitative modulator of
have such diverse effects, including increasing striatal neuronal activity rather than simply
activity, mood, appetite suppression, and so as an inhibitory modulator of D, receptor
forth, it seems likely that serotonin and nor- neurotransmission.
epinephrine play more or less important mod- These studies, and many others, conclude
ulatory roles, depending on which aspects of that the acute locomotor stimulant effects of
the specific drug's effects are being studied. caffeine in animal models are mediated in part
Caffeine and the other methylxanthines in- by dopaminergic systems and dopamine recep-
hibit phosphodiesterases, the enzymes that tors. Recent studies suggest that tolerance to
degrade CAMP.For many years it was believed the locomotor stimulant effects of chronic caf-
that the stimulant effect of caffeine was attrib- feine may also be related to specific changes in
uted to this enzyme inhibition. At the plasma dopaminergic function (128). Thus, in spite of
concentrations obtained after two to three the fact that methylxanthines are structurally
cups of coffee ( ~ 1 @),
0 however, antagonism different from other psychostimulants, and do
of adenosine A, (and A,) receptors in brain is not directly affect dopamine transporters or
believed to be the most relevant action to ex- receptors, in fact their stimulant action is de-
plain the stimulant effects of caffeine (119, rived from effects on central dopamine path-
120). Perhaps not surprisingly, in view of ear- ways.
lier discussion in this chapter, caffeine admin-
istration has been shown to lead to elevated
5 STRUCTURE-ACTIVITY RELATIONSHIPS
levels of brain dopamine (121, 122). It is
thought that adenosine receptor stimulation
Examination of the structure-activity rela-
facilitates GABA- or acetylcholine-mediated
tionships (SARs)of several of the classic stim-
inhibition of dopamine receptors in striatopal-
ulants provides not only an understanding of
lidal and striatonigral neurons (123), with the
the development of other drugs, but provides
end result of decreased dopaminergic func-
important clues as to the underlying mecha-
tion; adenosine antagonists would thus have a
nisms involved in interaction with the target
reverse action. Many studies have examined
protein(s). The following sections will hope-
the interaction between adenosine A,, recep-
fully illustrate both of these points.
tors and dopamine receptors, both of which
are highly concentrated and colocalized in the
5.1 Amphetamine
striatum and have reciprocal antagonistic in-
teractions (124-127). There is abundant evi- There are a number of related structures that
dence for pre- and postsynaptic interactions are often referred to as "amphetamines," al-
between adenosine and dopamine receptors, though the name amphetamine refers to one
by which adenosine inhibits doparninergic ac- specific molecular entity. Grouped in this class
tivity [e.g., (128)l. With respect to stimulation would be (+)-amphetamine (101,N-methyl-
5 Structure-Activity Relationships

: amphetamine [S-(+)-methamphetamine, 181,


phentermine (19), phenmetrazine (Preludin,
20), and phendimetrazine (21). Diethylpro-
pion (Tenuate; 16) is used as an appetite sup-
pressant and, although it has the amphet-
amine skeleton, its effects are much weaker as
a stimulant than those of the other structures
listed here. The stereochemistry at the a side-
chain methyl group is the same for the most
potent enantiomer of each structure, although
the pure enantiomer has not generally been
marketed except for the cases of (+)-amphet-
amine (10)and (+)-methamphetamine (18).

5.1.1 Length of the Side-Chain. The length


of the side-chain is limited to two carbon at-
oms (134, 135). That is, for transporter sub-
strates, the optimum pharmacophoric tem-
plate appears to be a basic nitrogen two carbon
atoms removed from an aromatic ring system.
This observation of course is not too surpris-
ing, given that the transporter substrates do-
pamine, norepinephrine, and serotonin all
bear this essential core.

5.1.2 Nitrogen Substituents. Nitrogen sub-


stituents are very limited. The primary amine
(amphetamine)and the N-methylamine (meth-
amphetamine) are the most potent com-
pounds (135). An N-methyl increases the po-
tency of both amphetamine and cathinone (2)
(136). Larger alkyl groups (135, 137) or N,N-
dialkylation, either dramatically attenuate or
completely abolish stimulant activity (138).
Nevertheless, N,N-dimethylamphetamine has
appeared on the illicit market (139) and does
appear to have behavioral effects in rats and
The structural requirements of the dopa- monkeys similar to amphetamine (138, 140).
mine (and norepinephrine) transporter ap- The rapid onset of action suggested that the
pear to be fairly rigid. There is very little mo- N,N-dimethyl compound itself had pharmaco-
lecular variation that is tolerated without logical effects, rather than the N-demethyl-
significant loss of activity. The relatively lim- ated metabolite, methamphetamine, although
ited information that is available, mostly from the latter is one of the known metabolites of
animal studies, can be summarized by consid- N,N-dimethylamphetamine (141).
ering the various areas of substitution for a Active metabolites may be much more im-
general phenethylamine structure. These portant in N,N-dialkylated compounds that
structure-activity relationships have been re- possess a p-keto function, as in cathinone (2).
cently surveyed (132), and an extensive and In that case, the N,N-dimethyl compound is
comprehensive review by Biel and Bopp (133) nearly as active as the N-monomethyl com-
covered the older literature. pound (142). It is known, however, that the
CNS Stimulants

alkyl groups of p-aminoketones are readily leling the potency difference found with the
cleaved metabolically. Thus, the N,N-di- enantiomers in vitro, using rat brain striatal
methyl cathinone analog is likely converted in synaptosomes (149). The two isomers were of
vivo to the N-monomethyl compound meth- nearly equal potency in their effects on norepi-
cathinone. This argument is based on evi- nephrine accumulation by rat hippocampal
dence that for diethylpropion, the N,N-diethyl synaptosomes (149). This stereochemical re-
congener of cathinone, it is the N-monoethyl quirement applies to p-keto derivatives as
metabolite that is the active species (70, 71). well; the corresponding active isomer has the
Although longer N-alkyl groups lead to less S-(-) configuration (136).
active compounds, one exception to this gen-
eralization is benzphetamine (Didrex),N-ben- 5.1.4 The a-alkyl Substituent. The a-alkyl
zyl-N-methylamphetamine (22). Despite the group cannot be much larger than a methyl.
N,N-dialkyl groups in benzphetamine, in hu- Phenethylamine itself, lacking the side chain
mans it produces subjective effects character- a-methyl group, is inactive in vivo because of
istic of amphetamine-like drugs such as phen- its rapid inactivation by monoamine oxidase.
metrazine (20) (143). Althoughpara-hydroxy- Addition of the a-methyl group retards metab-
N-benzylamphetamine is a major metabolite olism by this route, leading to the orally bio-
of benzphetamine, methamphetamine and available drug amphetamine. The uptake
amphetamine are also detectable in urine and transporter, however, cannot tolerate large
hair following administration of benzphet- groups in this region and the a-ethyl analogs
m i n e (144-146). It is not clear from the liter- of both amphetamine and methamphetamine
ature whether the reinforcing effects of benz- had markedly attenuated activity in a drug
phetamine are attributable to metabolic discrimination assay with rats trained to dis-
formation of amphetamine or methamphet- criminate (+)-amphetamine (150). a,a-Di-
amine. Based on the studies with N,N-dimeth- methyl groups, as in phentermine (19),
ylamphetamine by Witkin (138),however, one though giving an active compound, still reduce
would predict that the parent molecule has activity.
some pharmacological activity. Attempts to incorporate the side chain into
ring structures also led to compounds with at-
5.1.3 Stereochemistrv at the a Carbon. tenuated activity. For example, in drug dis-
The stereochemistry at the a carbon atom, crimination assays using rats trained to recog-
when enantiomers exist, is homochiral to that nize the effect of (+)-amphetamine (lo),
of S-(+)-amphetamine (lo), shown earlier. compounds (23) and (24) either failed to pro-
Both the releasing actions at dopamine and duce amphetamine like effects, or had much
norepinephrine transporters in isolated rat lower potency (150, 151). When n = 3, the
brain slices (147) and the locomotor and ste- compound lacked any amphetamine-like ac-
reotypic effects in rodents (148) are more po- tion.
tently affected by the S-(+) isomer of amphet-
amine than by the R-(-1 isomer. In this latter 5.1.5 Other Side-Chain Substitutions. Lim-
study, the (+) enantiomer was about five ited substitution of the side chain is tolerated.
times more potent than the (-1 isomer, paral- A p-hydroxy group on methamphetamine
5 Structure-Activity Relationships

substitution decreases their potency at these


sites. The serotonin carrier is relatively pro-
miscuous and tolerates a variety of ring sub-
stituents, many of which dramatically in-
crease the potency at the serotonin carrier
from that of amphetamine itself. No ring mod-
ifications are known that give rise to a substi-
tuted amphetamine that completely retains
gives ephedrine (I), shown earlier. Although amphetamine-like psychostimulant activity.
ephedrine is a CNS stimulant, its effects are para- Fluoroamphetamine (26; X=F) has
much weaker than those of methamphet- been reported to have effects in rats resem-
amine. Similarly, addition of a P-hydroxy to bling those of amphetamine, but substitution
amphetamine gives phenylpropanolamine, a with larger halogens (e.g., chloro or iodo) leads
compound that is nearly devoid of CNS stim- to compounds that have significant serotonin
ulant effects. One may speculate that the polar releasing potency, and that produce behav-
hydroxy group reduces the hydrophobicity of ioral effects that are different from those of
these compounds such that CNS penetration amphetamine itself (154).
is much reduced. The N-methyl of ephedrine
increases lipid solubility, so ephedrine has a
greater CNS action than that of phenylpropa-
nolamine. Addition of a keto function to the
structure of amphetamine or methamphet-
amine gives cathinone (2) or its corresponding
N-methyl derivative, methcathinone, the lat-
ter of which also has greater potency than that
of the primary m i n e (142). It should be noted 5.2 Methylphenidate
that an oxygen at the P position can be incor- The R,R-(+)-stereoisomer of methylpheni-
porated into a heterocyclic ring as in phen- date (8)is known to be the more active (155)
metrazine (20) and phendimetrazine (21). and is often referred to as the active "threo"
Methyl aminorex (25) is also a potent stimu- isomer. The (-)-enantiomer and the erythro
lant that incorporates the essential features of stereoisomers are much less potent. One study
the amphetamine template into an oxazoline has reported a series of aromatic ring-substi-
ring. The 4S,5S-trans isomer shown (25) is tuted analogs. The most potent compounds in
the most potent of the four possible stereoiso- that report were halogen substituted in the 3-
mers (152, 153). or 3,4- positions of the ring. For example, the
dichloro compound (27) was 32-fold more po-
tent than methylphenidate itself in inhibiting
dopamine reuptake (156). That finding paral-
lels a recent report by Deutsch et al. (1571,
that replacing the phenyl ring with a P-naph-
thy1 moiety (158) gave a compound with about
eightfold higher affinity for the dopamine
transporter. Those workers also reported that
the corresponding a-naphthyl analog had only
about one-tenth the potency of methylpheni-
date at the DAT. Taken together, these latter
5.1.6 Aromatic Ring Substitution. Simple observations indicate that the DAT must have
ring substituents can change the targets of the a hydrophobic region that generally extends
amphetamines from one monoamine uptake from the 3,4- positions of the aromatic phenyl
carrier to another. The dopamine and norepi- ring of methylphenidate.
nephrine uptake carrier proteins have the Deutsch et al. (157) also examined the ef-
most stringent structural demands, and any fect of heterocyclic ring size. The pyrrolidyl
CNS Stimulants

will not be presented. A useful perspective on


the SAR of cocaine analogs as it was under-
stood in 1992 has been presented by Carroll et
al. (159), with more a recent update in 1997
(160).
An attempt will be made here to distill down
the essence of the SAR of cocaine as it relates to
its stimulant properties. In many cases, com-
pounds have been reported that have not been
tested in vivo, but have only been compared for
affinity at the monoarnine transporters or in an
in vivo assay. Some of these data will be summa-
rized if they are reported in the context of the
stimulant effects of cocaine. Similarly, there
have been numerous attempts to develop co-
caine analogs that may bind to the dopamine
transporter and actually block the stimulant or
reinforcing effects of cocaine itself, in efforts to
develop treatments for cocaine addiction. This
chapter largely ignores many of those studies
and azepino, as well as the azacyclooctane con-
unless they contain in vivo data suggesting they
geners, were significantly less potent than
are relevant to a discussion of stimulant effects.
methylphenidate itself. That report also con-
Nevertheless, because stimulant properties
tained data for the morpholine analog of
have been associated with binding to the DAT, a
methylphenidate (158),which had an approx-
good deal of the SAR discussion here must be
imately 15 times lower affinity at the DAT.
discussed in the context of in vitro DAT affinity.
Beyond the studies cited here, very little addi-
A consideration of the structure-activity re-
tional SAR work has been done with methyl-
lationships of cocaine can focus on a number of
phenidate. key elements in the structure, as indicated be-
low. Each of the following sections includes a
5.3 Cocaine
discussion of the particular numbered struc-
Of all the psychostimulants, cocaine has prob- tural element.
ably been most studied, particularly within
the last decade, as a result of its widespread
abuse. Structure-activity studies have been
carried out with numerous analogs, not only
to elucidate the molecular requirements for
interaction with the various monoamine
transporters, but also in attempts to develop
treatments that might be useful for cocaine
addiction. Ideally, understanding the struc-
ture-activity relationships will be useful to un-
derstanding the functional topography of the
binding site of the transporters, and, if a
three-dimensional structure of the transport-
ers can be developed, these features would
map onto the binding site. Nevertheless, be-
cause the topic of this chapter is stimulants,
and not the structure-activity relationships of
monoamine transporters, an exhaustive sum-
mary of the more than 200 papers that have 5.3.1 N-substituents. N-demethylation of
appeared on the SAR of cocaine and its analogs cocaine has only a minor effect on affinity at
5 Structure-Activity Relationships

monoamine transporters (161). In phenyl- would suggest that this interaction should be
tropane analogs where the ester linkage has very weak.
been removed (281,extensions of the N-alkyl Replacement of the nitrogen atom with ox-
out to n-butyl have no effect on dopamine ygen as in (30) gives compounds that retain
transporter affinity (162). Effects a t the se- high affinity for the dopamine transporter
rotonin transporter are variable, but affinity (165).This finding was accommodated by pro-
only decreases modestly. At the norepineph- posing that the oxygen atom could act as a
rine transporter, affinity drops about three hydrogen bond acceptor at the transporter
times with the longer N-alkyl group. (165),a conclusion that would at least be con-
sistent with the activity of the N-sulfonated
derivatives (29).
It was even more surprising, therefore,
when the report appeared that even a polar
oxygen was not required for good uptake in-
hibitors. Carbocyclic compounds such as (31)
proved to have transporter affinities nearly
equal to those of their amine-containing coun-
terparts (166)!

5.3.2 Basic Nitrogen Atom. For many years


it was assumed that the basic nitrogen of co-
caine was required for activity. It seemed log-
ical to believe that the nitrogen, protonated at
physiological pH, would interact with an an-
ionic site such as an aspartate residue in the
transporter (163). It was surprising, there-
fore, when nonbasic N-sulfonyl cocaine ana-
logs such as (29) were found to possess high
affinity for the dopamine transporter (164).
These compounds are not protonated at phys-
iological pH, and if hydrogen bonding were re-
quired for activity, these analogs could serve
only as hydrogen bond acceptors. Even then,
the low electron density remaining on a nitro-
gen with the powerfully electron-withdrawing
trifluoromethylsulfonyl group attached,

These authors postulated that there are


various acceptor sites in the dopamine trans-
porter, where an inhibitor may bind and cause
dopamine uptake inhibition. The topography
of these sites is probably different in the three
monoamine transporters.

5.3.3 Substituent at C(2). Epimerization of


the ester function to give pseudococaine (32)
CNS Stimulants

results in about a 150-fold loss in affinity for


the dopamine transporter (161). In com-
pounds lacking the ester linkage (see section
below) the effect is more dramatic, resulting in
a more than 1000 times lower potency.

(33) R = alkyl

The ester is not an essential function. Re-


placement of the ester with an ethyl or vinyl
group did not lead to significant loss of binding
affinity, demonstrating that a polar function
capable of hydrogen bonding was not essential crimination paradigm in rats trained to dis-
(167, 168). Indeed, substitution at the 2P po- criminate the effects of cocaine. In contrast,
sition with alkyl groups as long as n-butyl, whereas cocaine increased locomotor activity
2-phenethyl, or 2-stryl gave compounds (e.g., in mice, RTI-15 had no effect on activity and at
33) with exceptionally high affinities at the high doses even decreased this measure (172).
dopamine transporter (168). Because this compound was a potent inhibitor
Kelkar et al. (169) have extended the 2P- of the dopamine transporter, it suggests that
alkyl group to include a polar hydroxy or high selectivity for the dopamine transporter
methyl ester function at the distal end of a may lead to differential retention of cocaine-
three carbon chain, with no significant loss of like effects.
affinity compared to that of a simple carbome-
thoxy function. They concluded that this re-
gion of the cocaine binding site must be either
a large cleft in the transporter protein or exte-
rior to the binding site. They also noted that
this region is relatively insensitive to electro-
static interactions. Chang et al. (170), found
that the 2P-phenyl analog (34)was equipotent
to the 2-carbomethoxy compound, but had en-
hanced selectivity for the dopamine trans-
porter over the serotonin transporter. These
authors also concluded that a hydrophobic
group at this region of the molecule might be a (35) (RTI 15)
contributing factor for binding at the dopa-
mine transporter. The isopropyl and phenyl esters in the
Esters larger than a methyl are quite po- 3-phenyltropane series of analogs have higher
tent. In the 3-benzoyl series of tropane esters, affinity for the dopamine transporter than
both the isopropyl and phenyl esters had high does the methyl ester (173).Similarly, tertiary
affinity and selectivity for the dopamine trans- amide analogs of cocaine and phenyltropane
porter (171). The phenyl ester (35; RTI-15) analogs are more potent than secondary or
dose-dependently substituted in the drug dis- primary amides, and also have enhanced selec-
5 Structure-Activity Relationships

tivity for binding at the dopamine transporter


over that of the norepinephrine or serotonin
transporters (173). Replacement of the ester
or amide function with a carboethoxy isox-
mole substituted substituent gave (36), a
highly potent inhibitor with selectivity for the
dopamine transporter (174, 175). This com-
pound had about twice the affinity of cocaine
at the DAT.

pseudochair, rather than the boat, conforma-


tion that occurs in natural (-)-3P-cocaine.
It was first reported by Clarke et al. (178)
that removal of the ester linkage from cocaine,
to give a compound with the phenyl ring di-
rectly attached to the tropane ring (WIN
35,065-2; 391, possessed higher affinity for the
dopamine transporter than did cocaine itself.
By contrast to benzoyl esters, however, the
configuration at the 3 position is not so critical
in phenyltropane compounds. That is, in the
WIN series where the ester has been removed,
the 3P phenyl orientation (39) was only about
twofold more potent than the 3a phenyl(40)
at the dopamine transporter. At the serotonin
transporter, however, the 3P compound was
significantly more potent (165). A similar
trend was observed in the 8-oxa analogs, lead-
ing to the conclusion that the dopamine trans-
porter is able to accommodate the 3-phenyl
ring when the bicyclic ring is in either the boat
or chair conformation, whereas the serotonin
transporter is less accommodating.

Similarly, Carroll et al. (176) reported that


the 1,2,4-oxadiazoles (e.g., 37) that are bio-
isosteres of ester groups, are potent cocaine
analogs. Compound (37) had low nanomolar
affinity for the dopamine uptake transporter
with greater than 100-fold selectivity for the
dopamine transporter over the norepineph- 5.3.5 Substitutions on the Aromatic Ring at
rine and serotonin transporters. Position 3. In the phenyltropane analogs of co-
caine, where the ester linkage has been re-
5.3.4 The Ester Linkage at C(3). In cocaine, moved and the phenyl ring is attached directly
the 3a epimer "allococaine" (38)has consider- to the tropane ring (WIN and RTI com-
ably reduced activity compared to that of co- pounds), substitution at thepara ring position
caine itself (177).This structural change, how- with halogens or a methyl group gave com-
ever, causes the tropane ring to favor the pounds (41) with increased affinities at the
CNS Stimulants

dopamine transporter compared with the un-


substituted compound, and with much in-
creased affinity compared to that of cocaine
itself (179). Behavioral potency paralleled the
affinity increases, with all of the phenyltro-
panes being considerably more potent in ele-
vating locomotor activity in mice (180) and in
substituting for a cocaine stimulus in the drug
discrimination paradigm in rats (181).

monoamine reuptake inhibition. It is perhaps


not too surprising, therefore, that the bridged
bicyclic tropane ring is not an essential struc-
tural feature. In a series of 6arylpiperidine
(41) X = F, C1, Br, I, CH3
carboxylic acid methyl esters, several of the
compounds were significantly better uptake
The rank order of affinity for aromatic ring inhibitors than cocaine (183).The most potent
substituents in the WIN series was 3,4-C12 > I compound in the series, (44), was about 20
> C1> F > H, whereas in the 8-oxa (3P) ana- times more potent at the dopamine uptake
logs it was 3,4-C1, > Br > C1> I > F > H (165). transporter than cocaine.
Replacing the 3pphenyl with either a 1- or
2-naphthyl substituent gave significantly en-
hanced affinity at all three monoamine trans-
porters, with the 2-naphthyl(43) being about
five- to sixfold more potent than the l-naph-
thy1 (42) (182). This result is parallel to simi-
lar findings reported by Deutsch et al. (1571,
where replacing the phenyl ring of methyl-
phenidate with a 2-naphthyl moiety gave an
analog with about 70-fold higher potency than 6 RECENT AND FUTURE DEVELOPMENTS
when the phenyl ring was replaced with a
1-naphthyl. As reviewed above, the drugs that have been
used for their stimulant properties were
5.3.6 Requirement for the Intact Tropane largely the result of compounds that were dis-
Ring System. We have seen earlier that there covered empirically over many centuries. Un-
is no absolute requirement for the basic nitro- derstanding the active principles of these
gen in the tropane structure, and that even a drugs has led to major advances in medicinal
polar oxygen isostere replacement is not chemistry. For example, one of the most excit-
needed for cocaine congeners to possess potent ing recent findings has to do with understand-
6 Recent and Future Developments

ing the monoamine transporters at the molec- may block the actions of cocaine without
ular level. Whereas it has been known in markedly affecting the normal transport func-
pharmacology for many years that cocaine tar- tion of the protein. Hence, there is presently
geted an energy-dependent reuptake pump, intense interest in such compounds because
the cloning and expression of these transport- they may provide new avenues for the treat-
ers has given access to high "purity" proteins ment of cocaine and psychostimulant addic-
that are amenable to more detailed study. tion.
These proteins have all been sequenced, and There also is a need for improved drugs to
shown to be membrane bound with 12 mem- replace existing CNS stimulants, as treat-
brane-spanning helical segments. A large ments for medical conditions like narcolepsy,
number of site-specific mutations have been ADHD, obesity, and for general attentional
used to correlate specific residues in the pro- purposes. Yet, virtually all of the existing
tein with specific functions. Nevertheless, it stimulants have the capacity to produce en-
will likely take a technical breakthrough to hanced mood, or euphoria. This side effect
obtain a crystal structure of one of these trans- means that they all possess abuse potential to
porters or one of their homologs, an accom- a greater or lesser degree. Advances in medic-
plishment that will no doubt lead to much inal chemistry and molecular neurobiology
greater understanding of how transporters have provided hope, however, for new genera-
function. Inability to crystallize these proteins tions of drugs. For example, recently the non-
is not a problem that is unique to monoamine amphetamine, nonstimulant drug modafinil
transporters, but continues to plague the (Provigil, 45) was approved for use in narco-
study of all membrane-bound transporters lepsy (see, e.g., Ref. 187). This drug has been
and receptors, and other membrane-bound shown to be more effective than amphet- -
proteins. amine, with fewer side effects, although its
Site-directed mutagenesis, cysteine-scan- mechanism of action has not yet been eluci-
ning accessibility methods, high field NMR, dated. The discovery that mutations of either
homology modeling, and continued develop- the gene for the novel neuromodulator orexin,
ment of structure-activity relationships will or the orexin receptor, can cause narcolepsy,
no doubt lead to better and better models of leads to the hope for even better and more
the monoamine transporters. These ap- specific drugs to treat that disorder, as well as
proaches are having the greatest impact on to the possibility of better treatments for obe-
studies of uptake inhibitors, rather than stud- sity (188-191).
ies of substrates.
Particularly interesting recent advances
indicate that ligands from different chemical
classes may bind in novel ways to the dopa-
mine transporter. Using site-directed mu-
tagenesis and photoaffinity labeling probes,
investigators have produced results suggest-
ing that the substrate uptake and cocaine
binding sites are probably not identical (184).
Indeed, it also now seems likely that different
chemical classes of uptake inhibitors may even
bind to distinct regions of the transporter
(185, 186), leading to different overall confor- Even those actions of the stimulants that
mations in the transporter protein and per- are absolutely dependent on activation of
haps subtly altered mechanisms of inhibition. monoamine systems may also be amenable to
These different transporter conformations breakthroughs in medicinal chemistry. For
would explain the observed differences in the example, the beneficial effects of stimulants
pharmacology of different chemical classes of on ADHD may be attributable primarily to ac-
DAT inhibitors. New derivatives that have se- tivation of only certain receptors. Recently,
lective affinity at these alternate binding sites the anatomical and functional substrates of
CNS Stimulants

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CHAPTER FIVE

Sedative-Hypnotics
JULIUSVIDA
Vida International Pharmaceutical Consultants
Greenwich, Connecticut

JOSEPH YEVICH
Pharmaceutical Research Institute
Bristol-Myers Squibb Company
Wallingford, Connecticut

Contents
1 Introduction, 202
1.1 Classification of Sedative-Hypnotics, 202
1.2 The Ideal Hypnotic Drug, 203
2 Clinical Use of Agents, 203
2.1 Current Drugs on the Market, 203
2.2 Side Effects, Adverse Effects, and Drug
InteradionslContraindications, 203
2.2.1 Barbiturates, 203
2.2.2 Benzodiazepines, 206
2.2.3 Halogenated Sedative-Hypnotics, 208
2.2.4 Heterocyclic Sedative-Hypnotics, 210 .
2.2.5 Antihistamines, 211
2.3 Absorption, Distribution, Metabolism, and
Elimination, 211
2.3.1 Barbiturates, 211
2.3.1.1 Absorption, 211
2.3.1.2 Distribution, 211
2.3.1.3 Metabolism, 214
2.3.1.4 Elimination, 216
2.3.2 Benzodiazepines, 217
2.3.2.1 Absorption, 217
2.3.2.2 Distribution, 217
2.3.2.3 Metabolism, 218
2.3.2.4 Elimination, 218
2.3.3 Halogenated Sedative-Hypnotics, 220
2.3.3.1 Chloral Hydrate, 220
2.3.3.2 Ethchlorvynol, 221
2.3.4 Heterocyclic Sedative-Hypnotics, 221
2.3.4.1 Glutethimide, 221
2.3.4.2 Clomethiazole, 221
2.3.4.3 Zopiclone, 221
Burger's Medicinal Chemistry and Drug Discovery 2.3.4.4 Zolpidem, 221
Sixth Edition, Volume 6: Nervous System Agents 2.3.4.5 Zaleplon, 223
Edited by Donald J. Abraham 2.3.5 Antihistamines, 223
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 3 Physiology and Pharmacology, 233
201
Sedative-Hypnotics

3.1 Physiology of Sleep, 223 3.2.3.2 Heterocyclic Sedative-


3.1.1 Wakefulness and Sleep, 223 Hypnotics, 234
3.1.2Sleep Studies, 224 4 History, 235
3.1.3States of Sleep, 224 4.1 Discovery of Important Hypnotic Drugs, 235
3.1.4 Alert Wakefulness, 224 4.1.1 Before Barbiturates, 235
3.1.5 NREM Sleep, 224 4.1.2 Barbiturates, 235
3.1.6 REM Sleep, 225 4.1.3 Halogenated Sedative-Hypnotics,235
4.1.4 Heterocyclic Sedative-Hypnotics, 235
3.1.7 Sleep Cycle, 225
4.1.4.1 The First Phase, 235
3.1.8 Neurotransmitters and Sleep, 225
4.1.4.2 The Second Phase, 235
3.1.9 Neurotransmitters and REM Sleep in 4.1.5 Benzodiazepines, 235
Humans, 225 4.1.6 Antihistamines, 236
3.1.10 Nonhypnotic Drugs Affecting REM 4.2 Discovery of Zolpidem, 236
On Switch, 225 4.2.1 The Use of Benzodiazepines, 236
3.1.11 Nonhypnotic Drugs Affecting REM 4.2.2 The Development of Zolpidem, 236
Off Switch, 227 5 Structure-Activity Relationships, 237
3.1.12 Neurotransmitters and NREM Sleep 5.1 Quantitative Structure-Activity
in Humans, 227 Relationships (QSAR), 237
3.2 Pharmacology, 228 5.1.1 Barbiturates, 237
3.2.1 Evaluation of Sedative-Hypnotics, 228 5.1.2 Benzodiazepines, 237
3.2.2 Pharmacologic Effects of Sedative- 5.2 Receptor Interactions, 242
Hypnotic Drugs, 228 5.2.1 Barbiturates, 243
3.2.2.1Before Barbiturates, 228 5.2.2 Benzodiazepines, 244
3.2.2.2 Barbiturates, 229 5.3 Structure-Function Relationships, 246
3.2.2.3 Benzodiazepines, 229 5.3.1 Barbiturates, 246
3.2.2.4Heterocyclic Sedative- 5.3.2 Benzodiazepines, 247
Hypnotics, 230 6 Recent Developments, 251
3.2.2.5Antihistamines, 230 6.1 Melatonergic Agents, 251
3.2.3 Clinical Pharmacology of Important 6.2 Oleamide, 254
Sedative-Hypnotics,230 7 Things to Come, 255
3.2.3.1Benzodiazepines, 230 8 Websites, 256

1 INTRODUCTION As health professionals have become more


aware of the importance of sleep, the treat-
People are becoming increasingly aware of the ment of sleep disorders has received increas-
I
ing attention. As a result, new drugs have
importance of sleep. One-third of our life is
become available on the market and new in-
spent in sleep, which has a major influence on
formation has become available on the role of
an individual's physical, social, and psycholog-
sleep factors, the homeostatic regulation of
ical well-being. Sleep has become the subject sleep, circadian rhythm, chronotherapy, the
of extensive clinical and research interest. role of immunology, and genetics of sleep dis-
At one time, wakefulness was considered as orders. The new knowledge will further en-
the active state and sleep as the passive state hance the ability of health professionals to de-
of all human functions. Today both wakeful- velop new medicines for the treatment of sleep
ness and sleep are considered to be active pro- disorders.
cesses, with wakefulness and sleep being at
two ends of a continuum.
1 .I Classification of Sedative-Hypnotics
Although wakefulness and sleep are two
distinct functional states, they seem to influ- Arbitrarily the sedative-hypnotics may be
ence each other. Disturbances during sleep classified as follows:
may impair daytime function and problems
experienced during wakefulness may ad- 1. Barbiturates
versely affect sleep. 2. Benzodiazepines
2 Clinical Use of Agents

3. Halogenated compounds (chloral hydrate, 2 CLINICAL USE OF AGENTS


ethchlorvynol, carbromal)
4. Heterocyclic compounds (piperidinediones, 2.1 Current Drugs on the Market
thiazoles, pyrrolopyrazinones, imidazopyr-
Current drugs on the market include barbitu-
idines, pyrazolopyrimidines)
rates, benzodiazepines, halogenated sedative-
5. Antihistamines hypnotics, heterocyclic sedative-hypnotics,
6. Other sedative-hypnotics (valnoctamide, antihistamines, and other sedative-hypnotics.
propofol, plant extracts, endogenous sleep
factors, melatonin) 2.2 Side Effects, Adverse Effects, and Drug
Interactions/Contraindications
1.2 The Ideal Hypnotic Drug
2.2.1 Barbiturates. Barbiturates (1) (see
The characteristics of an ideal hypnotic for the
Table 5.1) have a spectrum of deleterious side
elderly have been summarized as follows (1):
effects including lethargy, confusion, and de-
pression. Chronic use of barbiturates is asso-
r Induces sleep promptly after administra-
ciated with a potential for addiction involving
tion.
both physical and psychological dependence.
r Maintains sleep for an adequate period Tolerance and abstinence may develop
without undesired awakenings. with any of the barbiturates. It has been re-
r Promotes a sleep state identical to a non- ported that abrupt withdrawal of secobarbital
drug-induced or "natural" sleep. (given 0.8-2.2 g/d for 6 weeks) causes both
r Leaves the individual feeling refreshed and minor symptoms (tremors, anorexia, insom-
well rested on awakening. nia, and apprehension) and major symptoms
r Does not cause undesired daytime sedation (seizures, delirium, and hypothermia) that
or drowsiness. can persist for up to 2 weeks after discontinu-
r Causes no impairment of coordination and ation. Tolerance to barbiturates can develop
psychomotor function. within 2 weeks of treatment because of induc-
tion of hepatic microsomal enzymes (2).
r Does not lose efficacy when taken repeatedly Barbiturates are lethal at about 10 times
(for a number of consecutive nights or on a the hypnotic dose that is about 6-10 g of phe-
chronic basis). nobarbital or 2-3 g of secobarbital, pentobar-
r Does not accumulate in the body during bital, or amobarbital(3).
chronic usage. The adverse effects of the barbiturates in-
r Does not lead to dependence. clude respiratory depression, allergic reac-
r Is not harmful if overdose is taken. tions, skin rashes, hepatitis, cholestasis, and
r Does not cause "rebound insomnia" when photosensitivity.
suddenly discontinued. As with other sedatives, paradoxical excite-
ment and irritability may occur. This is com-
r Does not exacerbate sleep apnea or other
mon in children and the elderly.
conditions contributing to disturbed sleep.
The toxic effects of an overdosage result
r Causes no undesired reactions, such as car- from profound central depression and may in-
diovascular or gastrointestinal distress. clude coma, respiratory and cardiovascular de-
r Does not cause enzyme induction or partic- pression with hypertension, and shock leading
ipate in other clinically important drug in- to renal failure. Withdrawal of the drug is
teractions. more frequently a problem with barbiturates
r Is inexpensive. than with benzodiazepines. Withdrawal of
barbiturates leads to rapid eye movement
Although a lot of progress has been made (REM) sleep rebound and rebound insomnia.
towards the goal of finding the ideal hypnotic, Drug interactions of barbiturates are pro-
in the absence of having found such an agent, nounced because of the induction of hepatic
research towards the goal must continue. microsomal enzymes caused by barbiturates.
Table 5.1 Sedative-H~notic
Barbiturates in Clinical Use in the United States and Europe*

Average
Duration Adult
Trade Other of Action Onset of Hypnotic
Barbituric Acid Generic Name Name RS R Modifications (h) Action (h) Dose (g)
5-Ethyl-isopentyl Amobarbital Amytal 2-8 0.25-0.5 0.1-0.3
5-Allyl-5-isopropyl Aprobarbital Resedorm 2-8 0.25-0.5 0.065-0.13
5,5-Diethyl Barbital Barbitalum 4-12 0.5-1 0.3-0.5
5-(1-Cyclohexen-1- Hexobarbital Sombulex 1-4 0.25 0.25-0.4
y1)-1,5-dimethyl
5-Ethyl-l-methyl-5- Mephobarbital
phenyl
5-Allyl-5-(1-methyl- Methohexital Brevital
2-pentynyl)
5-Ethyl-5-(1- Pentobarbital Nembutal
methylbutyl)
5-Ethyl-5-phenyl Phenobarbital Luminal
5-Isopropyl-5-ethyl Probarbital Ipral
5-Allyl-5-(1-methyl Secobarbital Second
butyl)
5-Allyl-5-see-butyl Talbutal Lotusate
5-Allyl-5-(1-methyl Thiamylal surital
buty1)-2-thio
5-Ethyl-5-(1-methyl Thiopental Pentothal 4-12 30 Seconds 0.1-0.15
butv1)-2-thio
*The principal route of administration for barbiturates is oral. However many barbiturates (hexobarbital, methohexital, pentobarbital, thiopental, etc.) are also available in
injectable formulation but indicated for anesthesia (not as sedative hypnotics).
Table 5.2 Sedative-Hypnotic Barbiturates in Clinical Use Outside the United States
Average
Duration Adult
Trade Other of Action Onset of Hypnotic
Barbituric Acid Generic Name Name R5 R Modification (h) Action (h) Dose (g)
Allobarbital Dial,
Curral
Brallo barbital Vespoerone

5-see-Butyl-5-ethyl Butabarbital Butisol


5-Allyl-5-isobutyl Butalbital Sandoptal
5-(2-Bromoally1)-5-see- Butallylonal Pernoston
butyl
5-Butyl-5-ethyl Butethal Neonal
5-Crotyl-5-ethyl Crotyl Melidorm
Barbital
5-(1-Cyclohexen-1-yl)- Cyclobarbital Phanodorm
5 ethyl
5-Allyl-5-(2- Cyclopentenyl- Cyclopal
cyclopenten-1-yl) allylbarbituric
acid
5-(1-Cyclohepten-1- Heptabarbital Medomin
y1)-5-ethyl
5,5-Diethyl-1-methyl Metharbital Gemonil
5-(1-Methylbuty1)-5- Methitural Neraval
12-(methylthiol-
ethyl]-2-thio
1-Methyl-5-(2- Narcobarbital Narcotal
bromoally1)-5-
isopropyl
5-(2-Bromoally1)-5- Propallylonal Noctal
isopropyl

5-Ethyl-5-(1-methyl-1- Vinbarbital Delvinal


butenyl)
5-(1-Methyl-buty1)-5- Vinylbital Speda
vinyl
Sedative-Hypnotics

The rate of metabolism of several drugs (war- sion. Tolerance to benzodiazepines often de-
farin, phenytoin, tricyclic antidepressants, velops but occurs less frequently than that
oral contraceptives, etc.) is increased. with barbiturates.
Barbiturates are rarely used today, and Withdrawal of benzodiazepines can cause
when barbiturate treatment is initiated, it rebound of the original symptoms. A transient
should be restricted to 2 weeks because of the worsening of these symptoms may occur espe-
risk of tolerance developing. cially if benzodiazepines are used in high dose
and for a long duration.
2.2.2 Benzodiazepines. Benzodiazepines In 2001, Flunitrazepam has been subjected
(2) (see Table 5.3) in low doses have a sedative to the same prescribing restrictions as narcot-
effect; however, in higher doses, they induce ics in several countries because of its continu-
sleep and may even lead to coma. The sedative
ing abuse by drug addicts.
effect of benzodiazepinesimpairs motor skills,
The adverse effects of benzodiazepines in-
attention, memory, judgment, and if severe,
clude dizziness, vertigo, light-headedness,
may lead to confusion and incoordination. The
risk of accidents is increased, including an in- headache, changes in libido, ataxia, tremor,
crease of road traffic accidents. Consumption and urinary retention or incontinence.
of alcohol potentiates the effects of benzodiaz- The sedative and hypnotic effects of benzo
epines. diazepines are accentuated by other drugs act-
Benzodiazepines also cause anti-anxiety, ing on the gamma-aminobutyric acid,
muscle relaxant, and anticonvulsant effects, (GABA,) receptor, especially barbiturates
amnesia, depression, and respiratory depres- and alcohol. However, there are fewer drug

Table 5.3 Structures of Benzodiazepines

(2)
Benzodiazepine RI & % RS
Cinolazepam OH
Delorazepam H
Doxefazepam OH
Flunitrazepam H
Flurazepam H
Lorazepam OH
Lormetazepam OH
Nimetazepam H
Nitrazepam H
Nordazeparn H
Potassium clorazepate COOK

Quazepam H
Temazepam OH
Table 5.4 Benzodiazepines
No. Generic Structure Trade Name Originator Chemical Class First W/WLaunch Dose (mglday)
- - - - -

Bromazepam Lexotan Roche Pyridinyl-benzodiazepine 1973 3-6 p.o divided doses


Brotizolam Lendormin Boehringer Ingelheim Triazolo-diazepine 1974 0.25-0.50 p.0.
Cinolazepam Gerodorm Gerot (Austria) Benzodiazepine-propionitrile 1992 5-20 p.0
Delorazepam En Ravizza (Italy) BASFI Chlordesmethyl diazepam 1980 0.5-2.0 p.0.
Abbott
Doxefazepam Doxans Searle
Schiaparelli (Italy)
Estazolam Eurodin Takeda Abbott
Esilgan
Flunitrazepam Rohipnol
Flurazepam Dalmadorm
Dalmane
Loprazolam Dormonoct Roussel (Aventis)

Lorazepam Ativan Wyeth-Ayerst


j~glkgi.v.
11. Lormetazepam Noctamid Schering A.G. Chlorophenyl-benzodiazepine 1980 0.5-2 p.0.
Loramet Wyeth-Ayerst
12. Midazolam Dormicum Roche Imidazo-benzodiazepine 1982 7.5-15 p.0.
2.5-7.5 i.v.
13. Nimetazepam Erimin Sumitomo (Japan) Nitro-benzodiazepine 1977 3-5 p.0.
14. Nitrazepam Mogadon Roche Nitro-benzodiazepine 1965 5-10 p.0.
15. Nordazepam Madar Ravizza (Italy) Benzodiazepinone 1975 2.5-10 p.0.
BASFIAbbott
16. Potassium Tranxene SanofilAbbott Benzodiazepine carboxylate 1967 5-20 p.0.
Clorazepate
17. Quazepam Quazium Schering-Plough (Italy) Trifluoroethyl-benzodiazepine 1985 15 p.0.
Doral Wallace (US)
18. Temazepam Remestan Wyeth-Ayerst Benzodiazepinone 1969 5-30 p.0.
Normisonl Novartis
Restoril
19. Triazolam Halcion Upjohn (Pharmacia) Triazolo-benzodiazepine 1978 0.125-0.50 p.0.
208 Sedative-Hypnotics

Table 5.5 Halogenated Sedative Hypnotics


Structure
Structure Number Chemical Name Generic Name
Chloral hydrate compound with Chloralbetain
betaine

Chloralodol or
chlorhexadol
Carbochloral

Ethyl N-(2,2,2-trichloro-1-
hydroxyethyl carbarnate

Dichloralphen-
4-Dimethylamino-2,3-dimethyl- azone
1-phenyl-3-pyrazolin-5-one
compound with chloral
hydrate
Triclofos

2,2,2-Trichloroethanol, di-H-
phosphate, sodium salt

Pentaerythritol hemiacetal Petrichloral


with chloral
2-bromo-2-ethyl-butyryl urea Carbromal

Ethchlorvynol

interactions because benzodiazepines do not and dependence and their danger in overdose.
induce hepatic microsomal enzyme produc- Chloral hydrate (3) (see Table 5.5) seems the
tion. least problematic with relatively low abuse po-
The advantages of benzodiazepines over tential; it is still used as an alternative to
older hypnotic drugs and especially over bar- benzodiazepines. The adverse effects include
biturates are as follows: safer in overdose, less gastric irritation, light headedness, ataxia,
tendency to tolerance and dependency, less nightmares, excitement, confusion, allergic
adverse potential, greater sedation-to-anxioly- reactions, and skin rash. It also causes drows-
sis ratio, and fewer drug interactions. iness and motor incoordination; therefore,
chloral hydrate should not be used concomi-
2.2.3 Halogenated Sedative-Hypnotics. tantly with other CNS depressant drugs such
Most of these agents are only rarely used be- as alcohol. The adverse effects of ethchlorvy-
cause of their high risk of causing tolerance no1 (4) (see Table 5.5) are similar to those of
Table 5.6 Halogenated Sedative Hypnotics
Generic Name
No. (Structure) Trade Name Originator Chemical Class Dose (mgld)
1. Chloral hydrate Noctec Squibb 2,2,2-Trichloro-1,l-Ethandiol p.0. 500-1000
2. Chloralodol or Lora Wallace (USA) 2-Methyl-2(2,2,2-trichloro-1-hydroxy p.0.800-1600
chlorhexadol ethoxy)S-pentanol
3. Carbochloral Prodorm Parke-Davis Ethyl N-(2,2,2-trichloro-1- p.0. 400-800
hydroxyethyl carbamate
4. Dichloralphenazone Welldorm Smith & Nephew (UK) 4-Dimethylamino-2,3-dimethyl-1- p.0. 225-700
Chloral01 Homer (Canada) phenyl-3-pyrazolin-5-one
Bonadorm Ferroson (Denmark) compound with chloral hydrate
5. Triclofos Triclos Marion Merrell Dow 2,2,2-Trichloro ethanol, di-H- p.0.500-1000
phosphate, sodium salt
6. Petrichloral Petrin Parke-Davis Pentaerythritol hemiacetal with p.0. 1200-2000
chloral
7. Carbromal Carbrital Parke-Davis 2-Bromo-2-ethyl-butyryl urea p.0. 250-1000
Somben Chinoin (Hungary)
Talambrol Kwizda (Austria)
8. Ethchlorvynol Placidyl Abbott 1-Chloro-3-ethyl-pent-1-en-4-yn-3-01 p.0. 100500
210 Sedative-Hypnotics

Table 5.7 Heterocyclic Sedative Hypnotics


Structure Chemical N a m e Generic N a m e
3-Ethyl-3-phenyl-2,6-piperidinedione Glutethimide
(5)

5-(2-Chloroethy1)-4-methylthiazole Clomethiazole
(6)

4-Methyl-1-piperazinecarboxylic acid Zopiclone


ester of 6-(5-chloro-2-pyridy1)-6,7- (7)
dihydro-7-hydroxy-5H-pyrrolo {3,4-
b jpyrazin-5-one

N f; A
OC-N
wN-CH3
(1)Imidazo[l,2-alpyridine-3- Zolpidem
acetamide,N,N,6-trimethyl-2-(4- (8)
methylpheny1)-,[R,-(R*,R*)]-2,3-
dihydroxybutanedioate (21);

N-(3-(3-Cyanopyrazolo[1,5-a] Zaleplon
pyrimidin- (9)
7-ylpheny1)l-N-ethylacetamide

chloral hydrate. Ethchlorvynol is contraindi- ment, hangover, blurred vision, and skin
cated in patients with porphyria, hepatic, and rashes.
renal failures. Overdose of glutethimide may cause even a
greater danger to life than barbiturate over-
2.2.4 Heterocyclic Sedative-Hypnotics. dosage (4); glutethimide has the highest
The adverse effects of glutethimide (5) (see mortality of drug-induced comas (5).Like bar-
Table 5.7) include nausea, headache, excite- biturates, glutethimide induces microsomal
2 Clinical Use of Agents

Table 5.8 Heterocyclic Sedative-Hypnotics


First
Trade W/W Dose (mg/
No. Generic Name Name Originator Chemical Class Launch day
1. Glutethimide Doriden Ciba-Geigy Piperidinedione 1954 250600 p.0.
Dorimide Cenci (USA)
2. Clomethiazole Heminevrin Astra (Sweden) Methylthiazole 1957 192-384 p.0
8 mg/kg i.v.
3. Zopiclone Imovane RPR Pyrrolopyrazinone 1985 7.5 p.0.
4. Zolpidem Stilnox Synthblabo Imidazopyridine 1988 5-10 p.0.
Ambien Searle (USA)
5. Zaleplon Sonata Wyeth-Ayerst Pyrazolopyrimidine 1999 10-20 p.0.

hepatic enzymes and can cause increased me- nausea, vomiting, diarrhea or constipation,
tabolism of anticoagulants and other drugs anorexia, or increased appetite. They may also
with reduced effects. produce antimuscarinic effects such as
Clomethiazole (6) (see Table 5.7) may pro- blurred vision, dysuria, micturition, dryness
duce nasal irritation and sneezing - on admin- of mouth, tightness of the chest, hypotension,
istration, conjunctival irritation, headache, muscular weakness, tinnitus, euphoria, and
gastrointestinal disturbances, nausea, vomit- occasionally headaches. Antihistamines should
ing, fever, cough, and tachycardia. It is contra- not be given to neonates and are contraindi-
indicated in patients with chronic pulmonary cated during acute attacks of asthma. All an-
insufficiency, renal failure, or liver disease. tihistamines used as sedative-hypnotics be-
Zopiclone (7) (see Table 5.7) has a short half- long to the class of HI-receptor antagonists.
life but can cause daytime sedation. However, it
causes less morning-after drowsiness and fa- 2.3 Absorption, Distribution, Metabolism,
tigue than longer-acting hypnotics. Rebound and Elimination
phenomena following withdrawal have not
proved a serious problem. Zopiclone causes min- 2.3.1 Barbiturates
imal impairment of psychomotor performance 2.3.1.1 Absorption. Barbiturates are well '

and mental alertness the morning after night absorbed after oral administration usually
time administration (6). given as sodium salts. They have a long dura-
Zolpidem (8) (see Table 5.7) rarely causes tion of action, usually 6-10 h. Peak plasma
daytime
- sedation because of its short duration levels occur in 2-12 h and are dose related.
of action. However, it may cause nausea, vom- 2.3.1.2 Distribution. The lipid solubility
iting, diarrhea, headaches, and dizziness. (lipophilicity)of barbiturates varies and deter-
Tolerance to its use can develop, but this is mines how readily they cross the blood-brain
less than with benzodiazepines. It may also barrier.
cause mild respiratory depression. With- It is possible to calculate the amount of bar-
drawal symptoms associated with zolpidem bituric acid in the undissociated form at vari-
are unusual. ous pH values from the equation:
Zaleplon (9) (see table 5.7) is a very short-
acting hypnotic that occasionally causes head-
aches and dizziness and may lead to respiratory
depression. It rarely causes daytime sedation be-
cause of its short duration of action. Psychomo- where [A-I = Concentration of the anion
tor impairment is unusual. The risk of tolerance
is unknown; the withdrawal symptoms are rare, [HA] = Concentration of the undis-
and dependency is unlikely. sociated acid

2.2.5 Antihistamines. Antihistamines may The values of several examples are given in
produce gastrointestinal disturbances such as Table 5.13.
Table 5.9 Antihistamines
Structure Chemical Name Generic Name

9 CH-0-CH2-CH2-N
/CH3
2-Benzhydryloxy-N,N, -dimethylamine Diphenhydramine

d \
CH3

q C-0CH2CH2N
/CH3

\
Doxylamine

CH3
3
l . t

1-(p-Chloro-a-phenylbenzy1)-4-[2-[2-(2- Etodroxizine
hydroxy-ethoxy)ethoxy]-
ethylldiethylenediamine

Hydroxyzine
f.7 2-[2-[4-[(4-Chloropheny1)phenyl-methyl]-
N- C H ~ - CH~-- 0- C H ~ - C H ~ - OH 1-piperazinyll- ethoxylethanol
N-[3-[4-(p-Fluropheny1)-1-piperazinyl]-1- Niaprazine
methyl-propyllnicotinamide

CH3

N,Na-Trimethyl-1OH-phenothiazine-10- Promethazine
ethanamine

Propiomazine

Pyrilamine
214 Sedative-Hypnotics

Table 5.10 Antihistamines


Generic Name Trade Dose
No. (Structure) Name Originator Chemical Class (mglday)
1. Diphenhydramine Benadryl Warner Lambert Ethanamine 25-50 p.0.
2. Doxylamine Unisom Pfizer Ethanamine 25 p.0.
3. Etodroxizine Indunox UCB (Belgium) Piperazinyl-ethoxy- 12.5-50 p.0.
ethanol
4. Hydroxyzine Atarax UCB (Belgium) Piperazinyl-ethoxy- 50-100 p.0.
Roerig (USA) ethanol
5. Niaprazine Nopron Sanofi- Piperazinyl- 2 mg per kg
Synthelabo pyridine
carboxamide
6. Promethazine Phenergan RPR Phenothiazine 15-50 p.0.
7. Propiomazine Propavan Pharmacia Phenothiazine 25-50 p.0.
8. Pyrilamine Kriptin Whitehall-Robins Ethanediamine 25-50 p.0.
(Mepyramine) Anhisan RPR

Among the given examples, only 5-ethyl-5- from 0.36 to 0.67 Llkg. Phenobarbital enters
phenylbarbituric acid and l-methyld-ethyl-5- the brain in a manner reflecting blood flow
phenylbarbituric acid have a proper ratio of patterns, and in steady state, it is evenly dis-
dissociated forms present at physiological pH tributed in gray and white matter. The bind-
to enable them to cross the blood-brain barrier ing to plasma proteins of barbiturates plays a
and exert an effect in the CNS. minor role in distribution.
Lowering serum pH increases the non-ion- 2.3.1.3 Metabolism. The principal site
ized (undissociated) portion in the serum, en- of metabolic inactivation is in the liver. In
hancing diffusion into tissue, whereas higher the metabolism, the lipophilic character of
serum pH has the opposite effect (7). the barbiturates decreases, which in turn
Estimates of the apparent volume distribu- decreases the ability of the barbiturates to
tion for phenobarbital vary nearly twofold penetrate into the CNS. There are four pri-

Table 5.11 Other Sedative-Hypnotics


Structure Chemical Name Generic Name
C2H5CH-CHCONHz 2-Ethyl-3-methyl valeramide Valnoctamide
I I

CH3 OH CH3 2,6-BisU-methylethy1)phenol Propofol

N-[2-(5-Methoxy-lH-indol-3-yl)ethyl] Melatonin
acetamide
2 Clinical Use of Agents 215

Table 5.12 Other Sedative-Hypnotics


Generic Name Chemical Dose (mg/
No. (Structure) Trade Name Originator Class day)
1. Valnoctamide Axiquel nirvanil McNeil (J&J) Valeramide 400-800 p.0.
Recordati (Italy)
2. Propofol Diprivan Zeneca Phenol 0.3-0.5 IV
mg/kg/h
3. Melatonin Cronocaps melatol Medix (Mexico) Indolylethyl 1-3 p.0.
Elisium (Argentina) acetamide

mary metabolic processes that may take


place.

1. Oxidation of substituents attached to C5 is


the most important pathway of metabolism
for the barbiturates. The oxidative pro-
cesses may yield alcohols, ketones, and car-
boxylic acids. For example, pentobarbital is 1-Methyl-5-ethyl- 5-Ethyl-5-phenyl
oxidized to a hydroxy compound and a car- 5-phenylbarbituric acid barbituric acid
boxylic acid (8) as shown in Fig. 5.2. The
oxidative process may also yield phenols. If
the barbiturate has a phenyl group at-
tached to C5, by far the most important
metabolic product is the p-hydroxyphenyl
derivative, which has been shown to be
formed through the intermediate epoxide
(9). For example, phenobarbital is metabo-
lized top-hydroxyphenobarbital (Fig. 5.3).
The oxygenated metabolites (alcohols, phe-
nols, ketones, and carboxylic acids) may be
Thiopental
excreted in the urine in the free form or
conjugated with glucuronic or sulfuric acid. CH3
I
2. N-Dealkylation (N-demethylation) is an
important metabolic pathway for N-substi-
tuted barbiturates (10). Mephobarbital(1-
methyl-5-ethyl-5-phenylbarbituric acid) is
metabolized to phenobarbital (5-ethyl-5-
phenylbarbituric acid), which is subject to
further metabolic processes.
HN7fNH0

3. Desulfurization of 2-thiobarbiturates is a Pentobarbital


common metabolic process. For example,

Table 5.13 Percentage of Various Barbituric Acids in Undissociated Form


at Physiological pH (7.4)
Percentage of
Compound PK, Undissociated Form
Barbituric acid
5-Phenylbarbituric acid
5-Ethyl-5-phenylbarbituricacid
acid
1-Methyl-5-ethyl-5-phenylbarbituric
acid
1,3-Diethyl-5-ethyl-5-phenylbarbituric
Sedative-Hypnotics

) Bmrnazepam I
Brotizolam

Loprazolarn Midazolam

Estazolam: X=H.Y=H
Figure 6.1. Benzodiazepine Triazolam: X = CH,. Y = CI
structures.

pentobarbital [5-ethyl-5-(1-methylbutyl) 2.3.1.4 Elimination. Barbiturates are elim-


barbituric acid] is one of the metabolic inated from the body both by hepatic metabo-
products of thiopental [5-ethyl-5-(1-meth- lism and by renal excretion. In the liver,
ylbuty1)-2-thiobarbituricacid]. phenobarbital is parahydroxylated and subse-
4. Ring scission of the barbituric ring leads to quently conjugated to glucuronic acid.
the formation of acetamides or acetyl urea Both unmetabolized and parahydroxylated
derivatives. Both acetyl urea and acet- phenobarbital are excreted in the urine. The
arnide derivatives are more hydrophilic extent of glucuronide formation of phenobar-
than barbiturates. The biotransformations bital varies widely. Phenobarbital elimination
of barbiturates have been reviewed (11,12). has first-order kinetics and thus is indepen-
2 Clinical Use of Agents

0 0
Pentobarbital 5-Ethyl-5-(3-hydroxyl-1-
methylbutyl) barbituric
acid
CH3
I

0 Figure 5.2. Metabolism


5-Ethyl-5-[2-(4-carboxybutyl)] barbituric acid of pentobarbital.

cally as a hypnotic. It has been suggested that


only those benzodiazepines are suited as hyp-
cleavage
along a notics that are rapidly detoxified and excreted
(13). The most important factors contributing
to the pharmacokinetic profile of a compound
are absorption, distribution, metabolism, and
elimination/clearance.

\
Acetylurea
cleavage derivative 2.3.2.1 Absorption. The rate of absorption
along b (5.3) from the gastrointestinal tract after oral dos-
age determines the speed of the onset of action
of a benzodiazepine. For a quick onset of ac-
tion, the benzodiazepine must dissolve com-
pletely in the stomach and cross the stomach
mucosa into the systemic circulation. The dif-
Acetamide ferent dissolution and absorption kinetics of
derivative benzodiazepines will affect their onset of ac-
tion. Once the benzodiazepine is in the sys-
dent of concentration. From 11% to 50% of temic circulation, it must also cross the blood-
phenobarbital is eliminated from the body per brain barrier to enter the CNS. Therefore, the
day, corresponding to a half-life range of 24- lipophilicity of the benzodiazepine is important
140 h. Average half-lives after single doses in determining the entry into the CNS and the
range from 75 to 126 h and are not influenced onset of clinical action. Most benzodiazepines
by route of administration. Alkalization of are highly lipophilic with the 3-hydroxy-substi-
urine increases phenobarbital excretion. tuted benzodiazepines (lormetazepam, loraz-
epam, temazepam, and doxefazepam); triazo-
2.3.2 Benzodiazepines. The pharmacoki- lam is the least lipophilic.
netic properties of benzodiazepines are most 2.3.2.2 Distribution. Distribution is one of
important in selecting a specific drug for the the important factors contributing to the du-
treatment of sleep disorders. In fact, pharma- ration of action of benzodiazepines. Benzodi-
cokinetic parameters provide a rational azepines normally cross the blood-brain bar-
method for selecting a benzodiazepine specifi- rier quite easily and exert a pharmacodynamic
Sedative-Hypnotics

determined by redistribution of the drug into


inactive storage sites, elimination, and metab-
olism.
The presence of active metabolites contrib-
utes heavily to the duration of action of ben-
zodiazepines. Some active metabolites have
much longer plasma half-lives than their par-
ent compounds. If the parent drug is not bio-
0 0 transformed into active metabolites, the dura-
5-Ethyl-5-phenyl Epoxide tion of action is determined by the rate of
barbituric acid intermediate elimination of the parent compound. The bio-
transformation pathways of several benzodi-
azepines are shown in Figs. 5.4, 5.5, 5.6, and
5.7.
Benzodiazepines may be divided into three
classes based on their pharmacokinetic char-
acteristics:

1. Short half-life drugs, such as triazolam,


midazolam, and brotizolam, with elimina-
tion half-lives of up to 6 h.
2. Medium half-life drugs, such as temaz-
0
epam, estazolam, lormetazepam, and lo-
5-Ethyl-5-(4-
hydroxypheny1)- prazolam, with half-lives of 6-12 h.
barbituric acid 3. Long-acting drugs, such as nitrazepam,
flurazepam, and flunitrazepam, with half-
Figure 5.3. Metabolism of phenobarbital. lives over 12 h.

The elimination half-lives of a number of


effect as long as their plasma concentration benzodiazepines and their metabolites are
remains above a certain level. However, redis- shown in Table 5.14.
tribution may influence plasma concentra- 2.3.2.4 Elimination. Elimination half-life
tions. Redistribution of a benzodiazepine may indicates the rate of drug disappearance from
involve its reentry from the CNS across the plasma (and from brain) after distribution
blood-brain barrier into the systemic circula- equilibrium has been reached and after the
tion and subsequent distribution into active elimination curve has entered its terminal
storage sites. The phenomenon may explain phase (also called the /3 phase). Clearance is
the finding that the duration of clinical activ- the ratio of the rate of elimination over the
ity of a benzodiazepine is shorter than would arterial plasma concentration and would bet-
be expected based on its elimination half-life. ter describe the elimination process. However,
Using the elimination half-life alone to pre- it is more difficult to measure clearance than
dict duration of action of a benzodiazepine can half-life; therefore, half-life is used most often.
be misleading (14). However, it can also be Half-life is useful in describing the relative
said that if elimination of a benzodiazepine is extent of drug accumulation. The longer the
the rate-determining step and the absorption half-life, the greater the accumulation ratio.
and distribution are comparable and fast, then The accumulation ratio is defined as the dif-
the elimination half-life may provide a relative ference of plasma concentration during 24 h
estimate of duration of action. following a dose after steady state has been
2.3.2.3 Metabolism. The role of decline in reached compared with the plasma concentra-
plasma concentration of benzodiazepines is tion during 24 h following the first dose.
2 Clinical Use of Agents

CI %'5
0
0
CH3

Minor pathway

- cl
0
CH3

OH - Glucuronide

Diazepam Temazepam

t
0

CI

Diazepam Nordazepam Oxazepam

0
Clorazepate
Figure 5.4. Biotransformation pathways of potassium clorazepate, diazepam, nordazepam, oxaze-
Pam, and temazepam.

Half-life also determines the time necessary tor impairment produced next day after drug
to attain steady state. Long half-life hypnotics administration. In general, these residual ef-
accumulate slowly but extensively, whereas fects occur more often after long-acting drugs
short half-life benzodiazepines reach steady (such as nitrazepam or flurazepam) than after
state rapidly and accumulate to a small extent. intermediate (temazepam) or short-acting
Half-life also determines the time required benzodiazepines (triazolam).
for drug washout after multidose treatment is Drug dose is a critical issue in determining
discontinued. Short half-life benzodiazepines unwanted daytime sedation. Thus, 5 mg of ni-
disappear quickly, whereas long half-life com- trazepam produces few effects compared with
pounds are eliminated slowly following the 10 mg. Similarly, large doses (over 0.5 mg) of
last dose. triazolam produce definite hangover effects.
These factors are important when consid- After stopping benzodiazepines, patients
ering the daytime drowsiness and psychomo- may experience rebound insomnia or anxiety.
Sedative-Hypnotics

Bromazepam 3-Hydroxy-bromazepam

Br a""'
- A"".
- CI = O Br C1 = O Conjugates

2-Aminod- 2-Arnino-3-hydroxy-5-
bromobenzoylpyridine bromobenzoylpyridine

Figure 5.5. Biotransformation pathways of bromazepam.

Rebound insomnia occurs more often with EEG changes in many subjects on the morning
short-acting and intermediate-acting benzodi- after drug administration (13). Subjects given
azepines, when given in high doses and with-
-
benzodiazepines should be warned of this fad.
drawn abruptly. Conversely, very long-acting
benzodiazepines (such as flurazepam and 2.3.3 Halogenated Sedative-Hypnotics
quazepam) show milder rebound effects. 2.3.3.1 Chloral Hydrate. Chloral hydrate
Ideally, a hypnotic drug should not produce is rapidly absorbed from the stomach and
unwanted drowsiness or heavy-headedness on starts to act within 30 min. However, no chlo-
awakening. Several studies in humans have in- ral hydrate blood levels are found in humans,
dicated that benzodiazepines produce morning- because the metabolic conversion of chloral
after effects visible in EEG recordings. Nitraz- hydrate is very fast (Eq. 5.4).
epam (5-10 mg) and flurazepam (15-30 mg), for
example, produce a shift to low voltage, high fre-
quency activity in the EEG (15,161, which is still
present 12-18 h after a single dose of the drug.
There is disagreement whether benzodiazepine
administration also produces an impairment of Chloral hydrate Trichloroethanol
performance of intellectualand motor function.
Several investigators observed impaired perfor- The long-lasting hypnotic effect is caused
mance (15-18), whereas others have not con- by its metabolite, trichloroethanol(20).
firmed these findings (19). Trichloroethanol passes into the cerebro-
It is generally agreed, however, that even spinal fluid and has a half-life of 7-11 h. In
though the symptoms of hangover may be rec- addition to trichloroethanol, chloral hydrate is
ognized, benzodiazepines, like all other seda- also metabolized to trichloroacetic acid, which
tive-hypnotics, do produce psychomotor and is inactive. Both trichloroethanol and trichlo-
2 Clinical Use of Agents

Delorazepam Lorazeparn

Lormetazeparn
Figure 5.6. Bic>transformationpathways of delorazepam, lormetazepam, antd lorazepam.

roacetic acid are excreted in the urine and in 2.3.4.2 Clomethiazole. Clomethiazole is rap
the bile, in part, as glucuronides. idly absorbed from the gastrointestinal tract
2.3.3.2 Ethchlorvynol. Ethchlorvynol is rap- and produces peak plasma concentrations in
idly absorbed from the gastrointestinal tract about 15-45 min after oral administration. It
and is extensively metabolized mainly in the is broadly distributed in the body and is exten-
liver and to a lesser extent in the kidney. The sively metabolized in the liver and excreted in
half-life of ethchlorvynol is biphasic with a the urine with only very small amounts of un-
rapid initial phase and a 10- to 25-h-long ter- changed drug appearing in the urine.
minal phase. Only traces of unchanged drug 2.3.4.3 Zopiclone. Zopiclone is well ab-
appear in the urine. The metabolic half-life is sorbed from the gastrointestinal tract with
5.6 h, and it disappears from the plasma with a peak plasma concentration reached within 2 h
rapid a phase and a much slower P phase, be- after administration. It has a half-life of 4-6 h
cause of extensive tissue redistribution. and a duration of action of 6-8 h. It is metab-
olized in the liver to N-desmethylzopiclone
2.3.4 Heterocyclic Sedative-Hypnotics and zopiclone N-oxide, and these two metabo-
2.3.4.1 Glutethimide. Glutethimide is ir- lites constitute about 36% of the dose excreted
regularly absorbed from the gastrointestinal in the urine along with small amounts of zopi-
tract and is extensively metabolized in the clone. Excretion of drug and metabolites was
liver. It is about 50% bound to plasma proteins essentially complete 48 h after the final dose.
and has a biphasic plasma half-life. It is ex- 2.3.4.4 Zolpidem. Zolpidem is rapidly ab-
creted in the urine with only up to 2% of un- sorbed from the gastrointestinal tract and has
changed drug and 98% as metabolites. Glu- a half-life of 1.5-2.5 h. It has a rapid onset of
tethimide is highly lipid soluble and may be action that is detectable within 15-30 min.
stored in adipose tissue. The peak plasma level is reached within 1-2 h
Sedative-Hypnotics

Quazepam \ Oxoquazepam

Figure 5.7. Biotransfor-


mation pathways of quaz-
epam and flurazepam. Flurazepam
after administration. Its clinical effect lasts are eliminated primarily by renal secretion.
5-7 h. It is metabolized in the liver and gives The mean elimination half-life is 2.6 h. Zolpi-
rise to nitrogen demethylated and hydroxy- dem should not be administered with or imme-
methylated metabolites that are inactive and diately after a meal, because with food, the
Table 5.14 Elimination Half-Lives of a Number of Benzodiazepines and Their Metabolites
Elimination Half-Life of Elimination Half-Life
Drug Parent Compound (h) Active Metabolite of Metabolite (h)
Short half-life
Brotizolam 5.0 (3-5) 1-Hydroxymethyl derivative Short
Triazolam 2.3 (1.63.3) 1-Hydroxymethylderivative Short
Midazolam 2.5 (1-3) 1-Hydroxymethylderivative Short
Intermediate half-life
Loprazolam 5.3 (4-8) None
Lormetazepam 9.9 (7-12) None
Temazepam 12.0 (8-21) None
Estazolam 12.00 None
Long half-life
Flunitrazepam 15.0 (9-25) 7-Amino derivative 23
Flurazepam Very short N-Desalkyl-flurazepam 87
Nitrazepam 28 (20-34) None
Clorazepate 1 (0.6-1.2) Nordazepam 64
(Desmethyldiazepam)
Quazepam Oxoquazepam 40
N-Desalkyl flurazepam 87
3 Physiology and Pharmacology

mean area under the curve and C,, were de- larger molecular size or their electrostatic
creased by up to 25%. charge. The relative contribution of these fac-
2.3.4.5 Zaleplon. Zaleplon is rapidly ab- tors is unknown.
sorbed from the gastrointestinal tract and Serum elimination half-life values differ
reaches peak plasma level within 1 h after in- greatly from one antihistamine to another.
gestion. It has avery fast onset of action. It has Most of the antihistamines are metabolized by
a half-life of 30 min and a short duration of the hepatic cytochrome P450 system and give
action, less than 5 h. Zaleplon has a terminal rise to metabolites that are usually excreted in
phase elimination half-life of approximately the urine.
1 h. Zaleplon does not accumulate with once-
daily administration, and its pharmacokinet- 3 PHYSIOLOGY AND PHARMACOLOGY
ics are dose proportional in the therapeutic
range. The absolute bioavailability of zaleplon The clinical effects of sedative-hypnotics in-
clude sedation and sleep. Sedative-hypnotic
is approximately 30% because it undergoes
drugs depress the function of the CNS and in a
significant presystemic metabolism. Zaleplon
dose-dependent fashion produce drowsiness
is a lipophilic compound. The blood-to-plasma
(sedation). Several sedative-hypnotic drugs,
ratio for zaleplon is approximately 1, indicat- especially the older ones, produce sedation,
ing that zaleplon is uniformly distributed sleep, unconsciousness, surgical anesthesia,
throughout the blood with no extensive distri- coma, and ultimately may cause fatal depres-
bution into red blood cells. sion of respiration and cardiovascular regula-
Zaleplon is primarily metabolized by alde- tion.
hyde oxidase to form 5-0x0-zaleplon. Other Because these drugs facilitate the onset
metabolites include desethylzaleplon and and maintenance of a state of sleep that re-
5-0x0-desethylzaleplon.Approximately 70% of sembles natural sleep, the physiology of sleep
the administered dose is recovered in urine is of significant importance and is described
within 48 h, almost all as zaleplon metabolites below (Section 3.1). In the second part, the
and their glucuronides. An additional 17% is pharmacology is addressed (Section 3.2).
recovered in feces within 6 days, mostly as
3.1 Physiology of Sleep
5-0x0-zaleplon. The effects of zaleplon on
sleep onset are reduced if it is taken with or
3.1.1 Wakefulness and Sleep. Sleep and
immediately after a high-fat or heavy meal.
wakefulness are two easily recognizable dis-
tinct functional states. The person in sleep
2.3.5 Antihistamines. Antihistamines are shows a reduced awareness and responsive-
rapidly absorbed from the gastrointestinal ness both to internal and external stimulation
tract. After oral administration the onset of and hisher motor functions are inhibited. The
action of HI-receptor antagonists is prompt, sleeping person seems quiescent. However,
occurring within 0.5 h, although the peak his- the sleeping person exhibits some movements,
tamine blockade may not occur until 5-7 h indicating that sleep is an active process.
after oral administration. The cerebral activity of a human in wake-
Bioavailabiity has not been well studied be- fulness and in sleep display significant differ-
cause of the lack of intravenous formulations. ences. In the human electroencephalogram
Most fmt-generation histamine HI-receptor an- (EEG), wakefulness is characterized by low
tagonists readily cross the blood-brain barrier, amplitude waves and a rhythm. On the other
which consists of the endothelial lining of the hand, the EEG in sleep consists of high ampli-
capillaries of the CNS. The first-generation an- tude slow waves and spindles, indicating slow
tihistamines listed in Section 2.1.5 are used as synchronized, idling neural activity. Eledro-
sedative-hypnotics. oculographic (EOG),electromyographic (EMG),
The second-generation HI-receptor antag- and electrocardiographic (ECG) data have
onists, such as fexofenadine, loratadine, and lent additional support to the finding that
cetirizine, are relatively lipophobic and pene- both wakefulness and sleep are active pro-
trate poorly into the CNS because of their cesses.
Sedative-Hypnotics

3.1.2 Sleep Studies. As early as 1907, Leg- sleep consisted of two distinct organismic
endre and Pieron discovered the existence of states. As a result the following three physio-
endogenous sleep factors (21). Injection of logical states exist:
blood serum from sleep-deprived dogs could
induce sleep in dogs who were not deprived of 1. Alert wakefulness
sleep. The search for endogenous sleep factors 2. Nonrapid eye movement (NREM) sleep
is still continuing. 3. REM sleep
In the 1920s and 1930s, Kleitman studied
the effects of sleep deprivation (22) and con- 3.1.4 Alert Wakefulness. In wakefulness,
cluded that the build-up of endogenous sleep the EEG shows a high level of low voltage fast
factors did not exceed certain limits, and hu- (LVF) frequency activity (9-10 Hz a activity
mans became as impaired as they would get mixed with low amplitude P activity). The
after approximately 2.5 days of wakefulness. EMG shows a high level of tonic activity and
The first EEG recordings were reported by the EOG shows frequent eye movements.
Berger in 1930 (23). He discovered differences
in the electrical rhythms of subjects when 3.1.5 NREM Sleep. This consists of four
awake or asleep. stages:
In the late 1940s,sleep research in animals
was conducted by implantable electrodes. This 1. Stage 1 NREM Sleep. The first state of
led to the designation of the ascending reticu- sleep (also called drowsy state). This is
characterized by a 50% diminution of the a
lar activating system by Moruzzi and Magoun
waves of wakefulness in the EEG and low
(24). They discovered that an important struc-
amplitude, mixed frequency activities (in
ture of the brain stem was interposed between the range of 3-7 Hz) consisting of 8 and
sensory input and the higher centers of the some p waves. The muscular tone in the
brain. High frequency electrical stimulation of EMG becomes slightly relaxed, and slow
the brain stem reticular formation through rolling eye movements (SEM) are observed
implanted electrodes produced activation of in the EOG. The state of drowsiness
the EEG, wakefulness, consciousness, and be- quickly changes to definite sleep.
havioral arousal. On the other hand, reticular 2. Stage 2 NREM Sleep. The onset of stage 2
deactivation produced by EEG synchroniza- NREM sleep is observed by bursts of 12- to
tion leads to sleep and lack of consciousness. 16-Hz sleep spindles in the EEG. The EMG
In the early 1950s,Aserinsky and Kleitman activity is less than in wakefulness and
(25) deployed the method of EOG for the mea- stage 1, and the EOG does not show eye
surement of eye mobility. Soon thereafter, movements. Stage 2 sleep lasts about
Aserinsky and Kleitman (26) discovered that 30-60 min.
sleep onset is characterized by slow eye move- 3. Stage 3 NREM Sleep. Stage 3 sleep follows
ment, which in time, changes to REM sleep. stage 2 sleep and is characterized by slow
Subsequent research by Aserinsky and Kleit- wave sleep. The EEG shows 20-50% of 6
man led to the conclusion that REM sleep is waves of 2 Hz or less with amplitudes
associated with dreaming. greater than 75 pV from peak to peak. The
Dement and Kleitman (27) expanded their muscle tone in the EMG is more relaxed
research in all-night sleep recordings using than before, and there are no eye move-
EEG and EOG techniques. They observed a ments in the EOG.
sequence of patterns over the course of the 4. Stage 4 NREM Sleep. This stage is charac-
night that revealed a basic sleep cycle. terized by 6 waves of 2 Hz with amplitudes
greater than 75 pV, which constitute more
3.1.3 States of Sleep. EEG studies have re- than 50% of the total. Toward the end of
vealed that the activity of the brain is not con- the deep sleep (6 sleep), sleep lightens, of-
stant during sleep. EOG and EMG data have ten abruptly to stage 2 NREM sleep, ac-
lent additional support to the finding that companied by body movements. After a
3 Physiology and Pharmacology

brief period of stage 2 NREM sleep, the first than a normal amount of time in REM sleep
REM sleep occurs about 60-90 min after when allowed to follow a normal pattern. This
sleep onset. rebound affect is also observed after REM-
sleep suppressing drugs are withdrawn (29).
3.1.6 REM Sleep. This is characterized by Sleep laboratory studies are usually per-
rapid eye movements. The slow wave pattern in formed by applying the standardized methods
the EEG is desynchronized and changes to a low developed by Rechtschaffen and Kales (30).
amplitude mixed frequency 0 including some a
pattern and often displaying saw tooth waves. 3.1 .a Neurotransmitters and Sleep. Based
No sleep spindles are seen. The muscle tone be- on the very elegant studies performed in cats,
low the chin is totally relaxed or abolished. Jouvet postulated that there is a direct relation-
ship between 5-hydroxytryptamine(5-HT,sero-
3.1.7 Sleep Cycle. The first REM period tonin) and NREM sleep (31,321.
lasts a few minutes and changes to stage 2 and Correlations were also obtained for other
subsequently to stage 3 and stage 4 of NREM neurotransmitters as well.
sleep before the second REM sleep period oc-
3.1.9 Neurotransmitters and REM Sleep in
curs. Accordingly, a full sleep cycle consists of
Humans. Neurotransmitters have both a di-
a sequence of NREM sleep and REM sleep, rect and indirect action on REM sleep. The
and a cycle lasts about 90-110 min. Alto-
indirect action is manifested by a self-inhibi-
gether, three to five REM periods occur during
tory feed back mechanism (Equation 5.5).
the night in 90- to 110-min cycles alternating
Cholinergic transmission (acetylcholine) acti-
with NREM sleep. However the various
vate neurons in their pontine reticular forma-
NREM sleep stages change in duration. The
tion (PRF) and produce REM sleep. REM
first two cycles are dominated by stages 3 and
sleep gradually activates REM-off monoamin-
4 NREM sleep. Subsequent cycles are domi-
ergic neurons, which produce a self-inhibitory
nated by stage 2 NREM sleep and stage 3 and
feedback and eventually terminates REM
4 NREM periods are brief or do not appear at
sleep. As the REM sleep period changes to
all. NREM sleep, the REM-off neuronal activity
Conversely, the REM sleep duration in-
gradually decreases during NREM sleep, and.
creases from the first to the last cycle. The last
is at minimum at the onset of REM sleep.
REM cycle is usually the longest REM cycle
The role of REM sleep on and off switches
and may last as long as an hour. As a result,
are further accentuated by the effects of vari-
the first third of sleep is dominated by stages 3
ous drugs in humans in the NREMIREM sleep
and 4 NREM sleep and the last third of the
cycle (Equation 5.5 and Fig. 5.8).
sleep is dominated by REM sleep.
Sleep deprivation studies (28) have demon- 3.1 .I 0 Nonhypnotic Drugs Affecting REM
strated the need for both NREM and REM On Switch
sleep. Subjects deprived of sleep tend to spend
more than a normal amount of time in NREM 1. Muscarinic Agonists. The muscariniclnico-
sleep when allowed to sleep. Similarly, if the tinic agonist carbachol produces a long
subjects are awakened every time that REM lasting REM sleep that is blocked by the
sleep begins, they become selectively deprived administration of atropine. The same effect
of REM sleep, because every time they fall was obtained by using the selective musca-
asleep again, the sleep cycle begins with rinic agonist bethanecol. Further studies
NREM sleep. As a result, REM sleep occurs revealed that M, muscarinic agonists are
after shorter and shorter times. Furthermore, active, whereas the M, muscarinic agonists
subjects deprived of REM sleep spend more are without effects (33).

Cholinergic Monoaminergic
REM sleep
off switch (5.5)
Transmission Transmission
Sedative-Hypnotics

Muscarinic agonists Norepinephrine agonists


Vasoactive Intestinal Peptide Serotonin agonists
(VIP) Histamine-1 agonists
Excitatory Amino Acids (EAA) Cholinergic antagonists

Serotonin
Norepinephrine
MA01

-
AMPT Amphetamine
REM sleep Apomorphine
Disulfiram & fusaric acid GABA + GABA.
on switch compounds
6-OHDA Opioids
IL-1
TN Fa

a Adrenergic blockers SSRl antidepressants


a Methyl DOPA NSRl antidepressants
Reserpine
Figure 5.8. REM sleep on and off switches.

2. Excitatory Amino Acids (EAAs). Excitatory 6. 6-Hydroxydopamine (6-OHDA). Adminis-


amino acids are claimed to be the principal tration of 6-OHDA destroys catechol-
excitatory transmitters in the reticular for- amine-containing neurons and therefore
mation (34). EAAs including glutamate are decreases norepinephrine brain levels. In
involved in the positive feedback interac- turn, REM sleep is increased.
tion between the cholinergic and the retic- 7. Reserpine. Reserpine depletes monoamines
ular neurons. (serotonin, dopamine, and norepinephrine)
3. Vasoactive Intestinal Peptide. The peptide in the brain in a nonspecific manner. De-
is found in the same neurons of the reticu- pletion of these neurotransmitters in the
lar formation where acetylcholine is also brain facilitate REM sleep.
present. On injection, it enhances REM 8. a-Methyldopa. Administration of a-methyl-
sleep. dopa results in the synthesis of the false
4. a-Methylparatyrosine (AMPT). Adminis- transmitter a-methylnorepinephrine, which
tration of AMPT, an inhibitor of catechol- selectively displaces norepinephrine from
amine synthesis, reduces both doparnine the vesicles. The decreased norepinephrine
and norepinephrine brain levels and in brain levels facilitate REM sleep.
turn, increases REM sleep. 9. a Adrenergic Blockers. Administration of
5. Disulfiram and Fusaric Acid. Administra- phenoxybenzamine, thyrnoxamine, piperox-
tion of these dopamine-p-hydroxylase in- ane, and yohimbine, all a, adrenoreceptor
hibitors produces an increase in REM sleep blockers, facilitates REM sleep. All these
several hours after the drug administra- agents reduce norepinephrine concentration
tion. This is caused by depletion of norepi- in the brain by enhancing norepinephrine re-
nephrine brain levels. lease from the synaptic vesicles.
3 Physiology and Pharmacology

Interestingly, the p adrenergic receptor amine. In addition, the effect of amphet-


blockers in general have no effect on wakeful- amine on sleep in cats is not attenuated by
ness, REM sleep, or NREM sleep, indicating destruction of norepinephrine neurons,
that only a adrenergic receptors and not the P which seem to indicate that amphetamine-
adrenergic receptors may be involved in the induced arousal and insomnia are medi-
maintenance of sleep (35). ated by dopaminergic mechanisms.
5. Apomorphine. This nonselective DID, re-
3.1 .I 1 Nonhypnotic Drugs Affecting REM ceptor agonist may interact with either
Off Switch presynaptic or postsynaptic receptors de-
pending on the dose. Large doses of apo-
1. Cholinergic Antagonists. Atropine, which morphine delay and reduce REM sleep.
is a muscarinic antagonist that in some 6. SSRI Antidepressants. Selective serotonin
cases also blocks the effects of nicotinic reuptake inhibitor (SSRI) antidepressants
agonists, suppresses REM sleep. The ef- decrease REM sleep. This is ascribed to the
fects of the muscariniclnicotinic agonist increase in postsynaptic serotonin levels.
carbachol, which facilitates REM sleep, are Several drugs, including fluoxetine, that
prevented by systemic administration of specifically inhibit the reuptake of seroto-
atropine. Similarly, scopolamine delays the nin induce wakefulness during sleep and
appearance of REM sleep (35). increase alertness during the day.
2. Histamine H, Receptor Agonists. Selective 7. NSRI Antidepressants. Nonselective sero-
HIreceptor agonists decrease both NREM tonin reuptake inhibitors (NSRI) also block
and REM sleep stages. This action can be the reuptake of norepinephrine. Several of
prevented by pretreatment with H, antag- the old tricyclic antidepressants belong in
onists. In addition, it seems that blockade this category. Imipramine and desipramine
of CNS H, receptors leads to sedation ac- reduce REM sleep because of the increased
counting for the well-known sedative activ- norepinephrine levels at postsynaptic re-
ity of antihistamines (36). ceptors caused by reduced reuptake of
3. Monoamine Oxidase (MAO) Inhibitors. In- norepinephrine.
hibitors of the catabolic enzyme MA0 in- 8. GABA, opioids, interleukin-1 (IL-I), and
crease both catecholamine and serotonin tumor necrosis factor a (TNFa) all inhibit
brain levels, which in turn produce signifi- REM sleep.
cant and prolonged decrease in REM sleep.
This is especially the case with phenelzine 3.1 .I2 Neurotransmitters and NREM Sleep
and nialamide nonselective MA0 inhibi- in Humans. Several agents that influence the
tors and less pronounced with the revers- brain levels of neurotransmitters have a pro-
ible MAO-A inhibitor moclobemide. In nor- found effect on NREM sleep in humans. Most
mal subjects, moclobemide reduces REM studies indicate that tryptophan, a precursor
sleep period during the first night, but by of serotonin, increases NREM sleep time and
the third night, REM sleep returns to nor- decreases sleep latency (38, 39). Tryptophan
mal levels (37). was used one time as a sleep-inducing agent,
4. Amphetamine. Amphetamine facilitates but it is no longer available because it causes
dopamine release and inhibits norepineph- eosinophilic myalgia syndrome.
rine reuptake, which results in increased Low and moderate L-DOPA dosages that are
postsynaptic norepinephrine levels. Am- converted to doparnine produced no consistent
phetamine increases wakefulness and effects on NREM sleep (40,411, but high doses
reduces REM sleep. These effects may be of L-DOPA suppress NREM sleep and total
prevented by the preadministration of sleep, resulting in nearly total insomnia.
pimozide, a specific D, receptor antagonist, Parkinson's syndrome patients treated with
which inhibits presynaptic dopamine re- L-DOPA often complain of insomnia.
lease. Propranolol, a p-adrenergic blocker, AMPT and a-methylphenylalanine (AMPA),
does not prevent the effect of amphet- both of which decrease catecholamine brain
Sedative-Hypnotics

levels, had very few measurable effects on cat, and monkey by measuring drug-induced
NREM sleep. In general, GABA (inhibitory changes in the sleep-wakefulness cycle. These
amino acid) promotes NREM sleep and influ- studies have been reviewed (55).
ences sensory transmission and seems to have The ultimate answer for the usefulness of a
an opposite action to glutamate excitatory drug candidate is found in humans (56). Sleep
amino acid. laboratory studies in humans have been in-
creasingly used recently in the evaluation of
NREM On Switch Promoters the effectiveness of hypnotic drugs. These
studies have been reviewed (57, 58).
Serotonin DSIP
Melatonin CCK Briefly, evaluation of the effects of hypnot-
GABA Insulin ics on sleep physiology and sleep architecture,
Adenosine IL-1 as measured by electroencephalography, has
PGD, IFN received increased attention. Continuous all-
GHRH TNF-a! night electrophysiological measurement of
CCK, cholecystokinin; DSE', 6 sleep inducing peptide; sleep termed polysomnography (PSG) has
GHRH, growth hormone releasing hormone; IFN, interfer- made it possible to evaluate the action of hyp-
ons; IL-1, interleukin-1; TNF-or,tumor necrosis factor or. notics on sleep. PSG assessment as a means of
GAB& gamma-aminobutyric acid; PGD,, prostaglandin D,. evaluating the hypnotic effects of a drug can-
didate is now required by the U.S. FDA.
There is a mutual interaction of the factors This method is used to determine sleep pa-
controlling NREM and REM sleep. It is well doc- rameters including total sleep time, number of
umented that during selective REM sleep depri- awakenings during sleep, sleep latency, sleep
vation, there is also a significant reduction in the efficiency, effects on sleep stages, and sleep
low frequency activity of the NREM sleep EEG architecture (reduction of slow wave sleep or
(42). To explain the interaction between NREM REM sleep, changes in the latency of REM
and REM sleep, several models were proposed sleep, etc.). Assessment of hypnotics on sleep
(43). The reciprocal interaction models on the include measures of nighttime sleep and day-
NREM and REM sleep cycle (44) evolved from time function, and quality of sleep, which is
neurophysiological data obtained in animals. It measured by changes in stage 1 sleep, which
is postulated that NREM-REM sleep cycle is typically is increased in many insomnia
caused by the reciprocal interaction of two neu- conditions.
ronal systems in the brain stem with self-ex- In addition to showing statistically signifi-
citatory and self-inhibitory connections. For cant improvement on various parameters (for
further details, recent monographs on sleep example, latency of sleep, onset of sleep, or
medicine should be consulted (45-47). total sleep time in transient insomnia or main-
taining sleep and reducing wakefulness in
3.2 Pharmacology chronic insomnia) the adverse effects caused
Additional details are described in Section 5.3. by hypnotics are also measured. These include
effects on residual sedation, rebound insom-
3.2.1 Evaluation of Sedative-Hypnotics. The
nia (referring to increase in wakefulness or
methods usually employed in the evaluation of anxiety), amnesia, and adverse cardiopulmo-
nary effects.
sedative-hypnotic drug candidates in small ro-
dents (mouse or rat) involve measurements of The goal of sleep research is to help find
hypnotic drugs that will approximate the ideal
the levels of CNS depression. These involve
measurements of sleeping time (48), loss of hypnotic drug.
righting reflex (491, performance on the ro-
tarod (50), behavior in the activity cage (51- 3.2.2 Pharmacologic Effects of Sedative-
531, and finally, potentiation of other CNS de- Hypnotic Drugs
pressants (54). 3.2.2.1 Before Barbiturates. In ancient times,
Recently more emphasis has been placed on alcoholic beverages and herbal potions have
the evaluation of drug candidates in the rat, been used to induce sleep.
3 Physiology and Pharmacology

The first chemical used specifically as a sed- Barbiturates induce hepatic microsomal
ative and later as a hypnotic was bromide in drug-metabolizing enzymes resulting in an
the middle of the 19th century. increased degradation of barbiturates, ulti-
Bromides were followed by paraldehyde, mately leading to barbiturate tolerance.
urethane, and sulfonal. These medications Because of their enzyme-inducing effects,
were no great improvement because they barbiturates can cause increased inactiva-
could be addictive, and an overdose could kill. tion of other compounds (anticoagulants,
The launching of chloral hydrate was an im- phenytoin, theophylline, digoxin, glucocor-
provement because chloral hydrate is a rela- ticoids, etc.). This may lead to serious prob-
tively safe hypnotic drug. lems with drug interactions.
Pharmacologic effects of chloral hydrate:
3.2.2.3 Benzodiazepines, The launch of
It induces sleep in 0.5 h. Librium in 1960 was quickly followed by the
0 The sleep lasts about 6 h.
launch of diazepam in 1961, oxazepam in
1964, nitrazepam in 1965, clorazepate potas-
r It causes a relatively small reduction in sium in 1967, temazepam in 1969, lorazepam
REM sleep. in 1971, and so on.
r It is used mainly in children and the elderly. The benzodiazepines overtook the barbitu-
It is most effective when used for only 1-3 rates because of the following disadvantages
nights to treat transient insomnia. of barbiturates:

They have a narrow therapeutic-to-toxic


3.2.2.2 Barbiturates. A major event in the
dosage range.
field was the launching of barbital (5,5-dieth-
0 They suppress REM sleep.
ylbarbituric acid) in 1903 and phenobarbital
(5-ethyl-5-phenylbarbituric acid) in 1912. The Tolerance develops relatively quickly.
barbiturates dominated the field for nearly 50 0 They have a high potential for physical de-
years, until the launch of Librium (chlordiaz- pendence and abuse.
epoxide) in 1960, the first of the benzodiaz- Drug interactions secondary to microsomal ,
epine class drugs. Benzodiazepines completely enzyme induction are frequent.
overtook the barbiturates and had become
The dominant class of sedative hypnotic drugs The pharmacological effects of benzodiaz-
until the launch of retrocyclic sedative-hyp- epines are outlined as follows:
notics.
The pharmacologic effects of barbiturates 1. Benzodiazepines exert multiple pharma-
are outlined as follows: cologic effects on CNS structures, includ-
ing sedation, hypnosis, decreased anxiety,
muscle relaxation, and anticonvulsant
0 Barbiturates are general CNS depressants. activity.
They depress the CNS at all levels in a dose- 2. Benzodiazepines are not general neuronal
dependent fashion. depressants as are barbiturates.
r Barbiturates decrease the amount of time 3. Benzodiazepines exert activity at various
spent in REM sleep. levels of the neuraxis, but some structures
0 In sufficient doses, barbiturates are anti- are affected to a much greater extent than
convulsant and suppress convulsant activ- are others.
ity. 4. Benzodiazepines have similar pharmaco-
In sedative doses, barbiturates have little ef- logic profiles, but the drugs differ in selec-
fect on the cardiovascular system. Toxic tivity. The clinical usefulness of benzodi-
doses can cause circulatory collapse. azepine drugs varies accordingly.
0 Barbiturates depress respiration at any dose 5. Benzodiazepines enhance GABAergic
level. transmission in all CNS structures.
230 Sedative-Hypnotics

6. Benzodiazepines get attached to receptor All these have a short half-life with no active
sites that are highly specific. By combin- metabolite.
ing with receptor sites, they elicit a phar- There is no objective evidence of rebound
macologic effect. insomnia or tolerance in studies of up to
7. All the effects of benzodiazepines that are 30-40 nights at recommended doses.
mediated by receptors can be prevented or All these have a favorable safety and tolera-
reversed by drugs that act as selective bility profile.
benzodiazepine antagonists. They generally preserve the stages of nor-
8. Benzodiazepines show less tendency to mal sleep.
tolerance and dependency than other
older sedative-hypnotic drugs, especially 3.2.2.5 Antihistamines. The pharmacologic
barbiturates. Also, benzodiazepines pro- effects of antihistamines are summarized as
duce less abuse potential. follows:
9. Benzodiazepines are safer in overdose es- Effects of first generation HI-receptor an-
pecially compared with barbiturates. tagonists in the CNS are mediated by block-
10. Benzodiazepines produce fewer drug in- ade of endogenous histamine neurotrans-
teractions because they do not induce he- mitter.
patic microsomal enzymes. Conversely, antihistamines at high concen-
trations may inhibit the metabolism of his-
3.2.2.4 Heterocyclic Sedative-Hypnotics. tamine methyltransferase thus increasing
Despite the advantages of benzodiazepines the availability of histamine to act at CNS
compared with other sedative-hypnotic drugs, histamine receptor.
tolerance and dependency do occur. Rebound These agents also block a-adrenergic recep-
insomnia may also occur either during each tors, serotonin receptors, and/or cholinergic
night of treatment with benzodiazepines or muscarinic receptors, causing dysuria, mic-
during withdrawal of treatment extended for turition, dryness of the mouth, and tight-
several days. Cessation of benzodiazepines ness of the chest.
may also lead to recurrence of the original 0 High dose therapy may produce allergic re-
symptoms or even to transient worsening. actions and cross-sensitivity to related
Heterocyclic compounds were synthesized drugs.
and tested as sedative-hypnotics with the di- Continuous use of antihistamine may pro-
rect purpose of substituting them for both bar- duce tolerance, rendering the sleep-induc-
biturates and benzodiazepines (Table 5.7). ing effects essentially non-existent.
In quick succession, two heterocyclic
3.2.3 Clinical Pharmacology of Important
non-benzodiazepine sedativeihypnotics were
Sedative-Hypnotics
launched in 1985 by Rhone-Poulenc as zopi-
3.2.3.1 Benzodiazepines. Bromazepam is
and in lgg8 S~nthelaboas zol~idem' usually administered orally between 3 and 18
In 1999, W ~ e t hA ~ e r slaunched
t another het- mg daily in divided doses. a clinical trial in
erocyclic non-benzodiazepine sedativekyp- children, bromazepam suppos~toryand chlo-
notic, zaleplon. ral hydrate suppository were compared as an-
The ~harmacologiceffects esthetic premedication. Increasing doses of
sedative-hypnoticsare summarized as ~ O ~ ~ O W S : bromazepm were used in &Idren. The group
younger than 5 years were inadequately se-
e All these drugs, zo~iclone,zol~idem,and dated compared with those receiving chloral
zaleplon, display affinities to the benzodiaz- hydrate. However, in the group 5 years and
epine receptor. However, problems with de- older, bromazepam and chloral hydrate were
pendency and/or tolerance have not been re- equally effective (59).
ported. Brotizolam in 0.25- or 0.50-mg doses was
All these drugs elicit rapid onset of action. compared in 38 clinical and epidemiological
3 Physiology and Pharmacology

studies with triazolam, zopiclone, zolpidem, ioral impairment in humans, but no such ef-
midazolam, temazepam, lormetazepam, and fects were observed after a 1-mg dose or a
loprazolam. A total of 5506 patients partici- 100-mg dose of amobarbital (66). The plasma
pated in the parallel-design and crossover levels of delorazepam correlated well with
studies. To provide clinically relevant compar- sleep-inducing effects. In a single-blind study,
isons, only studies using comparator agents in delorazepam in a 2-mg dose proved to be a
doses equipotent to the triazolam doses were highly effective hypnotic agent in 22 patients
included. who suffered from long-lasting severe insom-
Two general findings emerged. First, sig- nia (67).
nificant CNS side effects such as excitement In 20 psychiatric patients, delorazepam (2
and violence were not observed with any of the mgld) was as effective as lorazepam (5 mgld) in
hypnotic agents including brotizolam. With the improvement of anxiety and insomnia. No
regard to other CNS side effects, depression, serious side effects were reported (68).
irritability, rebound insomnia, and early Doxefazepam in a 5-mg dose in a controlled
morning insomnia were observed for all hyp- clinical study in humans was equivalent to a
notics in these studies. Second, the authors 15-mg dose of flurazepam in terms of sleep
claim that remarkable similarities were found induction time, sleeping time, and quality of
among all these agents in terms of efficacy, sleep. Moreover, doxefazepam caused signifi-
side effects, and performance-related effects cantly less hangover effect compared with that
(60). caused by flurazepam (69).
However, epidemiologic studies do not In 40 patients, the efficacy of doxefazepam
carry the same significance as direct compar- in a 20-mg dose did not diminish over 1 year,
ative randomized double-blind studies con- and no major side effects were reported (70).
ducted against placebo and a comparator In a double-blind study involving 1139 pa-
drug. tients, estazolam in a 2-mg dose seemed to be
Brotizolam (0.25 mg) in randomized dou- equivalent to a 10-mg dose of nitrazepam in
ble-blind studies was as effective as flunitraz- efficacy. A higher dose of estazolam (4 mg) was
epam (2 mg) (61) and triazolam (0.25 mg) (62). more effective but also caused more incidence
However, brotizolam produced markedly of side effects than a 10-mg dose of nitrazepam
fewer adverse side effects than flunitrazepam. (71). The incidence of unsteadiness caused by
In addition, it was also reported (63) that the 2 mg of estazolam was the same as that caused
incidence of hangover and gastrointestinal by 5 mg of nitrazepam.
problems was greater in patients treated with In a double-blind crossover study, estazo-
2 mg flunitrazepam than in those treated with lam (2 and 4 mg) was compared with nitraz-
0.5 mg brotizolam. epam (5 and 10 mg). Administration of 2 mg of
Brotizolam (0.5 mg) was as effective as 2 estazolam prolonged total sleep time and de-
mg flunitrazepam in inducing sleep and was creased stage 1 and stage 2 sleep, whereas 4
superior in maintaining sleep in a double- mg of estazolam reduced stage 2 sleep and
blind trial involving 40 patients due to un- REM sleep. Nitrazepam (5 mg) produced pro-
dergo surgery (64). longation of total sleep and a decrease in fre-
Cinolazepam was evaluated in a double- quency of awakenings, whereas 10 mg of ni-
blind placebo controlled trial in 20 normal trazepam prolonged stage 2 sleep and reduced
subjects. The subjects were given either pla- the total wakefulness during the night (72).
cebo or 40 mg cinolazepam orally 30 min be- Flunitrazepam in a 2-mg dose was com-
fore bedtime. A significant improvement in pared with zolpidem in a 20-mg dose. Forty-
sleep maintenance was obtained with 40 mg two insomniac female in-patients between 30
cinolazepam, measured by sleep disruption and 65 years of age were included in a double-
using nocturnal traMic noise. Sleep architec- blind, parallel group trial and were randomly
ture was only minimally affected, and sleep allocated to the two treatments. Study dura-
quality improved significantly (65). tion was 9 days with 2 days of placebo run-in, 5
Delorazepam in 2-mg doses in a controlled days of active medication, and 2 days of pla-
trial produced a hangover effect and behav- cebo withdrawal. Sleep latency, sleep dura-
Sedative-Hypnotics

tion, number of awakenings, and time spent secutive nights in insomniac patients. Both
asleep during the night were given an ordinal flurazepam and estazolam significantly im-
score; condition in the morning was evaluated proved sleep. There was no significant differ-
by visual analogue scale (VAS), and the psy- ence in hypnotic effect between flurazepam
chomotor performance was evaluated by the and estazolam.
following tests: night-day for anterograde am- The percentage of patients reporting any
nesia, digit span for verbal recall, and Grun- adverse effect was greatest for flurazepam fol-
berger's fine motor function test. lowed by estazolam and placebo.
There was no difference between zolpidem Estazolam and flurazepam effectively, and
and flunitrazepam for any of the variables; the comparably, relieved insomnia when adminis-
drugs were significantly better than placebo tered for seven nights in adult patients com-
baseline for all the sleep efficacy variables.
plaining of insomnia. Estazolam demon-
The results of this study indicate that zolpi-
strated a more favorable side effect profile
dem is as effective as flunitrazepam in induc-
ing and maintaining sleep, but it does not in- than flurazepam (76).
duce a sense of weakness in the morning and Loprazolam (1mg) was compared with tri-
does not impair memory (73). azolam (0.25 mg) in a cross-over double-blind
In a double-blind study of 102 patients with trial. The drugs were administered by a design
a mean age of 70 years, flunitrazepam was of cross-over on the first two nights and con-
compared with zopiclone (74). The patients tinuation of the preferred treatment. Sixty-
rated their sleep in a diary. There was no sta- seven outpatients suffering from chronic in-
tistically significant difference between the somnia took part in the study.
relatively low dose of 5 mg zopiclone and 1 mg Both drugs provided improvement in sleep
flunitrazepam for 11of the 12 variables mea- quality (decreased sleep latency, increased to-
suring subjective sleep quality and quantity. tal duration of sleep, decreased number of
There was no difference between the drugs in night awakenings) and were equally well tol-
regard to patients' feelings of being rested or erated (77).
alertness. Lorazepam (1 mg) was compared with tri-
A multi-center, double-blind, randomized, azolam (0.25 mg), zolpidem (10 mg), zopiclone
placebo-controlled, parallel-group study com- (7.5 mg), and placebo in a randomized doub1.e-
pared the next-day residual effects, hypnotic blind study using 10 nocturnal polysomno-
efficacy, and sleep staging effects of fluraz- grams with at least 72-h washout intervals.
epam (30 mg) and zolpidem (10 and 20 mg) Six healthy middle-aged subjects who were
with those of placebo in patients with chronic normal sleepers (three men and three women)
insomnia. received single dose of the drugs both under
As measured by objective and subjective basal and under perturbed conditions. For
criteria, both zolpidem and flurazepam were each individual, five recordings were carried
effective hypnotics. Sleep stages were affected out under basal conditions (sound pressure
more by flurazepam than by zolpidem. The in- level not higher than 30 dB) and five record-
cidence of treatment-emergent adverse events ings under acoustically perturbed conditions
was approximately the same for zolpidem (10 (continuous white noise at 55 dB). Sleep qual-
mg), flurazepam, and placebo. The 20-mg dose ity was assessed by visual analogue scale
of zolpidem (twice the therapeutic dose) was (VAS). Zolpidem produced the highest protec-
associated with a higher incidence of adverse tive action of the four drugs during perturba-
effects. It was concluded that no next day re- tion (78).
sidual effects are associated with nightly in- Lormetazepam (1mg) was compared with
take (three nights) of the recommended dose midazolam (15 mg) and zopiclone (7.5 mg) as
of zolpidem. At this dose, zolpidem was an ef- night medication in patients scheduled for
fective and safe hypnotic (75). elective surgery the next morning. Sixty pa-
Flurazepam (30 mg) was compared withes- tients divided at random into three groups
tazolam (2 mg) and placebo in a multi-center, (double-blind) received the medication at one
randomized, double-blind study for seven con- time.
3 Physiology and Pharmacology

The three hypnotics were equally effective epate increased total sleep time and reduced
as sleep medication for sleep onset latency, du- the number of awakenings, and the time re-
ration of sleep. and condition on awakening, quired to fall asleep was decreased. A dose of 5
whereas zopiclone provided significantly mg of nordazepam had no effect on the dura-
fewer spontaneous awakenings. tion of sleep stages. Nordazepam (10 mg) and
On the other hand. the lormetazepam potassium clorazepate (15 mg) decreased the
group scored significantly better in an ocular duration of stage 2 sleep. During the recovery
imbalance test than the zopiclone group (79). night, stage 1 sleep was reduced and stage 2
Midazolam (7.5 mg), flunitrazepam (1mg), sleep was increased. No effects of stage 3 sleep
and placebo were compared in a double-blind were observed, but stage 4 sleep seemed to be
crossover trial to study the effects of drugs on suppressed.
sleep, nighttime respiration, and body move- Potassium clorazepate is decarboxylated
ments in five elderly insomniac patients. No rapidly at the pH of the stomach to form nor-
signs of increased respiratory resistance was dazepam (desmethyldiazepam), which is
seen with either of the drugs or placebo. There quickly absorbed. The peak plasma nordaz-
were no differences in the quality and quan- epam concentration is obtained 45 min after
tity of sleep induced by either drug. Only the clorazepate administration of 15 mg (93).
sleep onset latency was shorter with flunitraz- Potassium clorazepate is used in the
epam compared with midazolam and placebo United States in rather high doses of 15-60
(80). mg daily in two to four divided doses or as a
Nimetazepam is metabolized to nitraz- single dose at night. In the United Kingdom, a
epam. It is used as a hypnotic in 3- to 5-mg single dose of 15 mg potassium clorazepate is
doses. The features and characteristics of usually given at night or a dose of 7.5 mg is
nimetazepam are very similar to those of ni- given three times a day.
trazepam. Clorazepate in 22.5-mg daily doses admin-
Nitrazepam in doses as low as 5-10 mg pro- istered for 8 days decreased REM sleep, stage
duces a hypnotic effect in humans comparable 4 sleep, sleep latency, and total waking (94),
with a 100- to 200-mg dose of amobarbital(81- whereas total sleep time was increased. Dur-
83), 50- to 200-mg dose of butabarbital (18, ing recovery, REM sleep, and sleep latency
83-85), 100- to 200-mg dose of secobarbital were increased (95).
(86),and 250- to 500-mg dose of glutethimide Quazepam (15 mg) was compared with tri-
(87). Nitrazepam suppressed REM sleep (88) azolam (0.5 mg) and placebo in 65 insomniac
in humans but the extent of suppression de- patients. The patients were treated with pla-
creased with time (88).Sleep is longer lasting cebo for 4 days into the study, and if no ame-
and less broken while using nitrazepam, and lioration of insomnia was observed, they were
no tolerance was obvious after 2 months of allocated randomly to the drugs with 32 pa-
nitrazepam use (89). After stopping nitraz- tients receiving quazepam and 33 triazolam
epam, there is a rebound of REM sleep, which for 8 weeks and finally placebo for another
reaches a maximum in 1-2 weeks (90). Com- week. The sleep quality, sleep efficacy, un-
plete recovery after nitrazepam use takes 3-6 wanted side effects, and the rebound effects
weeks (91). Nitrazepam also produces hang- had been assessed by specific evaluation.
over effects with impairment of psychomotor Quazepam had significantly less night awak-
performance and difficulty in falling asleep enings. At the treatment's interruption, only
that may be longer lasting than those pro- the patients treated with triazolam had longer
duced by sodium amobarbital(17). awakenings and rebound symptoms. In con-
Nordazepam is the principal metabolite of clusion, quazepam has good hypnotic effect
diazepam. It has been administered as a hyp- without inducing rebound effects (96).
notic in 7.5- to 15-mg daily doses (92). Temazepam (15 mg) was compared with
The effects of nordazepam and a precursor, triazolam (0.125 mg), zolpidem (5 mg), and
potassium clorazepate, on sleep were evalu- placebo. After a single-blind placebo screening
ated in humans (92). A dose of 5 or 10 mg weak 335 elderly insomniacs were randomized
nordazeparn or 15 mg of potassium cloraz- to 28 days of double-blind treatment with the
Sedative-Hypnotics

drugs or placebo followed by a 14-day single- and that the two drugs are relatively safe and
blind placebo withdrawal period. The primary effective in the treatment of insomnia (99).
efficacy parameters were self-reported sleep Zolpidem (10 mg) or triazolam (0.25 mg)
latency (SSL) and self-reported total sleep du- were given to patients for 14 days in a random-
ration (SSD); they were measured by re- ized double-blind study. Data form 139 pa-
sponses on daily morning questionnaires. tients were used in the analysis. No statisti-
Compared with placebo, zolpidem and cally significant differences were found
temazepam produced significantly shorter between the two groups regarding sleeping
SSL over the 4 treatment weeks, but triazolam time, number of awakenings, or sleep quality.
did not. In the zolpidem group, SSL was sig- Morning feeling and day feeling were numeri-
nificantly shorter than in the placebo group in cally better for zolpidem, although not statis-
all 4 treatment weeks; in the temazepam tically significant. There was no statistically
group, SSL was significantly shorter than in significant difference in the number of pa-
the placebo group at weeks 1, 3, and 4. SSD tients experiencing side effects in the two
was increased above baseline levels in all treatment groups. On a short-term basis, ad-
groups. No tolerance to the subjective effects ministration of zolpidem (10 mg) seemed as
or rebound above baseline levels occurred in effective and well tolerated as triazolam (0.25
any of the treatment groups. Overall, the mg) (100).
drugs were well tolerated. No difference was Zaleplon was evaluated for efficacy and
found among the placebo and treatment safety compared with zolpidem. After a
groups in overall adverse event incidence 7-night placebo (baseline) period, 615 adult
rates. However, compared with zolpidem and patients were randomly assigned to receive, in
placebo, temazepam produced significantly double-blind fashion, one of five treatments
higher incidences of drowsiness and fatigue, (zaleplon: 5,10, or 20 mg; zolpidem: 10 mg; or
and triazolam produced a significantly higher placebo) for 28 nights followed by placebo
incidence of nervousness than zolpidem (97). treatment for 3 nights. Sleep latency, sleep
Triazolam was compared with zolpidem maintenance, and sleep quality were deter-
and placebo in a double-blind randomized mined from sleep questionnaires that patients
study in elderly insomniacs. The patients re- completed each morning. The occurrence of
ceived zolpidem (5 mg; 70 patients), zolpidem rebound insomnia and withdrawal effects. on
(10 mg; 74 patients), or triazolam (0.25 mg; 77 discontinuation of treatment were also as-
patients). The 3-week active treatment period sessed. All levels of significance were P I0.5.
was preceded by 3 days and followed by 7 days Median sleep latency was significantly lower
of placebo administration. Both patients and with zaleplon (10 and 20 mg) than with pla-
clinicians evaluated sleep quality. The im- cebo during all 4 weeks of treatment and with
provements between the end of placebo phase zaleplon (5 mg) for the first 3 weeks. Zaleplon
and the end of the active treatment phase (20 mg) also significantly increased sleep du-
were significant for all treatments. Overall ration compared with placebo in all but week 3
evaluation indicated that zolpidem and triazo- of the study. There was no evidence of re-
lam are both effective in geriatric insomniac bound insomnia or withdrawal symptoms af-
patients (98). ter discontinuation of 4 weeks of zaleplon
3.2.3.2 Heterocyclic Sedative-Hypnotics treatment. Zolpidem (10 mg) significantly de-
Zopiclone (7.5 mg) was compared to temaz- creased sleep latency, increased sleep dura-
epam (30 mg) and placebo in a double-blind tion, and improved sleep quality at most time
3-week study in insomniac patients. The pa- points compared with placebo; however, after
tients were assessed before and at the end of discontinuation of zolpidem treatment, the in-
each of the 3 weeks active treatment phase cidence of withdrawal symptoms was signifi-
and 1 week and 3 weeks posttreatment. The cantly greater than that with placebo and
results indicated that zopiclone and temaz- there was an indication of significant rebound
epam possess a clinically significant hypnotic insomnia for some patients in the zolpidem
activity with no rebound insomnia or anxiety group compared with those in the placebo
occurring during the week of drug withdrawal group. The frequency of adverse side events in
4 History

the active treatment groups did not differ sig- and Roche followed with the introduction of
nificantly from that in the placebo group. Zale- Noludar (methyprylone) in 1955. However,
plon is effective in the treatment of insomnia. these two sedative hypnotic drugs displayed
In addition, zaleplon seems to provide a favor- many of the unwanted side effects of the bar-
able safety profile, as indicated by the absence biturates. Noludar is no longer marketed and
of rebound insomnia and withdrawal syrnp- the sales of Doriden are insignificant today.
toms once treatment was discontinued (101). 4.1.4.2 The Second Phase. The second
phase of the development of heterocyclic sed-
ative-hypnotics was initiated after the devel-
4 HISTORY opment and launch of the benzodiazepine
sedative-hypnotics. Although the 1,Cbenzodi-
4.1 Discovery of Important Hypnotic Drugs azepines are safe and effective drugs, they too
have produced certain undesirable side ef-
4.1.1 Before Barbiturates. The introduc- fects. This compelled some companies to de-
tion of ether and chloroform in the 1820s led velop non-benzodiazepine sedative-hypnotic
to the synthesis of similar chemical com- drugs.
pounds. The famous German chemist Justus These include Rhone Poulenc (Aventis),
Liebig synthesized chloral in 1831 by passing the developer of zopiclone (launched in 19851,
chlorine through alcohol (hence its name). Synthelabo (Sanofi Synthelabo) the developer
This led to the development of chloral hydrate, of zolpidem (launched in 19881,and Wyeth Ay-
the first synthetic potent hypnotic drug that erst, the developer of zaleplon (launched in
was safe enough for routine use. Chloral hy- 1999).
drate was introduced in 1869. All three compounds elicit rapid onset of
In 1887, a number of new sulfur com- action and a full night's sleep. They have a
pounds were synthesized by Eugen Baumann short half-life with no active metabolites.
at the University of Freiburg, Germany and There is no objective evidence of rebound in-
evaluated by Alfred Kast. One of these, sul- somnia or tolerance in studies of up to 30-40
fond, was acquired and launched by Bayer in nights at recommended doses. They have a fa-
Germany. vorable safety and tolerability profile and gen-
,
erally preserve the stages of normal sleep.
4.1.2 Barbiturates. Based on the finding Zopiclone, zolpidem, and zaleplon have
that some compounds containing a quater- made major inroads in capturing significant
nary carbon (sulfonal and amylene) displayed market shares of the sedative-hypnotic mar-
hypnotic properties, in 1903, Emil Fischer and ket segment.
J. von Mehring synthesized 5,5-diethylbarbi-
turic acid. This was marketed by Bayer as 4.1.5 Benzodiazepines. ARer the first phase
Verona1 in the early 1900s. Since 1903, hun- of the launch of heterocyclic sedative-hypnotics,
dreds of barbiturates have been synthesized, as exemplified by glutethimide and methypry-
but only a few turned out to be useful. In ad- lone, most significant milestones were reached
dition, because of their side effects, the syn- by Roche. In 1960, Roche launched Librium
thesis of non-barbiturate hypnotics has been (chlordiazepoxide) and in 1963, Valium (diaz-
undertaken. epam). These two compounds were the first
two 14-benzodiazepine class compounds
4.1.3 Halogenated Sedative-Hypnotics. At- launched in the world. Subsequently a num-
tempts to develop effective halogenated seda- ber of companies launched several other 1,4-
tive hypnotic drugs without bothersome side benzodiazepines for a number of indications
effects have not met with success and resulted (sedative-hypnotic, anxiolytic, anticonvulsant,
in only marginally useful products. and muscle relaxant).
Nitrazepam (Mogadon) was the first benzo-
4.1.4 Heterocyclic Sedative-Hypnotics diazepine marketed in 1965 by Roche as a spe-
4.1.4.1 The First Phase. CIBA (Novartis) cific sedative-hypnotic drug. At that time it
introduced Doriden (glutethimide) in 1954 was already well known that diazepam mar-
Sedative-Hypnotics

keted in 1963 had also displayed sedative-hyp- azepines represented a major step forward.
notic activity, but diazepam was marketed pri- They replaced the barbiturates, which were
marily as an anti-anxiety agent. very effective but produced significant side ef-
The benzodiazepines became widely used fects. The biggest problem was the potential
and dominated the market for approximately fatal respiratory depression caused by over-
25 years. dose of barbiturates, which led to the barbitu-
However, the contention that benzodiaz- rates being used in suicide attempts.
epines have solved the problems usually asso- The launch of benzodiazepines eliminated
ciated with the use of barbiturates has been the risk associated with using barbiturates.
contraindicated. It has been pointed out that The benzodiazepines are well tolerated and
in humans, benzodiazepines produce a consid- produce only low toxicities. However, after ex-
erable reduction in REM sleep, and in addi- tensive use of benzodiazepines in millions of
tion, an appreciable reduction of stage 3 and patients, it became apparent that benzodiaz-
stage 4 sleep. Furthermore, it has also been epines also produce side effects, although to a
reported that a distinction between barbitu- considerably lower degree than barbiturates.
rates and benzodiazepines on the basis of The most important side effects of benzodi-
withdrawal effects on the sleep pattern as doc- azepines include the following:
umented by EEG measurements seems un-
warranted. On the other hand, it should also 1. Benzodiazepines disturb the natural archi-
be noted that, although in humans larger dose tecture of sleep, shortening REM sleep,
of the benzodiazepines suppress REM sleep, stage 3 and 4 (the deep sleep) periods, and
the extent of REM sleep suppression is usually lengthening stage 2 sleep.
smaller than with most other types of hyp- 2. Extensive use of benzodiazepines may lead
notic drugs. to psychological and physical dependence,
Benzodiazepines drugs are often taken in withdrawal syndromes, and rebound in-
suicidal attempts but have rarely been fatal somnia on discontinuation of benzodiaz-
following even a large overdose. In this re- epine treatment.
spect, benzodiazepines possess tremendous 3. Benzodiazepines may also cause memory
advantage over barbiturates and several other loss (anterograde amnesia), apneas, dis-
classes of hypnotic drugs. abling residual effects on alertness, and
may potentiate the CNS depressing effects
4.1.6 Antihistamines. A number of antihis- of alcohol.
tamines display sedative activity. Some of
these drugs have been employed as sedative- The recognition that benzodiazepines pos-
hypnotics. Several antihistamines are avail- sess these adverse effects caused Synthblabo
able on the OTC market, which explains their scientists to initiate research to develop a new
relative popularity. sleep-inducing drug that would be devoid of
4.2 Discovery of Zolpidem side effects.
In the early 1990s, the French company Syn- 4.2.2 The Development of Zolpidem. The
thblabo assembled a group of well-trained sci- fact that there are several benzodiazepine re-
entists to focus on research in the CNS area. ceptor (BZR) site subtypes preferentially lo-
The focus of the CNS department was to dis- cated in certain areas of the brain (see Section
cover innovative drugs that act through novel 5.2.2) encouraged Synthblabo scientists to
mechanisms and meet unfulfilled therapeutic search for new hypnotics that would lack the
needs. Another goal was to create new drugs unwanted pharmacologic activities generally
with improved efficacy or safety in the areas of associated with the hypnotic activity of benzo-
anxiety, depression, schizophrenia, sleep dis- diazepines and that would not cause tolerance,
orders, and neurodegenerative diseases. dependence, or rebound phenomena when
treatment was discontinued.
4.2.1 The Use of Benzodiazepines. In the The next step involved the search for com-
area of sleep disorders, the launch of benzodi- pounds that would display selective activity
5 Structure-Activity Relationships

for BZR subtypes. This research culminated in In Equation 5.6, C represents the moles of
the discovery of zolpidem, a selective agonist drug per kilogram of test animal producing
of the BZ-1 subtype that turned out to have hypnosis, P is the calculated partition coeffi-
selective hypnotic activity free of the disad- cient (based on the measured value for 5,5-
vantages of the benzodiazepines. diethylbarbiturate), and k , k t , and k" are con-
Synth6labo's strategy consisted of three stants derived by the method of least squares.
stages: The barbiturates were clustered into eight
groups depending on the species of test animal
1. Analysis of three-dimensional molecular and the means of measurement of hypnosis,
models helped determine the affinity of the such as ED,, or MED, as reported in the liter-
ligands for their receptors and elaborate ature from which the biological test data were
the chemical concept. taken. A constant termed log Powas derived
2. Synthesis of large number of heterocyclic by setting the derivative (d) log(1lC)ld log P
compounds corresponding to the chemical equal to zero and solving for log P. log Powas
concept led to the identification of the im- defined as representing "ideal liphophilic
idazopyridine class of compounds. character" for a set of congeners under specific
3. Lead optimization of imidazopyridines dis- test conditions. For the five groups of barbitu-
playing optimal hypnotic properties led to rates for which confidence intervals could be
the selection of SL 80, 0750 (zolpidem). calculated, there was good general agreement
among the Povalues with a mean value of 1.9.
Zolpidem showed powerful sleep-inducing Po values of about 2 were also obtained for
activity in EEG tests in rats with a short du- various non-barbiturate hypnotics (e.g., acety-
ration of action. In addition, zolpidem did not lenic alcohols, N, N'-diacylureas) and it was
alter the architecture of sleep and thus in- suggested that any organic compound with
duced physiological sleep. Clinical trials in hu- -
log P 2, which is not rapidly metabolized or
man with zolpidem began in 1983 and con- eliminated, would possess some hypnotic
firmed the results obtained in animals. properties.
Furthermore, in humans, zolpidem had a In a subsequent study, Hansch reported
short half-life combined with fast elimination that the induction of cytochrome P450 by a
from the body. Zolpidem was first marketed in series of 5,5-substituted barbiturates was di-
France in 1988 and subsequently it was mar- rectly related to their hydrophobicity (105).
keted worldwide. The features of zolpidem are Analysis of the in vitro data for barbiturate-
described elsewhere in the chapter. induced P450 in cultured chick hepatocytes
yielded Equation 5.7, where C is the drug con-
centration that caused a 50% increase in
5 STRUCTURE-ACTIVITY RELATIONSHIPS cytrochrome P450 and P is the octanol-water
partition coefficient.
5.1 Quantitative Structure-Activity
Relationships (QSAR)

5.1 .I Barbiturates. QSAR studies by Hansch


presented evidence that the hypnotic activity of
barbiturates depends largely on their relative li-
pophilic character as determined by octanol-wa- n =number of observations, r = correlation
ter partition coefficients (102-104). Employing coefficient, s = standard deviation, F = sta-
Equation 5.6, a QSAR analysis was conducted tistical significance factor.
on over 100 barbiturates as well as a number of
non-barbiturates having hypnotic activity. 5.1.2 Benzodiazepines. Sternbach's dis-
covery of the benzodiazepines, a major class of
drugs having a diversity of therapeutically
Sedative-Hypnotics

(5.8)

chlordiazepoxide benzodiazepinones

useful pharmacological effects, must certainly ported by Sternbach and that bore a variety of
rank among the landmark achievements in substituents at positions 7 and 2' (108). Using
the annals of medicinal chemistry. Discovery CND0/2 methodology and calculated values
of the prototype compound, chlordiazepoxide, for dipole moment (p) and net charge on the
was serendipitous in that it, rather than the carbonyl oxygen (qo), analyses of the data for
simple substitution product, was formed by an several different in viuo tests were conducted.
unexpected ring enlargement from the Equations 5.9 and 5.10 were derived from data
treatment of a quinazoline N-oxide deriva- for the pentylenemetrazole test (a measure of
tive with methylamine (Equation 5.8) (106, anticonvulsant activity) and the "Cat" test ( a
107). After its structural elucidation, it was measure of sedative/muscle relaxing activity
found that this compound possessed desir- in cats), respectively.
able pharmacological properties including
anxiolytic, sedative, muscle relaxant, and
anticonvulsant activities. Ensuing preclini-
cal and clinical studies corroborated the ini-
tial findings and led to its introduction in
1960 as Librium. Synthetic investigations
aimed a t finding compounds with even bet-
ter pharmacological profiles led to the con-
version of N-oxides such as chordiazepoxide
to the classical 1,4-benodiazepin-2-one che-
motype (Equation 5.8); compounds of this
type were found to have activity at least
equivalent to that of chlordiazepoxide and Improvements in regression by qo were gen-
some, such as diazepam, showed severalfold erally not significant, and the introduction
greater potency in various tests. Thus, alter- of the Hansch lipophilic substituent con-
nate synthetic procedures were developed t o stant failed to produce improvement. It was
obtain a variety of analogues and study SAR. suggested that the negative term containing
A summary of the earlier qualitative SAR p might be caused by a binding process in-
findings based exclusively on in viuo data is volving dipole interactions that remove drug
graphically shown in Fig. 5.9. molecules from the active site.
A QSAR study was carried out on over 50 In the decades after the first synthesis of
1,4-benodiazepinonesthat were previously re- the prototypical agents chlorodiazepoxide and
5 Structure-Activity Relationships

Activity decreased by groups larger than methyl


I
Activity decreased by substituents
other than C7
R3

Activity increased by electron Activity increased by halogen


withdrawing groups, decreased by subsituents
electron donating groups

b~ctivitvsianificantlv decreased bv subsitunents h


Figure 5.9. Qualitative structure activity relationships of benzodiazepin-2-ones.

diazepam, thousands of benzodiazepine con- this analysis supported the importance of a


geners were synthesized and studied by nu- carbonyl at position 2, the detrimental effect
merous laboratories. The discovery and char- of groups larger than H or CH3 at positions 1
acterization of the BZR in the late 1970s led to and 3, and the negative impact of substituents
the development of BZR radioligand binding at position 4'; the latter observation suggests
assays, thus affording an in vitro method for that the pendant phenyl ring occupies a hydro-
the rapid screening of large numbers of com- phobic pocket in the receptor binding site and
pounds. The ensuing wealth of BZR binding that the depth of the pocket cannot accommo-
data afforded the opportunity for further date apara substituent. The importance of hy-
QSAR studies that have been reviewed (109, drophobic effects was demonstrated by a sig-
110); a summary of a number of these analyses nificant correlation between inhibition of BZR'
follows. binding and lipophilic character (measured by
A Free-Wilson analysis by Borea of in vivo
chromatographically determined R, values)
data of 55 benzodiazepines led to the following as shown in Equation 5.11 (113).
rank orders of contributions to activity of sub-
stituents at position 7 and 2' (as depicted in
Fig. 5.9), thus showing the importance of elec-
tron withdrawing groups at these positions
(111):
Position 7: NO, > CF, > Br > CN > C1>
N(CH,), > SOCH, > SBu > SCH, > CH, > H
> SO,CH, > Ph > F
Position 2': C1> F > Br > NO, > CF, > H Conformational and electronic properties of
> OCH, > CH, 21 benzodiazepines were calculated using
Despite several obvious inconsistencies, empirical energy and semiempirical molecu-
the results indicate the importance of electron lar orbital methods (114). Compounds that
withdrawing groups at positions 7 and 2'. An- were either highly active or very weakly ac-
other study by Borea employing the Free-Wil- tive in BZR binding (e.g., diazepam, Ki = 8.9
son method was based on the inhibition of nM and medazepam, Ki = 3850 nM) were
[3H]diazepam binding by a set of 39 benzodi- found to have very similar low energy con-
azepines (112). In addition to corroborating formations, thus indicating that conforma-
the positive effect of electron withdrawing tional factors are not important for receptor
moieties at positions 7 and 2', the results of recognition. However, mapping the electro-
Sedative-Hypnotics

static potential of the benzodiazepine mole-


cule led to the postulation that interactions
between electron withdrawing substituents
at C7, the carbonyl oxygen at position 2 and
the N4 imine nitrogen with three different
cationic receptor sites are required for high-
affinity analogs.
A distance geometry approach using a In the above equation, I, is an indicator
three-dimensional structure-directed QSAR value having a value of 1 or 0 for the pres-
method (REMOTEDISC) was employed to an- ence or absence of a 2' substituent. The con-
alyze the inhibition of [3H]diazepam binding clusions of the study were that the positive
by 29 benzodiazepines (115). The results of sign of the a, descriptor suggests that the C7
the method, which uses three-dimensional substituent interacts with a complementary
structure, conformational energies, and atom- hydrophobic pocket on the receptor and that
based physiochemical properties to model the binding to the receptor is enhanced by in-
receptor binding cavity were based on Equa- creasing negative values of E-LUMO, which
tion 5.12. are associated with decreased electron den-
sity in the fused benzene ring. It was postu-
lated that a charge-transfer interaction oc-
curs between the ligand and a n electron-rich
site of the receptor binding domain.
However no explanation was offered for the
beneficial effect of a 2' substituent.
In this Equation, E, is the conformational As shown in Equation 5.14, hydrophobicity
energy with the weighting factor W, C values of the C7 substituent was found to be an im-
are the site pocket and physiochemical prop- portant factor in the correlation of binding
data with the physicochemical parameters of
erty-dependent coefficients determined by
benzodiazepines and P-carbolines (117).
regression analysis, n, is the number of site
pockets, n, is the number of ligand atoms
occupying the site pocket, Pj, is the j t h phys-
icochemical property of the kth occupying
atom of the ligand, and r is the correlation
coefficient. The derived model, which was
comprised of nine binding site pockets, sug-
gested that N1 substituents should be small
and hydrophilic; C7 substituents should be
dispersive and hydrophilic; and the 4' posi-
tion encounters steric repulsion. Except for
C3, little role was found for hydrophobic
interactions. A positive correlation was also established
A study employing a combined QSAR- with the Hammett electronic parameters for
CoMFA (comparative molecular field analysis) positions C7 and C2', but the negative corre-
used observed C3H]diazepam PIC,, values, cal- lation with the I, term shows that presence of
culated HOMO and LUMO energies and total a substituent at the 6 position decreases bind-
dipole moments; hydrophobic, steric, and ing affinity.
field/inductive substituent effects were also As part of a review and commentary on the
considered (116). Equation 5.13 was derived above-mentioned QSAR, Hansch reevaluated
for a set of 30 compounds that varied only in the earlier work and derived some new results
substitution at the C7, C2', and N1 positions (110). His analysis of the [ 3Hldiazepam bind-
(the latter varied only between H and CH,). ing data of over 70 benzodiazepines led to
5 Structure-Activity Relationships

Equation 5.15, which shows a positive contri- The summary conclusion drawn was that
bution to binding affinity by both hydropho- overall ligand hydrophobicity is important for
bicity (logP) and sterimol parameters, Bl-, BZR binding and that for the classical benzo-
and B1-,, for substituents at the 7 and 2' posi- diazepinone chemotype the hydrophobic1
tions, respectively. steric effects of moieties appended to positions
C7 and C2' are positively associated with re-
ceptor affinity.
The computational construction of artifi-
cial neural networks has also been applied to
relate physicochemical parameters of benzodi-
azepines with their receptor affinity and to
predict BZR properties and BZR ligand affini-
ties. In a study by Maddalena and Johnston,
back-propagation artificial neural networks
were used to examine the QSAR between sub-
stituent constants at six positions on 57 ben-
zodiazepinones with their empirically deter-
mined binding affinities (118). Among the
The significance of the Bl-,term was inter- findings of the study were the following:
preted as pointing to a steric effect of the f i s t
atom of groups in the 7 position; i.e., the larger 0 Position 7 is the most important location for
the atom attached to C7, the more effective the enhancing BZR affinity; increases in sub-
binding. It was suggested that atoms at this po- stituent lipophilicty and electronic charge
sition produce a conformational change in the were found to be directly related to in-
receptor that is conducive to ligand binding. The creases in receptor binding. The optimal C7
positive steric effect of C2' substituents implies substituents from best to worst were deter-
that receptor binding is enhanced by the twist- mined to be CH,CF, > I > Br > CF, > C1>
ing of the 5 phenyl ring out of the plane of the C(CH,), > NO, > F > N, > CH=CH,.
seven-membered ring. No role was found in 0 Substituents at position 2' are of second-
Equation 5.15 for electronic parameters. most importance in positively influencing
Hansch's reevaluation of the earlier QSAR BZR affinity, and increases in the polar na-
study of in vivo data (108) resulted in Equation ture of these substituents were shown to be
5.16 for the pentylenetetrazole test. In contrast beneficial, although this effect was dimin-
to Equation 5.9), which shows no role for hydro- ished if the groups were bulky.
phobic effects, Equation 5.16 is positively corre- 0 Substitution at positions 3 and 8 is disfa-
lated with both hydrophobicityand steric effects vored, and electrostatic influences at these
of the C7 and C2' substituents as well as with qo positions are important.
(charge on the carbonyl oxygen).
Figure 5.10 summarizes the findings of the
various QSAR studies. It is somewhat discon-
certing that there is considerable disagree-
ment among the key conclusions drawn from
several of the studies, e.g., some propose a hy-
drophobic interaction of C7 substituents,
whereas others suggest that hydrophilic
groups are favored or that electrostatic inter-
actions of C7 groups with a cationic subsite of
the receptor are important. However compar-
ison of Figs. 5.9 and 5.10 shows that the vari-
ous QSAR largely corroborate the earlier qual-
itative SAR reported by Sternbach. Because
Sedative-Hypnotics

[ ~ r o u plarger
s than methyl disfavored (112, 115)

Substituents at benzene ring positions


other than C7 disfavored (117, 118)

r" site (114)

Electron withdrawing
groups favored (111, 112, 114, 116);
hydrophilic groups favored (115);
hydrophobic and/or sterically bulky
favored (110, 116, 117, 118)
pfL R2'
Electron withdrawing
groups favored (111, 112);
hydrophobic groups favored (110);
polar groups beneficial if not too
bulky (118)
Substituents disfavored (112, 115)

Figure 5.10. Summary of findings from QSAR studies of benzodiazepin-2-ones. References in


parentheses.

the latter were based exclusively on in vivo nition sites of differing affinities for GABA
data, whereas most of the QSAR studies have (10)itself as well as for GABA agonists such as
used in vitro binding data, the general agree- the natural product muscimol (11)and the
ment between the two suggests that the phar-
macological effects of the benzodiazepines are
due mainly, if not solely, to their BZR interac-
tions.

5.2 Receptor Interactions


Many of the pharmacological properties of
barbiturates and benzodiazepines, including
their therapeutic actions and their tolerance
and dependence, are associated with their ef-
fects on GABAergic neurotransmission in the
CNS. GABA (10) is a major inhibitory neuro-

synthetic analog THIP (12, gaboxadol), in


which incorporation of the basic nitrogen into
a 6-membered ring results in much greater
structural rigidity than in the conformation-
transmitter that mediates its effects through ally flexible GABA molecule. The 3-hydroxy-
interaction with several different receptor isoxazole moiety common to both (10) and
subtypes. Activation of the GABA, receptor, a (11) mimics the carboxyl group of GABA.
member of a superfamily of transmitter-gated Based on the equipotent agonist activity of
ion channels, opens an ion channel allowing GABA and THIP despite the disparity in their
the entry of chloride ion with the result of structural mobility, it has been suggested that
dampening neuronal activity through hyper- GABA interacts at the receptor level in an ex-
polarization of cell membrane potential. The tended near planar conformation (119).In ad-
GABA, receptor complex bears distinct recog- dition to its GABAergic activity in preclinical
-:
Structure-Activity Relationships 243

Choride ion channel


.@

GABAA
igonists Agonists Antagonists
rntagonists Bicuculline

lembrane

Barbiturates
Figure 5.11. Schematic represen-
Phenobarbital tation of the GABA, receptor com-
Pentobarbital plex. Reprinted with modification
'icrotoxin
butylbicyclophosphorothionate(TBPS) from P.A. Saunders and I.K. Ho,
Prog. Drug Res., 34, 261 (1990)
;opropylbicyclophosphate (IPPO)
'entylenetetrazole I with permission from Birkhauser'
Verlag AG.

sts, THIP has been found to be an effective been grouped into six classes based on se-
:dative-hypnotic in humans (120-122). quence homology. The 16 human GABA, re-
As shown in Fig. 5.11, the GABAAreceptor ceptor subunits (al- 6, pl-4, yl-4, 6, &) that
~mplexalso has binding sites for drugs such have been cloned to date show approximately
r barbiturates and benzodiazepines as well as 30% sequence identity among subunits and
r certain convulsive agents such as picro- about 70%homology among subunit subtypes
~xinwhich inhibit chloride channel activity. (125). Despite the enormous number of possi-
ABA receptors, their diversity, and pharma- ble arrays, it seems that a rather limited num-
)logy have been extensively reviewed (123- ber of hetero-oligomeric combinations actu-
18). ally occur in nature and that a functional
Electron microscopy studies have revealed GABA, receptor requires both an a and P and
at, like acetylcholine receptors, the ion one other subunit type. The pentameric as-
lannel of the GABA, receptor is formed by sembly is illustrated in Fig. 5.11.
le pentameric assembly of hetero-oligomeric
ibunits (129); each subunit has four trans- 5.2.1 Barbiturates. Barbiturate interactions
embrane spanning domains and all five sub- with the GABA, receptor complex have been
nits are arranged so that their second trans- reviewed (130,131). Barbiturate effects on re-
embrane domains comprise the ion channel ceptor-mediated chloride ion flux have been
all. Cloning of the subunits from vertebrates extensively studied employing electrophysio-
ss resulted in nearly 20 cDNAs, which have logical techniques either in vivo or in isolated
Sedative-Hypnotics

or tissue-cultured neurons. Patch-clamp stud- In addition to their interaction with the


ies in cultured mouse spinal neurons have GABA, receptor complex, the pharmacologi-
shown that barbiturates such as pentobarbital cal effects of barbiturates may in part be me-
increase the duration of channel opening diated by other mechanisms (135). For exam-
while causing a slight decrease in the fre- ple, pentobarbital has been shown to depress
quency of opening (132). The increased open- responses to quisqualate and kainate but not
ing occurs both in the presence and absence of NMDA, suggesting a receptor subtype-specific
GABAAagonists, and whereas synaptosomal blockade of excitatory glutamatergic neuro-
ion flux studies employing [36C1-l show that transmission. Barbiturates may act also inter-
pentobarbital enhances the effect of GABA- act with voltage-gated ion channels such as
stimulated ion flux, the maximal response of sodium, potassium, and calcium channels, al-
the combination is no greater than the re- though at concentrations beyond the thera-
sponse to pentobarbital alone (133). Such ob- peutic range. Inhibition of potassium chan-
servations indicate that barbiturates stabilize nels could explain the paradoxical pro-
the open conformation of the chloride ion convulsant activity of some barbiturates and
channel (129). blockade of certain voltage-gated calcium
A study of the effects of highly purified op- channels may be responsible for the cardiac
tical isomers of several barbiturates (hexobar- depressant actions of this class of drugs.
bital, pentobarbital, and thiopental) showed
the S-enantiomers to be about two to four 5.2.2 Benzodiazepines. The BZR is dis-
times more potent than the R-enantiomers in cussed in previously cited reviews of the struc-
the potentiation of GABA-induced ion cur- ture and function of GABA, receptors and is
rents (134). These results support a direct ac- the focus of several other reviews (137, 138).
tion of barbiturates at the receptor level as Even though a number of benzodiazepines
opposed to non-specific effects on membranes. had been marketed and widely prescribed for
A direct action of barbiturates on the nearly two decades, their mechanism of action
GABA, receptor complex has been further remained unknown until the identification of
demonstrated by their chloride-dependent, pi- high affinity benzodiazepine binding sites in
crotoxin- and bicuculline-sensitive allosteric rat brain tissue in the late 1970s (139,140). A
enhancement of GABA and benzodiazepine plethora of BZR binding studies soon fol1owe.d
receptor binding (135). The efficacy of com- and served to establish structure-affinity rela-
pounds to act as benzodiazepine receptor ago- tionships as discussed in Section 5.1.2.
nists, inverse agonists or antagonists has been Earlier investigations had indicated a di-
correlated with the ratio of their IC,, versus versity of CNS actions for benzodiazepines, in-
[3H]flunitrazepam binding in the presence cluding modulation of calcium and adenosine
and absence of pentobarbital (136). The "bar- uptake, inhibition of the effects of excitatory
biturate shift" is >1 for agonists, <1 for in- amino acids, and alterations of sodium ion per-
verse agonists, and -1 for antagonists. As will meabilities; however, ensuing studies focused
be subsequently discussed, the effects of vari- on the effects of benzodiazepines on GABA-
ous barbiturates on benzodiazepine binding mediated synaptic inhibition. There is now an
may be associated with their functional abundance of empirical evidence that shows
activity. that compounds interacting as agonists at
The molecular pharmacology of barbitu- BZRs on the GABA, receptor complex cause
rate action at GABA, receptors remains to be an allosteric potentiation of GABA-gated chlo-
elucidated. Neither specific amino acid point ride current intensity. Electrophysiological
mutations within GABAA receptor subunits experiments have established that benzodiaz-
nor chimeras between GABAAand glycine re- epines, like barbiturates, increase chloride ion
ceptors have unequivocally established the lo- flux. However, unlike barbiturates, which
cation of barbiturate binding sites, although cause a increase in the duration of chloride
some studies suggest that the barbiturate-re- channel opening, benzodiazepines augment
ceptor interactions may occur solely within channel opening frequency (132, 141). Agents
the fl subunit (135). such as diazepam were found to potently en-
d
i
5 Structure-Activity Relationships

hance GABA responses at low nanomolar con- was further substantiated by the finding that
centrations and the effects of diazepam were Hido2of the bovine a1 subunit is the major
blocked by the benzodiazepine antagonist, site of photoaffinity labeling by [ 3Hlflunitraz-
flumazenil (Ro 15-1788). The sedative-hyp- epam (148, 149). It was postulated that the
notic, zopiclone, also potentiated GABA re- residue interacts directly with the pendant
sponses, but at high nanomolar concentrations. phenyl group of diazepam and other 5-phenyl
Two distinct sets of BZR, designated as benzodiazepines. Other amino acids within
BZ-I and BZ-I1 (also called 0-1and 0-2, respec- the a1 subunit that may be part of the benzo-
tively), are prevalent in the CNS (142). Pe- diazepine binding site are Gly200,Thr206,and
ripheral type (0-3) BZRs are located in mito- TyrZo9(150, 151). Replacement of Tyr209 by
chondrial membranes and glial cells, but their Ala, Phe, or Gln afforded mutant receptors
relevance to the central action of benzodiaz- that showed moderate to total loss of affinity
epines has not been established. BZ-I recep-
for diazepam or flunitrazepam (Tyr209Phe:2-
tors have abundance in the cerebellum but
to 8-fold decrease, T y ? O g A l a : -40-fold decrease,
paucity in the hippocampus, whereas the con-
verse is true for BZ-I1 receptors; both receptor Ty?OgGln: no detectable affinity). The 6 t y
types are equally expressed in the cerebral cor- for GABA of these Xenopus oocyt~expressed
tex (125). Recombinant studies of GABAAre- receptors was only slightly diminished, but the
ceptor subunits have demonstrated that the ability of flunitrazepam to stimulate GABA-in-
a1 subunit is important for BZ-I receptor duced currents was abolished.
characteristics and that the y2 subunit pro- Phe77and Met130within the y2 subunit have
motes benzodiazepine binding (137). The been shown to be necessary for high affinity
alp2y2 combination was the first GABAAre- binding of andlor modulation by BZR ligands
ceptor subtype to be clearly identified and is (152). Receptors containing a y2Phe7711emuta-
thought to be the most abundant subtype in tion retained high affinity for flunitrazepam
adult mammalian brain (143). Numerous BZR but not for other ligands such as flumazenil
ligands, including benzodiazepines, p-carbo- and methyl p-carboline-3-carboxylate.How-
lines, and imidazopyridines such as zolpidem, ever the mutation prevented allosteric modu-
interact with this receptor subtype. Both a lation of ion channel currents by flunitraz-
and y subunits contribute to the benzodiaz- epam. It was suggested that Phe77serves as a
epine binding site, which seems to be situated contact point for certain BZR ligands, al-
at the interface of these subunits (144, 145). though it is not essential for high affinity bind-
Mapping the benzodiazepine binding site by ing, the energy requirements for which are
site-directed mutagenesis has revealed that al- satisfied by other contact points. But in the
terations of certain amino acids within the N- absence of Phe77, ligands may occupy the
terminal domains of the a and y subunits have binding site in a conformation that is incapa-
significant effects on the affinity and efficacy ble of initiating the allosteric changes leading
of ligands. One such site identified by alanine to channel modulation. A y2Phe77Tyrmodifi-
scanning of the a1 subunit is histidine 101 (rat cation resulted in significant loss of affinity for
numbering) or 102 (humadbovine number- benzodiazpinones bearing a 5-phenyl moiety,
ing) (146). Various other substitutions of the e.g., diazepam, which had a Ki of 3 f l at the
histidine have been examined and the effects mutant receptor versus 12 nM at the wild-type
of several BZR ligands on the mutant a1 sub- receptor (153). High affinity was retained by
units co-expressed with p2 and y2 subunits in BZR ligands lacking the phenyl moiety, thus im-
Xenopus oocytes were evaluated by electro- plying that the tyrosine hydroxyl interferes with
physiological techniques (147). Substitution the phenyl group and that the latter is in close
by Phe, Tyr, and Gln had little effect on the proximity to Phe77when diazepam and like mol-
ability of flunitrazepam to potentiate GABA- ecules bind to the wild-type receptor. Together
induced currents, but other mutations (Lys the cylHislO1, alGlYo0, a 1 T P o 6 , a l T y ? O g ,
and Glu) resulted in a drastic reduction of the y2Phe77, and y2Met130 residues may be in-
flunitrazepam response. The importance of volved in the formation of the binding pocket of
this amino acid residue for agonist recognition BZR ligands (151).
Sedative-Hypnotics

Of particular relevance to sedative-hyp- oms at both C-5 substituents is between 6


notic activity is the observation that zolpidem and 10. Further increase in the sum of the
is a drug that shows high affinity and selectiv- number of carbon atoms decreases hyp-
ity for GABA, receptors containing the a1 notic activity despite increased lipophilic-
subunit (154). Whereas many BZR ligands ity, indicating that lipophilicity must re-
bind potently to receptors bearing other a sub- main within certain limits.
units, zolpidem interacts only with those bear-
2. Within the same series, the branched chain
ing al; for example, it exhibits high affinity for
isomer generally has greater lipid solubil-
alP2y2 receptors but is inactive at a5P2y2 re-
ceptors. To determine the structural elements ity, hypnotic activity, and shorter duration
of the a1 subunit that are essential for zolpi- of action than the straight chain isomer.
dem's activity, chimeras of a1 and a 5 were Stereoisomers have approximately equal
constructed in the putative extracellular N- potencies.
terminal domain and transfected with P2 and 3. Within the same series the unsaturated al-
y2 subunits in HEK293 cells, and the affinities lyl, alkenyl, and alkynyl derivatives are
of the resulting combinations for zolpidem more hypnotic than the saturated analogs
were measured (155). Chimeras that showed with the same number of carbon atoms.
enhanced zolpidem binding relative to wild- Compounds bearing alicyclic or aromatic
type a5P2y2 served to identify the regions of substituents are more potent than those
a1 that are of critical importance to the bind- having aliphatic substituents with the
ing of this drug. Subsequent single amino acid same number of carbons.
replacements of various a5 residues by the
4. Conversion of a 5,5-disubstituted barbitu-
corresponding a1 amino acids within these re-
ric acid to a 1,5,5-trisubstituted analog
gions led to the finding that Thr16,, Gly200,
does not result in a significant change in
and Ser204of the a1subunit are important for
hypnotic activity.
zolpidem recognition. It was suggested that
T h P 2 and Gly200play a conformational role 5. Introduction of polar substituents (OH,
and orient the binding pocket in a manner NH,, COOH, CO, RNH, SO,H) into an ar-
that is optimal for zolpidem binding, whereas omatic moiety at the 5-position decreases
Ser204participates in hydrogen bond forma- lipid solubility and potency.
tion with the carbonyl group of the com- 6. Replacement of the oxygen at C-2 by a sul-
pound's acetamide moiety. Interactions be- fur atom results in faster onset but shorter
tween His1'' and a nitrogen atom of the duration of hypnotic activity. Replacement
imidazole ring of zolpidem and hydrophobic of more than one carbonyl oxygen by sulfur
interactions between the drug's aromatic ring causes a loss of activity, again indicating an
and ~ 2 P hore y2Met130
~ ~ were also postulated. upper limit to lipophilicity.
The cited reviews pertaining to GABA/ben-
zodiazepine receptors discuss numerous other The pharmacological activity of barbitu-
studies that employ chimeric receptors and rates is also influenced by their acidity, which
site-directed mutagenesis to determine the is attributed to the lactam-lactim tautomer-
key structural components of GABA, receptor ism that can occur in all derivatives in which
subtypes comprised of various a, P, and y sub- at least one of the ring nitrogens is unsubsti-
unit permutations. tuted; keto-en01tautomerism also takes place
in 5-unsubstituted or mono-substituted com-
5.3 Structure-Function Relationships pounds (Equation 5.17). Barbiturates must
have acidity within certain limits to possess
5.3.1 Barbiturates. Structural features of hypnotic activity (156). For example, barbitu-
barbiturates that are required for hypnotic ac- ric acid (R,, R,, R,, R, = H), which has a pKa
tivity include the following: of 4.1 and is >99% dissociated at physiological
pH, and the neutral N, N'-disubstituted com-
1. Hypnotic activity increases with lipid solu- pound (R,, R,, R, = Et, R, = Ph) that is com-
bility until the total number of carbon at- pletely undissociated, are devoid of hypnotic
5 Structure-Activity Relationships

ate balance between lipid solubility and ionic


character and that these physicochemcial
properties are influenced by the size and shape
of substituents at the 5-position. Such proper-
ties determine the membrane permeability of
the compounds and consequently their ab-
sorption and distribution and possibly their
susceptibility to metabolism as well. But as
mentioned in Section 5.2.1, the s e d a t i o n m -
nosis and other drug actions (anticonvulsant,
anesthetic) of barbiturates are unlikely to be
caused by unspecific effects on cell membranes
but instead on their interaction at recognition
sites on the GABA,receptor complex. This, in
turn, modulates the binding of both GABA
and benzodiazepines. Numerous barbiturates
have been shown to reversibly increase the af-
finity for equilibrium binding of C3H]diaz-
epam, and it has been shown that the efficacy
of binding enhancement can be correlated
with their structure/function categorization
as agonists, partial agonists or antagonists
(159). Compounds such as (+)-pentobarbital
and its stereoisomers, (5)-secobarbital, amo-
barbital, and (+) and (-1 pentobarbital, all of
which enhance [3Hldiazepambinding to about
the same maximal level (ca. 125% above base-
line), are classed as full agonists and are CNS
depressants with anesthetichypnotic activity.
Another group of barbiturates bearing N:
activity. In contrast, 5,5-disubstituted and methyl substituents also potentiate [ ,H]diaz-
1,5,54risubstituted derivatives (e.g., R, = H, epam binding but to a lesser degree (ca. 35-75%
R, = H or CH,, R, = Et, R, = Ph), which have above baseline) and reduce the pentobarbital en-
pKa in the range of 7-8 and are 40-60% dis- hancement down to their own maximal level,
sociated, are capable of crossing the blood- indicating that they h c t i o n as partial agonists.
brain barrier and exerting CNS effects, includ- A third group was found to lack the ability to
ing sedation. It was shown that the ionized enhance benzodiazepine binding and includes
form of barbiturates can permeate liposomal some derivatives that have in viuo excitatory ac-
bilayers provided that 5-substituents impart tivity and that reverse the binding enhancement
sufficient lipophilicity (157). of pentobarbital, thus classing them as func-
The dissociation of 5,5-disubstituted barbi- tional antagonists.
-
turic acids has been investigated on a thermo-
dynamic basis, and it was found that increas- 5.3.2 Benzodiazepines. BZR ligands of dif-
ing steric bulk of 5-substituents causes ferent structural types span a spectrum of in-
enthalpic changes that are acid-strengthening trinsic functional activity from full agonist to
but that are offset by acid-weakening entropic antagonist to inverse agonist. Agonists, which
effects (158). These findings were rationalized are comprised mainly of the classical benzodi-
in terms of ion-dipole forces in the ionized spe- azepine chemotype, exert a positive coopera-
cies, which produce a solvation shell capable of tive effect on GABA-induced chloride ion cur-
hindering the rotation of substituents. It is rents, and this action at the molecular level
apparent that the pharmacological activities translates into a variety of in uivo effects, in-
of barbiturates are dependent on an appropri- cluding anxiolysis, anticonvulsant, and mus-
248 Sedative-Hypnotics

FULL AGONISTS FULL INVERSE AGONISTS


Diazepam,
- . -
Triazolam DMCM

ANXIOLYTIC
SEDATIVE-HYPNOTIC ANTAGONISTS CONVULSANT
ANTICONVULSANT Flumazenil SPASMOGENIC
MUSCLE RELAXANT (Ro 15788) PROMNESIC
AMNESIC ZK 93426 GABA ANTAGONIST
I *
I
t*
PARTIAL AGONISTS
I
PARTIAL INVERSE AGONISTS
P-CCE
Bretazenil
hidazenil Sarmazenil
Abecarnil Ro 19-4603
Me

CI
CI Br
\
0

Diazepam Triazolam Zopiclone Bretazenil 1rnidaz.mil

Flumazenil ZK 93426 DMCM FG 7142

P-CCE Sarmazenil Ro 19-4603


Figure 5.12. Functional activity of representative BZR ligands.

cle relaxing activity and sedationkypnosis. reviewed (160, 161), and Fig. 5.12 shows ex-
Functional antagonists display no efficacy of amples of a number of such compounds that
their own, but their occupancy of the benzodi- are classified according to their pharmacolog-
azepine binding site can block the action of ical properties.
both agonists and inverse agonists. The latter, The mechanism of action of agents such as
which include some p-carboline and tricyclic DMCM as inverse agonists has been explained
azepine derivatives, exert a negative coopera- in terms of a two-state model for the benzodi-
tive effect on GABA binding, and thus are anx- azepine-GABA receptor complex (162). The
iogenic and proconvulsant. Some compounds model proposes that the complex exists in
with intermediate activities can be classed as equilibrium between interconvertable open
partial agonists or partial antagonists. BZR li- and closed channel conformations. GABA and
gands of various functional types have been BZR agonists such as diazepam exhibit recip-
5 Structure-Activity Relationships

rocal cooperativity in that they both bind se- the peripheral BZR (166) and development of
lectively to the open conformation and allow a three-dimensional pharmacophore model
chloride ion flux. Conversely, an inverse ago- for BZR ligands having anxiolytic activity
nist binds selectively to the closed conforma- (167).
tion and in so doing exhibits negative cooper- Cook and co-workers have published exten-
ativity by allosterically inhibiting GABA sively on their studies of BZR pharmacophore
binding. This rationale of inverse agonism is modeling (168-173). These studies have em-
supported by the observation that GABA re- ployed Comparative Molecular Field Analysis
ceptor stimulation reduces the BZR affinity of (CoMFA) of the structural parameters of a
DMCM (163),and thus it may be assumed that wide range of BZR ligands, many of which
DMCM reciprocally reduces the affinity of were designed and synthesized to probe the
GABA for its receptor. size, shape, and functional group tolerance of
There is evidence that the functional activ- the benzodiazepine binding domain. An exam-
ity of BZR ligands is caused by the interactions ple of a derived model showing the compara-
(hydrogen bonding, hydrophobic interactions) tive binding fit of an agonist (diazepam) and
of their structural moieties with kev " amino an antagonistlpartial inverse agonist (P-CCE)
acid residues that comprise the ligand recog- is depicted in Fig. 5.13.
nition site. The previously mentioned muta- Of particular relevance to sedativebyp-
tions of Hido1 in the a1 subunit have signifi- notic agents is the development of a pharma-
cant effects on binding affinities, as well as cophore for the sedation endpoint (173). Com-
altering the characteristic agonist, inverse ag- plementary behavioral and computational
onist, or antagonist responses to various li- studies of 21 structurally diverse BZR ligands
gands as determined by electrophysiology that influence spontaneous motor activity (a
(147).Introduction of a Hislo1Arg-mutated a1 behavioral indicator of sedation) were con-
subunit into mice has served to demonstrate ducted. A five-component three-dimensional
that certain behavioral actions of benzodiaz- pharmacophore consisting of two proton-ac-
epines are mediated by specific GABA, recep- cepting moieties, a hydrophobic region, a ring
tor subtypes (164). al(Hislo1Arg) transgenic with polar moieties, and an aromatic ring was
mice failed to show the sedative, amnesic, and derived and is represented in Fig. 5.14. The
in part, the anticonvulsant responses to diaz- model was shown to accommodate the ligand
epam, thus indicating that these behaviors are structural requirements in the overlapping
attributable to BZR agonist activation of the portion of the binding sites for agonists, in-
a1 containing GABA, receptor subtypes, verse agonists, and antagonists that impart
which are localized mainly in cortical areas effects on the behavioral sedation endpoint.
and thalamus. In contrast, the anxiolytic, my- Agonists decreased spontaneous motor ac-
orelaxant, motor-impairing, and ethanol-po- tivity, inverse agonists caused an increase,
tentiating effects of diazepam were retained and antagonists, while lacking intrinsic activ-
and must be caused by the drug's interaction ity of their own, blocked the effects of the ag-
with nonmutated GABAAreceptors in the lim- onist, flunitrazepam. The reliability of the
bic system ((u2, a5), in monoaminergic neu- model was evaluated in several ways: ligands
rons (a3), and in motor neurons (a2, a5). The without effect at the sedation endpoint did not
finding that benzodiazepine-induced behav- accommodate the pharmacophore require-
ioral responses are mediated through distinct ments; several BZR ligands that were not used
neuronal circuits has implication for drug de- in pharmacophore development but that were
sign. That is, agonists acting upon a2-,a3-, known to affect sedation satisfied the pharma-
and/or a5- but not on al-containing receptor cophore; and use of the pharmacophore pa-
subtypes could be nonsedative and nonarnne- rameters to search three-dimensional data-
sic anxiolytics. bases resulted in identification of additional
Numerous pharmacophore models of the BZR ligands known to have effects on the sed-
BZR have been proposed, and a number of
-
ative endpoint. The model may thus be useful
these were reviewed about a decade ago (165). for the design of novel chemotypes having sed-
More recent examples include the mapping of ative/hypnotic activity.
Sedative-Hypnotics

Figure 5.13. Pharmacophore/receptor


model for the BZR showing overlap of di-
azepam (right) and p-CCE (left).Sites HI
and H, designate hydrogen bond donor
sites on the receptor protein complex, A
represents a hydrogen bond acceptor site
necessary for potent inverse agonist ac-
tivity, L,-L, are lipophilic regions in the
binding pharmacophore and S,S, are re-
gions of steric repulsion within the recep-
tor ligand binding domain. Reprinted
from Q. Huang, et al., Drug Design and
Discovery, 16, 55 (1999) with permission
of Harwood Academic Publishers.

1,2 =Acceptor points

5 = Aromatic ring 3 =Variable


hydrophobic
region
5

polar moities
Distances in angstroms
D(l-2) = 4.9 f 0.9 1
D(l-3) = 5.0 _+ 1.3 oF2

DL
D(l-4)= l . 8 f 1.0
D(l-5) = 4.8 ?r 0.9
+
D(2-3) 6.1 2.0
D(2-4) = 3.3 f1.5
+
D(2-5) = 4.0 0.8
\ 'N1 \ /
D(3-4)
D(3-5) = 5.0 +
8.1 f 1.3
0.7
D(4-5) = 3.5 f 0.7 Zolpidem

Figure 5.14. Five component 3D pharmacophore for ligand recognition of GABA,lbenzodiazepine


receptors eliciting a response at the sedation endpoint. Zolpidem shown as one of the cbmpounds used
in construction of the pharmacophore model. Reprinted from D.L. Harris, et al., Eur. J. Pharmacol.
401, p. 271 (2000) with permission of Elsevier Science.
6 Recent Developments

6 RECENT DEVELOPMENTS However, it is most likely that central ef-


fects of melatonin are mediated primarily
6.1 Melatonergic Agents through its high aMinity binding to melatonin
receptors. Approximately 20 distinct melato-
Melatonin (13:R1, R,, R,, R,, R, = H; R =
nin receptor DNA sequences have been iden-
CHJ is an endogenous hormone that is bio-
tified in a variety of species, including humans
(179,180). Analysis of full-length receptor se-
quences indicates that they are members of
the seven-transmembrane spanning super-
family of G-protein coupled receptors and phy-
logenetic analysis supports their division into
three subtypes: mt, and MT, (formerly desig-
nated as rnel,, rnel,,) and rnel,, (181). Of
these, only the first two subtypes are found in
humans; the rnel,, receptor seems to be con-
fined to non-mammalian vertebraes. The in-
teraction of melatonin with each of the sub-
types, expressed in cell lines, attenuates
forskolin-stimulated cyclic AMP accumula-
synthesized within and secreted by the pineal tion, indicating that the receptors are func-
gland. It has a wide variety of biological effects tionally coupled to inhibitory G proteins (180).
in various species, but in humans its principal Various studies have demonstrated that
effect is the regulation of the body's circadian melatonin has sleep-enhancing properties in
rhythm (sleep-wake cycle). It is well-estab- animals. For example - IP administration of
lished that the pineal gland produces and re- melatonin to rats caused a dose-related reduc-
leases melatonin during.- the hours of darkness tion in time to sleep and time spent awake
and that the functions of the pineal gland are without alteration of either normal EEG pat-
controlled by light and changes in the dura- terns or brain concentrations of serotonin,
tion of the photoperiod (174,175). noradrenaline, or dopamine (182); Doses of 10
There is some evidence that the ~harmaco- mg/kg, IP, potentiated pentobarbital sleep
logical actions of melatonin may in part be time in mice, an effect that, unlike that of di-
mediated through the GABA-BZR complex. azepam, was not blocked by pretreatment
Melatonin has been shown to inhibit [3H]di- with the BZR antagonist, flumazenil (183).
azepam binding in human and bovine cor- These studies suggest that the sedative com-
tex, although only a t high (ca. 50 p H ) con- ponent of melatonin is probably mediated
centrations, and chronic injection of doses through its activation of melatonin receptors
ranging from 1 to 5 mg/kg for 3 weeks in rats and not by its modulation of monoaminergic
increased both high and low affinity GABA or GABAergic neurotransmission. Melatonin
binding in forebrain membranes (176). Sev- has rapid absorption, a short half-life, lack of
eral behavioral effects of melatonin in ro- toxicity, and manifests other pharmacological
dents, including depression of locomotor ac- effects only at doses 10- to 20-fold higher than
tivity, analgesia, and inhibition of seizure those producing sedation (184). These are
susceptibility, were blunted by the benzodi- highly desirable properties for a sedative-hyp-
azepine antagonist flumanezil, thus suggest- notic agent.
ing that these effects of melatonin may in- Thus, there has been considerable interest
volve central synapses employing GABA as in evaluating the use of exogenously adminis-
a neurotransmitter (177). Significant in- tered melatonin to normalize sleep patterns,
creases in levels of the serotonin metabolite, especially in cases where the normal secretion
5-HIM, in forebrain regions of pinealecto- of the hormone has been disrupted, e.g., in jet
mized rats suggests a nexus between the lag, shift workers, and the elderly. Clinical
mode of action of melatonin and the seroto- studies have demonstrated the ability of exog-
nergic system (178). enously administered melatonin to synchro-
Sedative-Hypnotics

nize circadian rhythms. It was effective in of substitution, and in fact, introduction of


phase-advancing the sleep of patients suffer- 2-substituents as large as phenyl affords more
ing from phase-delay syndrome (185), facili- potent ligands. Substitution at positions 1, 4,
tating post-flight adaptation to jet lag (186), 6, and 7 generally leads to loss of affinity, al-
and synchronizing the sleep-wake cycle of though analogs where R, is either C1 or CH,O
blind patients (187).As high as 50% of elderly have been reported to be MT, selective ligands
individuals suffer from sleep disorders that with 50- to 60-fold higher affinity for the MT,
may be attributed to their diminished levels of versus the mt, receptor (190).
endogenous melatonin. Results of several clin- Many non-indolic melatonergic agents
ical studies indicate a beneficial effect of mel- have been synthesized, thus demonstrating
atonin in elderly insomniacs. For example, that the indole ring is not required for recog-
1-week treatment of conventional release mel- nition at melatonin receptors. Some selected
atonin (2 mg) was as effective as 2-month examples of these are shown in Fig. 5.15,
treatment with a 1 mg sustained release for- whereas more comprehensive summaries are
mulation on sleep initiation. Sleep mainte- provided in several reviews (179, 180, 181,
nance (sleep efficiency and activity level) 191). Structure (14) represents the simplest
showed significant improvement only after chemotype to exhibit melatonin receptor af-
the Bmonth treatment with sustained release finity and homologs in which R is methyl and
melatonin (188). A review of data on night- n-propyl have Ki values of 63 and 5.5 nM,re-
time administration of melatonin to insomni- spectively, in binding to the receptor in
acs with noncircadian sleep disturbances led chicken brain (192). The side-chain carbon ap-
to the conclusion that there is not convincing pended to the aromatic ring corresponds to C3
evidence of the therapeutic efficacy of the drug of melatonin's indole nucleus, and the flexibil-
in this patient population (189). Nonetheless ity of the side-chain permits the molecule to
melatonin seems to be useful in improving adopt a conformation that should closely ap-
sleep parameters in individuals whose biolog- proximate receptor-bound melatonin.
ical clocks have been disrupted by normal ag- The naphthalene ring is an effective indole
ing or by work or travel habits. surrogate as exemplified by compound (15)(S-
There have been numerous reports of syn- 20098, agomelatine), which has been found to
thetic agents that exhibit high affinity for mel- have essentially equivalent affinity (Ki . =
atonin receptors. The great majority of such 0.035 nM) to that of melatonin in binding to
agents seem to be functional agonists and thus ovine pars tuberalis (193).Compound (15)has
may mimic the pharmacological properties of undergone extensive in vivo evaluations that
the natural hormone, including effects on have shown that it closely mimics the proper-
sleep. However, the wide disparity among the ties of melatonin. Several studies have shown
measurements of melatonin receptor binding agomelatine to entrain circadian rhythms in
(some employing various tissues from various rats in a dose-dependent manner (ED,, = 5.5
mammalian and non-mammalian species and mg/kg) and to be as effective as melatonin in
others using cloned receptors expressed in cell entrainment (194, 195). Agomelatine also re-
lines) make it very difficult to compare the po- sembled melatonin in that both compounds at
tency of such agents. 3 m a g IP reduced EEG power spectra in
The indole-containing analogs of melato- non-REM sleep without affecting vigilance
nin itself serve to establish a fairly tight SAR states and brain temperature in rats (196).
(181). The 5-methoxy group and the acylated The compound has been taken into clinical tri-
amino ethyl side-chain are essential for mela- als and evaluated in healthy young men. Com-
tonin receptor affinity; replacement of me- parison of both drugs in a double-blind, pla-
thoxy by H, OH, halogen, or even other alkoxy cebo-controlled cross-over study showed them
groups results in diminished affinity. Increas- to be equally effective in inducing an earlier
ing the size of the R group in (13)to n-propyl onset of the endogenous circadian nocturnal
enhances affinity, but further increase in size decline in core bAy temperature and heart
or branching is detrimental. Of the various rate (197). Single early evening doses of both
ring positions, only the 2-position is tolerant melatonin (5 mg) and agomelatine (5 and 100
6 Recent Developments

Figure 5.15. Melatonin receptor ligands.

mg) increased sleep propensity and advanced than the mt, receptor (190). Subtype-selec-
sleep termination in the subjects without af- tive compounds may prove to be of value in
fecting the EEG patterns in either REM or elucidating the relative importance of the
non-REM sleep (198). receptor subtypes in the pharmacology of
Other structural permutations of the naph- melatonin.
thalene chemotype, as exemplified by (16-181, Whether any synthetic melatonergic ago-
also retain potent melatonin receptor binding. nists will ever become approved drugs for the
The monomethoxy derivative (16) is less po- treatment of sleep disorders is a matter of
tent (Ki = 2.7 nM) in binding to ovine pars speculation. A major obstacle they face is that
tuberalis receptors than its regioisomer (151, the naturally occurring hormone is available
but addition of a second methoxy group in- on an over-the-counter basis in many coun-
creases the affinity (Ki = 0.7 nM) of (17) by an tries including the United States; thus, any
order of magnitude (199). Quinoline (18) is
synthetic drug would have to have some dis-
about as potent (K, = 5.9 nM)as melatonin in
tinct advantage over melatonin itself. Melato-
binding to human mt, receptors expressed in
CHO cells (200). The phenylene derivative nin receptors have been identified in the vas-
(19) (201), in which the arnide-containing culature and their activation by melatonin
side-chain is conformationally constrained, results in a vasoconstrictor response (181).
and (20) (202), in which the alkoxy group is Thus, melatonin could be contraindicated in
incorporated into a dihydropyran ring, also individuals, particularly the elderly, who have
exhibit potent binding with Ki values of 0.7 cardiovascular conditions. Perhaps a receptor
and 0.1 nM,respectively, at the receptors in subtype-selective agent would maintain the
chicken brain and ovine pars tuberalis. The beneficial effects of melatonin on sleep with-
tetralin derivative (21) is a MT,-selective li- out melatonin's vasoconstrictor properties
gand with 20-fold higher affinity for the MT, and other pharmacological effects.
Sedative-Hypnotics

0 0
Ki for FAAH inhibition = 1 nM 9 nM 17 nM

Figure 5.16. Inhibitors of F A A . .

6.2 Oleamide (2.8 mg) into rats caused sleep analogous to its
In the mid-1990s a collaborative team of IP administration (5 or 10 mglkg), thus indi-
chemists and biologists at the Scripps Re- cating a direct action in the brain. These ef-
search Institute reported on the isolation and fects were found to be compound-specific be-
structural and pharmacological characteriza- cause a number of close structural analogs
tion of a substance that accumulated under including the trans isomer, compounds with
conditions of sleep deprivation in cats (202- the cis double bond migrated to other posi-
205). Clues to the structure of the material, tions within the 18 carbon chain, a saturated
which was obtained in only trace quantities analog, and the corresponding carboxylic acid
from cat cerebrospinal fluid, were afforded by were all weakly effective or ineffective at in-
mass spectometry, which revealed an empiri- ducing sleep.
cal formula of C,,H,,NO and a lipid fragmen- Studies of the degradation and regulation
tation pattern. Subsequent comparison of the of oleamide revealed that it was hydrolyzed to
isolated material with a large number of syn- oleic acid and ammonia by the action of a.
thetic compounds having the correct formula membrane-bound enzyme, which based on the
and degree of unsaturation established its inhibition of its activity, seemed to be a serine
structure as 9(Z)-octadecanamide(22). or cysteine protease. Isolation and sequencing
of the protein led to the cloning of its cDNA
and expression in COS-7 cells. The expressed
enzyme was found to not only hydrolyze ole-
amide but a number of other fatty acid amides
and was thus designated as fatty acid amide
hydrolase or FAAH (206).
A number of inhibitors of FAAH have been
This material, referred to by the trivial synthesized (2071, and the more potent of
name, oleamide, proved to be of interest owing these are depicted in Fig. 5.16. The most po-
to the fact that the synthetic compound was tent compounds contain a highly electrophilic
found to induce sleep in rodents and cats. Var- carbonyl as part of either an a-ketoester, a-ke-
ious measures of sleep parameters after ole- toamide of trifluoromethyl ketone moiety,
amide administration showed the sleep to be structural features common to serinelcysteine
of a physiological quality. The compound was protease inhibitors. Several of these FAAH in-
found to dose-dependently increase the total hibitors caused sleep enhancement and lower-
time of slow wave sleep at the expense of wak- ing of body temperature in rats that were com-
ing and to lower body temperature, which is parable with those induced by oleamide. Based
characteristic of physiological sleep. Further- on these findings, it has been suggested that
more intraventricular injection of oleamide FAAH may represent a therapeutic target for
7 Things to Come

the discovery of sleep aids that potentiate the New opportunities for sleep therapy may
effects of oleamide by blocking its degrada- be forthcoming from recent discoveries per-
tion; some inhibitors (e.g., a-ketoamides) taining to the hypocretinlorexin ligand-recep-
might be dual acting agents that mimic the tor system. The hypocretinlorexin (Hcrt/Ox)
action of oleamide as well as attenuating its gene, described in 1998, encodes two neu-
metabolism (208). Of course, as with any class ropeptides, hypocretin-1 (Hcrtl) and hypocre-
of enzyme inhibitors, the potential clinical use tin-2 (Hcrt2), which are called orexin-A(0x-A)
of FAAH inhibitors is contingent on their se- and orexin-B (Ox-B), respectively (209, 210).
lectivity, because indiscriminate interaction Although the cell bodies in which the hypocre-
with other proteases could result in undesir- tins are made are restricted to the perifornical
able side effects. and dorsal and lateral hypothalamic areas,
A detailed review of oleamide, including a
they send projections to multiple neuronal
discussion of its possible modes of action such
systems throughout the brain including those
as serotonin receptor modulation and gap
junction inhibition, is available (208). containing neurons responsible for mainte-
nance of the waking state (211). mRNAs for
7 THINGS TO COME hypocretin receptors are differentially dis-
tributed in the brain with the highest levels
Pharmaceutical company research on seda- of HcrtlR mRNA occurring in ventromedial
tive-hypnotics rose and peaked within the sev- hypothalamic nuclei and locus coeruleus,
eral decades after the introduction of the ben- whereas Hcrt2R mRNA are found predomi-
zodiazepines and has waned since then nantly in hypothalamic paraventicular nuclei
because CNS-related drug discovery efforts and layer VI of the cortex (212). The hypocre-
have focused instead on improved therapy for tinlorexin ligand-receptor system and its im-
such disorders as depression and schizophre- plications for sleep and sleep disorders have
nia and the unmet medical need of stroke, been reviewed, and a model for the involve-
Alzheimer's disease, and other neurodegen- ment of the neuropeptides in arousal state
erative maladies. However, given the imper- control has been proposed (213). The model
fections of available drugs and the high inci- suggests that a balanced sleep-wake cycle may
dence of sleep disorders among the ever- depend on modulation by hypocretinlorexin
growing elderly population, more efficacious cell activation of monoaminergic neuronal
and safer agents are certainly needed. The populations in the locus coeruleus (noradren-
current stable of drugs typically act as CNS ergic), dorsal raphe nucleus (serotonerigic),
depressants that do not promote physiological and ventral tegmental area (dopaminergic),as
sleep and that may cause cognitive and mem- well as of cholinergic cells in the basal fore-
ory impairment, motor skills impairment (es- brain. In support of such a model are findings
pecially when ingested along with alcohol), that a mutation of the Hcrt2R gene resulting
and have potential abuse liability. Where in nonfunctional receptors causes narcolepsy
then, should we look for better agents, agents in dogs and that hypocretin knockout mice ex-
that may be better classified as sleep normal- hibit "behavioral arrest" and significantly in-
izers rather than sedative-hypnotics? Use of creased levels of REM and non-REM sleep. If
pharmacophore models such as that shown in removal of the hypocretinlorexin ligand-re-
Fig. 5.14 could conceivably lead to the design ceptor system results in a condition marked by
and synthesis of patentably-novel compounds, excessive and uncontrollable sleep (i.e., narco-
but their pharmacological properties would lepsy), then overactivity of this system may
most likely resemble those of the known seda- cause excessive arousal and impaired sleep. It
tive-hypnotics from whose structural parame- will be of interest to see if further research in
ters the models are constructed. As discussed this exciting area and the identification of
in previous sections, development of both mel- small non-peptide molecules capable of selec-
atonin receptor agonists and FAAH inhibitors tively blocking hypocretinlorexin receptors
could prove to be fruitful approaches, al- will lead to novel agents for the effective and
though both have some caveats. safe treatment of sleep disorders.
Sedative-Hypnotics

http://www.well.com/user/woaJfsseda.
htm: facts on sedative-hypnotics including
The following are a number of selected web- abuse potential
sites that pertain to sleep disorders and/or sed- http://www.hc-sc.gc.ca/hppb/alcohol-
ative-hypnotics. otherdrugs/pube/straight/sedative.html:com-
http://www.methodisth~~pitals.org/services/ monly abused sedative-hypnotics
dmgnostics/sleep/sleep4.html:dmgnosis and ther- http://www.aafp.org/afp/20000501/2763.
apy of sleep disorders html: abuse of and intoxication by psycho-
http://www.todoc.com/sleep/sleep.html: tropic drugs including sedative-hypnotics
sleep disorders and their treatment http://www.acnp.org/G4/GN401000173/
http://blueprint.bluecrossmn.com/article/ CH169.html: mechanism of action and phar-
iac/100547893:sleep disorders and their treat- macology of barbiturates
ment http://www.csusm.edu/DandB/Sedatives.
http://www.aafp.org/afp/20000501/2763. html: behavioral effects and mechanism of ac-
html: abuse of and intoxication by psycho- tion of barbiturates
tropic drugs including sedative-hypnotics http://www.sonatasleep.corn/healthpro/
http://www.acnp.org/G4/GN401000173/ about-sonatalabout -sonata.htm1: facts about
CH169.html: mechanism of action and phar- zaleplon (Sonata )
macology of barbiturates http://www.laurushealth.com/Library/
http://www.aafp.org/afp/20000501/2763. HealthGuide/DrugGuide~howTopic.asp?
html: abuse of and intoxication by psycho- topicid=9482&sequence =1: facts about zol-
tropic drugs including sedative-hypnotics pidem
http://www.acnp.org/G4/GN401000173/ http://www.sonatasleep.comlhealthpro/pi/
CH169.html: mechanism of action and phar- pi.htm: drug information on zaleplon (Sonata)
macology of barbiturates http://www.healthyplace.com/medications/
http://www.neuronic.com/neuronics/ triazolamhtm: pharmacology, indications,
sleepand2.htm: abstracts of clinical studies on contraindications, etc., of triazolam (Halcion)
sleep and sleep disorders
http://www.extendedcare.com/library/
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CHAPTER SIX

KENNETH R. SCOTT
School of Pharmacy
Howard University
Washington, DC

Contents
1 Introduction, 264
2 Clinical Applications, 265
2.1 Current Drugs, 265
2.2 Side Effects, Adverse Effects, Drug
Interactions/Contraindications,265
2.3 Absorption, Distribution, Metabolism, and
i Elimination, 273
2.3.1 Hydantoins, 273
2.3.2 Iminostilbenes, 275
2.3.3 Aliphatic Acid, 275
2.3.4 Benzodiazepines, 282

2.3.6 Barbiturate and 2-Desoxybarbiturate,


282
2.3.7 Oxazolidinedione, 284
2.3.8 GABA Analog, 284
2.3.9 Carbamate, 284
2.3.10 Triazine, 285
2.3.11 Oxcarbazepine, 286
2.3.12 Sulfonamide, 286
2.3.13 Nipecotic Acid Analog, 286
2.3.14 Sulfamate, 291
2.3.15 Pyrrolidinone Acetamide, 291
3 Physiology and Pharmacology, 291
3.1 Ion Channels, 292
3.2 GABAergic Mechanisms, 292
3.2.1 GABA, Receptors, 295
3.2.2 GABA, Receptors, 296
3.3 Glutamate Receptors, 296
3.4 T-Type Ca2+Channels, 297
4 History, 297
5 Structure-Activity Fklationships, 304
5.1 Hydantoins, 304
5.2 Iminostilbenes, 305
Burger's Medicinal Chemistry and Drug Discovery 5.3 Barbiturates, 306
-. N ~ r v n n aS v a t----
Sixth Edition, Vnli~mefi. .~m -----
Auenta"- 5.4 Benzodiazepines, 307
,.,
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PAitarl ,
,- , d d J. Abraham
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h.7 5.5 Valproate, 310
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 6 Recent Developments, 311
263
Anticonvulsants

6.1 AWD 131-138,311 7.2 AMP397A, 315


6.2 Harkoseride, 311 7.3 U-594494A, 316
6.3 LY 300164,312 7.4 SB-204269,316
6.4 NPS 1776,312 7.5 N-Channel Ca2+ Blockers, 318
6.5 NW-1015, 312 7.6 Models of the Anticonvulsant Receptor, 319
6.6 Pregabalin (CI-1008), 312 7.7 Porcine Embryonic GABAergic Cell
6.7 Remacemide, 313 Transplants, 320
6.8 Retigabine (D-23129), 313 7.8 A New Causative Agent for Epilepsy, 320
6.9 Rufinamide (CGP 33101), 313 8 Web Site Addresses and Recommended Reading
6.10 Losigamone (AO-33), 314 for Further Information, 320
6.11 Stiripentol, 314 8.1 For Information on Anticonvulsant
6.12 Ganaxolone (CCD 10421,314 Evaluations, 320
6.13 Soretolide (D 29161,315 8.2 For Information on Epilepsy, 320
7 Things to Come, 315 8.3 References on Animal Procedures, 320
7.1 (Ary1oxy)ArylSemicarbazones, 315 8.4 Sodium Channels, 320

1 INTRODUCTION A later Commission study expanded the


classification of seizures that occur in patients
The central nervous system (CNS)constitutes
with epilepsy. Patients are classified into ap-
the cerebral cortex, the limbic system, the
propriate types of epilepsy and epileptic syn-
midbrain, the brainstem, the cerebellum, and
dromes characterized by different seizure
the spinal cord (1).Epilepsy is one of the most
common disorders of the brain, affecting types, etiologies, ages of onset, and EEG fea-
about 50 million individuals worldwide (1, 2). tures (5). More than 40 distinct epileptic syn-
Epilepsy is a chronic and often progressive dis- dromes have been identified, making epilepsy
order characterized by the periodic and unpre- an extremely diverse collection of disorders.
dictable occurrence of epileptic seizures that The first major division of epilepsy is localiza-
are caused by abnormal discharge of cerebral tion-related (i.e., focal, local, partial) epilep-
neurons (2). Epilepsy is not a disease, but a sies, which account for about 60% of all epilep-
syndrome of different cerebral disorders of the sies. The remainder, about 40%, is composed
CNS. This syndrome is characterized by par- of generalized epilepsies (2). An epilepsy, or
oxysmal, excessive, and hypersynchronous epileptic syndrome, is either idiopathic, virtu-
discharges of large numbers of neurons (3). ally synonymous with genetic epilepsy; or
These seizures may be identified on the basis symptomatic, which is attributed to a struc-
of their clinical characteristics. These clinical tural lesion or major identifiable metabolic de-
attributes, along with their electroencephalo- rangements (2). Both types of seizure patterns
graphic (EEG) pattern, can be used to catego- and epilepsy determine the choice and progno-
rize seizures (4).Seizures are basically divided sis of therapy. As an example, the most com-
into two major groups: partial and general- mon, and most difficult to treat, seizures in
ized. Partial (focal, local) seizures are those in adult patients are complex partial seizures,
which clinical or EEG evidence exists to indi- whereas primary generalized tonic-clonic (for-
cate that the disorder originates from a local- merly, "grand mal" epilepsy) seizures respond
ized origin, usually in a portion of one hemi- in most patients to treatment with anticonvul-
sphere in the brain (4). Partial seizures may be sants. However, for many seizure types and
further subdivided into simple partial, com- epilepsy syndromes, there is little information
plex partial, and partial seizures evolving into about the pathophysiological basis. However,
secondarily generalized seizures. In general- on the other hand, and most fortuitously, in-
ized seizures, the evidence for a local origin sight into how partial seizures, generalized
is lacking. Generalized seizures may be tonic-clonic seizures, and generalized absence
further subdivided into absence (nonconvul- seizures arise is substantial, given that these
sive), myoclonic, clonic, tonic, tonic-clonic, seizure types constitute about 90% of seizures
and atonic seizures. (7).
2 Clinical Applications

In the absence of a specific etiologic under- felbamate (lo),lamotrigine (ll),oxcarbaz-


standing in any of the epilepsies or epileptic epine (12),zonisamide (131,tiagabine (14),
syndromes, approaches to drug therapy of ep- topiramate (15), and levetiracetam (16)
ilepsy must of necessity be directed at the con- (see Fig. 6.2).
trol of symptoms, that is, the suppression of 3. "Third-generation" agents are those
seizures. Currently, all available drugs are an- agents that are in preclinical or clinical
ticonvulsant (i.e., antiseizure) rather than an- development.
tiepileptic (2). The latter term should be used
only for drugs that prevent or treat epilepsy Table 6.1 provides the proprietary name,
and not solely its symptoms (2). The goal of USP or nonpropietary name, chemical class,
therapy with an anticonvulsant agent is to and the manufacturer of the nongeneric
have the patient seizure free without interfer- agent. The general therapeutic indications for
ing with normal brain function. Thus, the se- the first- and second-generation agents are
lection of an anticonvulsant agent is based pri- found in Table 6.2, whereas Table 6.3 lists the
marily on its efficacy for specific types of newer anticonvulsant agents for use in pediat-
seizures and epilepsy (7, 8). Although seizure ric patients (17). The third-generation agents
control is generally good in most patients, a are found in Sections 6 and 7 of this chapter.
significant proportion of patients with epi-
lepsy suffer from intractable or drug-resistant
2.2 Side Effects, Adverse Effects, Drug
epilepsy, despite early treatment and an opti-
Interactions/Contraindications
mum daily dosage of an adequate anticonvul-
sant agent (9-13). There is thus a need for Table 6.4 provides the side effects, adverse ef-
new drugs with a greater benefit as related to fects, and drug interactions and/or contraindi-
side effects and tolerability, even at the ex- cations for the listed anticonvulsants. Addi-
pense of efficacy, when compared to the exist- tional explanations as noted in the table are
ing antiepileptic agents (14, 15). provided as follows.
Phenytoin. As with all anticonvulsants,
phenytoin included, their central side effects
2 CLINICAL APPLICATIONS
include drowsiness and/or dizziness. In addi-
tion, phenytoin also produces blurred vision
As previously indicated, EEGs have been used
that may be serious to those individuals who
in the diagnosis of epilepsy. However, the EEG
operate heavy machinery. The adverse effects
findings should also be correlated with the ic-
with phenytoin can occur to the cardiovascu-
tal event for an unequivocal determination
lar system when the agent is administered
(16). For a complete discussion of seizure
rapidly by the intravenous route. Atrial and
types, refer to the previous edition of this
ventricular conduction depression and ven-
chapter (8).
tricular fibrillation have occurred, particu-
2.1 Current Drugs larly with the elderly or seriously ill patients
(18). Gingival hyperplasia occurs frequently
The anticonvulsant agents may be conve- with this agent and may be reduced with good
niently grouped into three general categories oral hygiene. Drug interactions with phenyt-
(2): oin are widely distributed and include valproic
acid, which increases the effects of phenytoin
1. "First-generation" or older agents as exem- by both inhibiting metabolism and displacing
plified by phenytoin (I), carbamazepine the bound phenytoin from plasma proteins,
(2), valproate ( 3 , the benzodiazepines (4), whereas the salicylates displace the drug from
ethosuximide (5), phenobarbital (6),primi- its plasma protein binding sites in a dose-de-
done (7), and trimethadione (171, all of pendent manner. Phenytoin concentrations
which were introduced between 1910 and may be decreased with the following drugs.
1970 (see Fig. 6.1). Barbiturates exert a variable effect on the phe-
2. "Second-generation" or newer agents con- nytoin concentration; thus the combination
sisting of vigabatrin (81, gabapentin (91, will present problems for the clinician, espe-
Anticonvulsants

Phenytoin, (1) Phenytoin sodium, (la) Mephenytoin, (1b)


0
-

/I. ON^
fP\ ONa

1 NH2
Ethotoin, (lc) Fosphenytoin, (Id) Carbamazepine, (2)

L _I n
Valproic acid, (3a) Divalproex sodium, (3b)

Clorazepate dipotassium, (4a) Clonazepam, (4b) Diazepam, (4c)

Clobazam, (4d) Nitrazepam, (4e)

Figure 6.1. "First-generation" anticonvulsants.


2 Clinical Applications

C2H5
Ethosuximide, (5a) Methsuximide, (5b) Phensuximide, (5c)

Phenobarbital, (6) Primidone, (7)


Trimethadione, (17)

Figure 6.1. (Continued.)

cially when initiating or stopping either drug. hepatotoxicity especially in children <2 years
Likewise, carbamazepine exerts a variable ef- old who are on multiple therapy; (2) teratoge-
fect on phenytoin levels; conversely, carbam- nicity that includes neural tube defects; and
azepine serum levels may also be decreased. (3) life-threatening pancreatitis.
Folate deficiency has been noted with long- Diazepam. The side effects of diazepam for
term phenytoin therapy, given that folate is a intravenous administration are similar to
cofactor in the metabolism of phenytoin those of phenytoin when administered by this
through hydroxylation (see metabolism). Sim- route, that is, cardiovascular collapse when
ilarly, influenza virus vaccine may increase, administered too rapidly.
decrease, or have no effect on the total serum Clonazepam. Clonazepam interacts with
phenytoin concentrations (18). phenytoin with the resultant decrease in
Carbamazepine. The adverse effects with plasma levels of the benzodiazepine.
carbamazepine include the potential to pro- Clobazam and Nitrazepam. Two new inves-
duce aplastic anemia and agranulocytosis; tigational benzodiazepines appear to be safe
however, it should be noted that the majority and effective as anticonvulsants. However,
of patients presenting with leukopenia have these agents have long elimination half-lives
not progressed to these more serious blood that increase the potential not only for drug
dyscrasias. Initial pretreatment hematologi- accumulation but also for residual side effects.
cal testing should be undertaken with all pa- Ethosuximide. This succinimide is rela-
tients with carbamazepine. Drug interactions tively safe from side effects and drug interac-
are focused on the 3A4 isoform of the P450 tions.
enzyme; inhibitors increase carbamazepine Phenobarbital. The older barbiturate is to
levels, whereas inducers produce the opposite be used with caution in patients with patent
effect. Special note should be taken with the liver or respiratory symptoms. Phenobarbital
carbamazepine-isoniazid interaction. Isonia- can cause fetal damage when administered to
zid inhibits carbamazepine metabolism, pregnant women.
whereas carbamazepine may increase isonia- Primidone. As noted from the structure
zid metabolism to hepatoxic products (18). and biotransforrnation pathway, primidone is
Valproic Acid. An adjunctive agent, val- closely related to phenobarbital; thus patients
proic acid bears three warning statements: (1) who are hypersensitive to phenobarbital should
Anticonvulsants

0
H
)-.Z
NH2 0
Vigabatrin, (8) Gabapentin, (9) Felbamate, (10)
0

Lamotrigine, (11) Oxcarbazepine, (12) Zonisamide, (13)

,,(3°xcH
4 0 CH3 N H2

e0
0'
CH3
H ~ C 0
CH3
Tiagabine, (14) Topiramate, (15) Levetiracetam, (16)
Figure 6.2. "Second-generation"anticonvulsants.

not be given this agent. Because the parent from Sweden disclosed a strong relationship
compound is metabolized to two active metab- between visual field effects (VFDs) and viga-
olites (see Section 2.3), patients with impaired batrin treatment (19). These VFDs were re-
liver function should be carefully monitored. lated to the duration and total dose of the
Trimethadione. This agent contains the agent. Further, the VFDs were irreversible
warning statement that, because of the poten- and, in a significant number of patients, pro-
tial to produce fetal malformations and seri- gressive.
ous side effects, trimethadione should be used Gabapentin. This agent is used as an ad-
only when other less toxic drugs have been junctive agent and is relatively safe from side
found ineffective in controlling petit ma1 sei- effects in nonpregnant adult patients. There
zures. was noted a small decrease in gabapentin ex-
Vigabatrin. A new investigational adjunc- cretion with concurrent cimetidine adminis-
tive agent in the United States, little is known tration, which was not clinically significant. It
about its side effects, drug interactions, or is recommended that gabapentin be taken at
contraindications. However, a recent article least 2 h after antacid administration.
2 Clinical Applications

Felbamate. Felbamate is an adjuvant


" anti- agent in patients with renal failure (GFR < 50
convulsant, containing the warning that its mL/min) because there is limited information
use is associated with a marked increase in the on dosing and toxicity (18). Fatalities have oc-
incidence of aplastic anemia and that patients curred, although rarely, as a result of severe
being started on the drug should have liver reactions to sulfonamides, including Stevens-
function tests performed before therapy is ini- Johnson syndrome, toxic epidermal necro-
tiated. Animal studies have revealed a statis- lysis, fulminant hepatic necrosis, agranulocy-
tically significant increase in hepatic cell ade- tosis, aplastic anemia, and other blood dyscra-
nomas in high dose studies (18). It is sias. Such a reaction may occur when a sulfon-
postulated that this cancer was induced by
amide is readministered, regardless of the
toxic by-products urethane and methyl car-
route of administration. If signs of hypersen-
bamate. Felbamate is not recommended as
sitivity or other serious reactions occur, dis-
first-line therapy and is indicated for those pa-
tients who respond inadequately to alterna- continue zonisamide immediately.
tive treatments and whose epilepsy is so se- Tiagabine. Tiagabine is an adjunctive agent
vere that a substantial risk of aplastic anemia that does not present any reported drug inter-
or liver failure is deemed acceptable in light of actions. However, this agent possesses clini-
the benefits provided by its use. cally significant side effects related to the
Lamotrigine. This agent is an adjuvant an- CNS. These are: (1)impaired concentration,
-
ticonvulsak that bears the warning that seri- speech or language problems, and confusion;
and (2) somnolence and fatigue. These effects
ous skin rashes requiring hospitalization and
cessation of treatment have been associated are mild to moderate and occurred to a greater
with its use. It is approved for use in pediatric frequency when used in combination with
patients r 16 years of age who have seizures other anticonvulsants.
associated with the Lennox-Gastaut syn- Topiramate. Topiramate is an adjunctive
drome. Discontinue treatment at the first sign agent that possesses clinically significant side
of rash, unless the rash is clearly not drug re- effects related to the CNS. These are: (1)psy-
lated. Visual problems (i.e. blurred vision) oc- chomotor slowing, difficulty with concentra-
curred more frequently with patients receiv- tion and speech, or language problems; and (2)
ing both carbamazepine with lamotrigine. somnolence and fatigue. These effects a+e
Oxcarbazepine. Oxcarbazepine is a new, mild to moderate and occurred to a greater
relatively
- safe anticonvulsant: however, cross- frequency when used in combination with
hypersensitivity was noted in patients previ- other anticonvulsants. Kidney stones oc-
ously hypersensitive to carbamazepine (25-
curred in 1.5% of patients exposed to topira-
30%). Asymptomatic hyponatremia has oc-
mate and may be related to the drug's weak
curred in clinical trials during the first 3
months of therapy. Clinicians are advised to carbonic anhydrase inhibiting properties.
monitor serum sodium levels for patients dur- Carbonic anhydrase inhibitors, such as acet-
ing maintenance treatment. azolamide or dichlorphenamide, increase kid-
Zonisamide. Zonisamide is a new sulfon- ney stone formation by decreasing citrate ex-
amide anticonvulsant. In one study it was cretion and by increasing urinary pH. Thus,
noted that 4% of the patients developed clini- the combination of topiramate with carbonic
cally possible or confirmed kidney stones (18). anhydrase inhibitors should be avoided (18).
Patients should report the appearance of sud- Levetiracetam. Levetiracetam is a new an-
den back pain, abdominal pain, or blood in the ticonvulsant agent that does not as yet present
urine that could indicate a kidney stone. In any drug interactions. Dizziness and somno-
several clinical studies, zonisamide was asso- lence occurred to a statistically significant ex-
ciated with a statistically significant 8%mean tent (14.8% versus 8.4% of the placebo pa-
increase from the baseline of serum creatinine tients) (18). This side effect occurred more
and blood urea nitrogen (BUN). This was in- frequently with patients receiving levetirac-
dicative of a decrease in the glomerular filtra- etam in combination with other anticonvul-
tion rate (GFR). Therefore, do not use this sant agents.
Table 6.1 Proprietary Names, USP o r Nonproprietary Name, Chemical Class, and Manufacturer of Antiepileptic Agents in Current Usea
- -

Generic Name (USP or Chemical


Nonproprietary Name) Classification Proprietary Name (Manufacturer) Route of Administration/Dose
Phenytoin, USP, (1) Hydantoin Dilantin (Parke-Davis) Dilantin Infatab (50 mg chewable tablet)
(5,5-diphenylhydantoin;5,5- Dilantin-125 (oral suspension containing
diphenyl-2,4-imidazolidinedione) 125 mgf5 mL)
Phenytoin sodium, parented, Hydantoin Dilantin (Parke-Davis) Injection: 50 mg/mL (=46 mg phenytoin)
(la)
Phenytoin sodium (SoloPak;Elkins-Sinn)
Phenytoin, Prompt, (la) Hydantoin Phenytoin sodium (various) Tablet (100 mg = 92 mg phenytoin)
Phenytoin sodium, extended, (la)b Hydantoin Phenytoin sodium (various) Capsules (100 mg = 92 mg phenytoin)
Dilantin Kapseals (Parke-Davis) Capsules (30 mg = 27.6 mg phenytoin; 100
mg = 92 mg phenytoin)
Mephenytoin, USP, (lb) Hydantoin Mesantoin (Sandoz) Tablet (100 mg)
Ethotoin, USP, (lc) Hydantoin Peganone (Abbott) Tablet (250 mg, 500 mg)
Fosphenytoin sodium, (Id) Hydantoin Cerebyx (Parke-Davis) Injection (150 mg = 100 mg phenytoin; 750
mg = 500 mg phenytoin)
N
u Carbamazepine, USP, (2) Iminostilbene Tegretol (Novartis) Tablets (chewable, 100 mg; 200 mg)
0
Suspension (100 mgf5 mL)
Tablets, extended release (100 mg, 200 mg,
400 mg)
Cabatrol (Athena Neurosciences) Capsules, extended release (200 mg, 300
mg)
Tablets (200 mg)
Atretol (Athena Neurosciences) Tablets (200 mg)
Epitol (Teva) Tablets (chewable,100 mg)
Carbamazepine (Various) Tablets (200 mg)
Valproic acid, USP, (3a) Aliphatic acid Depakene (Abbott) Capsules (250 mg)
Syrup [250 mg (as sodium valproate)/5mL1
Depakote, (3b)(Abbott) Tablets, delayed-release [I25 mg, 250 mg,
500 mg (as divalproex sodium)]
Capsules, sprinkle [I25 mg (as divalproex
sodium)]
Depakote ER (Abbott) Tablets, extended release (500 mg)
Depacon (Abbott) Injection [I00 mg/mL (as valproic acid)]
Valproic acid (various) Capsules (250 mg)
Syrup [250 mg (as sodium valproate)]
Clorazepate dipotassium, USP, (4a) Benzodiazepine Tranxene-T (Abbott) Tablets (3.75 mg, 7.5 mg, 15 mg)
Tranxene-SD Tablets (11.25 mg, 22.5 mg)
Gen-Xene (Alra) Tablets (3.75 mg, 7.5 mg, 15 mg)
Clorazepate (various) Tablets (3.75 mg, 7.5 mg, 15 mg)
Clonazepam, USP, (4b) Benzodiazepine Klonopin (Roche) Tablets (0.5 mg, 1 mg, 2 mg)
Clonazepam (various) Tablets (0.5 mg, 1 mg, 2 mg)
Diazepam, USP, (4c) Benzodiazepine Valium (Roche) Tablets (2 mg, 5 mg, 10 mg)
Injection (5 mg/mL)
Diazepam (various) Tablets (2 mg, 5 mg, 10 mg)
Diazepam (Roxane) Solution (1 mg/mL)
Diazepam Intensol (Roxane) Solution (Intensol) (5 mg/mL)
Diastat (Elan) Gel, rectal (2.5 mg," 5 mg," 10 mg," 10 mg,d
15 mg,d 20 mgd)
Ethosuximide, USP, (5a) Succinimide Zarontin (Parke-Davis) Capsules (250 mg)
Syrup (250 mg15 mL)
Ethosuximide (Copley) Syrup (250 mg/mL)
Methsuximide, USP, (5b) Succinimide Celontin Kapseals (Parke-Davis) Capsules, half strength (150 mg)
Capsules (300 mg)
N Phensuximide, USP, (54 Succinimide Milontin Kapseals (Parke-Davis) Capsules (500 mg)
2 Phenobarbital, USP, (6) Barbiturate; Ureide Phenobarbital (various) Tablets (15 mg, 16 mg, 16.2 mg, 30 mg, 60
mg, 90 mg, 100 mg)
Capsules (16 mg)
Elixir (15 mg/5 mL, 20 mg/5 mL)
Phenobarbital sodium (various) Injection (30 mg/mL, 60 mg/mL, 65 mg/mL,
130 mglmL)
Luminal Sodium (Sanofi Winthrop) Injection (130 mg/mL)
Primidone, USP, (7) Dihydrobarbiturate Mysoline (Wyeth-Ayerst) Tablets (50 mg, 250 mg)
Oral Suspension (250 mg/5 mL)
Primidone (various) Tablets (250 mg)
Trimethadione, USP, (17) Oxazolidinedione Tridione (Abbott) Dulcets (Tablets, chewable) (150 mg)
Capsules (300 mg)
Vigabatrin, (8) GABA analog Sabril (Marion Merrell Dow) -e
Table 6.1 (Continued)
Generic Name (USP or Chemical
Nonproprietary Name) Classification Proprietary Name (Manufacturer) Route of AdministrationjJlose
Gabapentin, (9) Cyclohexaneacetic Neurontin (Parke-Davis) Capsules (100 mg, 300 mg, 400 mg)
acid
F e l b d a t e , (10) Propanediol Felbatol (Wallace)
f
Tablets (400 mg, 600 mg)
carbamate Suspension (600 mg/5 mL)
Triazine Lamictal (GlaxoWellcome) Tablets (25 mg, 100 mg, 150 mg, 100 mg)
Lamictal Chewable Dispersible Tablets Tablets, chewable (5 mg, 25 mg)
(GlaxoWellcome)
Iminostilbene Trileptal (Novartis) Tablets (150 mg, 300 mg, 600 mg)
Sulfonamide Zonegran (Elan Pharma) Capsules (100 mg)
Nipecotic acid Gabitril Filmtabs (Abbott) Tablets (4 mg, 12 mg, 16 mg, 20 mg)
analog
Sulfamate analog Topamax (Ortho-McNeil) Tablets (25 mg, 100 mg, 200 mg)
Capsules, sprinkle (15 mg, 25 mg, 50 mg)
Acetamide Keppra (UCB Pharma) Tablets (250 mg, 500 mg, 750 mg)
-
"See Fig. 6.1 for the structures.
bMay be used for once-a-day dosing.
cpediatric.
d~dult.
qnvestigational drug.
t been recommended that use of this drug be discontinued if aplastic anemia or hepatic failure occurs unless, in the judgment of the physician, continued therapy is
f ~has
warranted.
2 Clinical Applications 273

Table 6.2 Anticonvulsant Effect of First- and Second-Generation Agents Against Different
Types of Seizures in Human Epilepsy"
Clinical Efficacy
Generalized Seizures
Partial
Agent Seizures Tonic-Clonic Absence Myoclonic
First-generation
Carbamazepine + + NE NE
Phenytoin + + NE NE
Phenobarbital + + NE +
Primidone + + + +
Valproate + + + +
Benzodiazepines + + + +
Ethosuximide NE NE + 2
Second-generation
Lamotrighe + + + +
Topiramate + + ? +
Oxcarbazepine + ? NE NE
Felbamate + + & +
Vigabatrin + ? NE NE
Tiagabine + ? ? NE
Gabapentin + ? NE NE
"Effect is indicated by the following: +, effective; ?, inconsistent data; NE, not effective; ?, no data available (or found).
Data are from Ref. 2. For a complete description of the seizure types, refer to previous edition (Ref. 8).

2.3 Absorption, Distribution, Metabolism, ment of the metabolite in urine can be used to
and Elimination determine the rate of metabolism, patient
compliance, or bioavailability (18).
Table 6.5 provides the pharmacokinetic pa-
rameters noted for the listed anticonvulsants, Mephenytoin. Chemically, mephenytoin is
which include, where possible, peak plasma 3-methyl-5-ethyl-5-phenylhydantoin (1.b)
levels, half-life, volume of distribution, and (Fig. 6.1) and is dispensed as the racemate.
plasma protein binding. Additional explana- The R and S forms undergo stereoselective
tions as noted in the table are provided as fol- oxidative biotransformation. The S-mepheny-
lows. toin undergoes rapidpara-hydroxylation (Fig.
6.3), whereas the R enantiomer is slowly de-
2.3.1 Hydantoins methylated to the active N-desmethyl metab-
Phenytoin. Phenytoin (1)is slowly absorbed olite (5-ethyl-5-phenylhydantoin, nirvanol),
from the small intestine. The rate, extent, and which is more potent than the parent com-
bioavailability vary because of the manufac- pound (21). The metabolism of mephenytoin
turer's formulation process. Intramuscular appears to be through cytochrome P450, spe-
injection tends to precipitate at the site of in- cifically through the CYP2 family (24). The
jection, resulting in erratic plasma levels; toxicity of this metabolite has limited its use
these levels are significantly lower than those (8).
obtained by the oral route. Phenytoin is me- Ethotoin. Chemically, 3-ethyl-5-phenylhy-
tabolized in the liver to inactive hydroxylated dantoin, ethotoin (lc) undergoes two bio-
metabolites (see Fig. 6.3) (20). For a complete transformation pathways leading to inactive
discussion, the reader is referred to the earlier products: p-hydroxylation [pathway (111 and
edition of this chapter (8).The metabolism of deethylation [pathway (2)l. This product has
phenytoin is capacity limited and shows satu- relatively low potency compared to that of
rability. Because the elimination of the p-hy- phenytoin. Like phenytoin, ethotoin displays
droxy glucuronide metabolite is rate limited saturable metabolism with respect to the for-
by its formation from phenytoin, measure- mation of the two metabolites (18).
Table 6.3 New Antiepileptic Medications: Pediatric Indications and Effectivenessa
Seizure Type or Epilepsy Syndrome
Agent (Initial
Availability) CPS PGS Abs JME LGS
Felbamate (1993) Monotherapy, ENL ENL ENL Adjunctive > 2 years ENL
Adjunctive > 14
years
N Gabapentin (1994) Adjunctive > 3 years ENL NE NE ? ?
4'
P Lamotrigine (1995) ENL ENL ENL ENL Adjunctive > 2 years ?
Topiramate (1996) Adjunctive > 2 years Adjunctive > 2 years ENL ENL ENL ENL
Tiagabine (1997) Adjunctive > 12 years ? NE NE ? ENL
Levetiracetam (1999) ENL ? ? ? ? ?
Oxcarbazepine (2000) Adjunctive 4-16 years ? ? ? ? ?
Zonisamide (2000) ENL ENL ENL ? ENL ENL
"CPS, complex partial seizures; PGS, primary generalized seizures; Abs, absence; JME, juvenile myoclonic epilepsy; LGS, Lennox-Gastaut syndrome; IS, infantile spasms; ENL,
effective, not labeled (although no indication exists, studies support its use in pediatric patients); NE, not effective; ?, not studied (no well-performed pediatric studies exist for this
indication). Data are from Ref. 17.
2 Clinical Applications

Fosphenytoin. The disodium phosphate es- 2.3.3 Aliphatic Acid


ter of 3-(hydroxymethy)phenytoin (Id) is a Valproic Acid. Valproic acid (VPA),is avail-
water-soluble derivative of phenytoin, which able in several chemical forms, including val-
is rapidly converted into phenytoin in the proic acid, sodium valproate, and divalproex
body. sodium, a stable coordination compound con-
taining equal proportions of valproic acid and
sodium valproate. In either of these forms, the
2.3.2 lminostilbenes dosage is expressed as valproic acid equiva-
Carbamazepine. Carbamazepine(5H-dibenz- lents (Table 6.1) (18).Oral valproic acid deriv-
[bfazepine-5-carboxamide, 2) is reasonably atives are rapidly absorbed; the absolute bio-
well absorbed and varies with the dosage form availability of divalproex extended-release
(Table 6.5). Compared to the suspension, the (ER) tablets was about 90% relative to that of
extended release tablet showed 89% bioavail- the intravenous infusion. The ER form had an
ability. Plasma levels are variable and may average bioavailability of 81-89% compared to
bear no apparent relationship to the daily that of divalproex delayed-release tablets
dose. Carbamazepine is 76% bound to plasma given twice daily. The relationship between
proteins and was similar for the active 10,ll- plasma concentration and clinical reSponse is
epoxide (see Fig. 6.3) (22). It has been shown not clear. This may be attributed to the non-
that the free fraction of carbamazepine is in- linear concentration-dependent protein bind-
versely correlated with the serum a,-acid gly- ing of valproic acid, which in turn affects the
coprotein concentration (23). Transplacental clearance of the agent (18).
transport is rapid (30-60 min) and the drug As noted in Fig. 6.3, valproic acid is exten-
accumulates in fetal tissues (18). The drug is sively metabolized by way of separate Phase I
pathways: p-oxidation, P45O-dependent de-
metabolized (Fig. 6.3) in the liver by the P450
saturation, P450-dependent w-hydroxylation,
3A4 isozyme to the active l0,ll-epoxide, and
P450-dependent (0-1)-hydroxylation,and P450-
subsequently to the inactive cis diol. As noted dependent (w-2)-hydroxylation(27). Two fac-
in Table 6.5, carbamazepine can also induce tors in the pharmacokinetics/pharmacody-
its own metabolism (autoinduction). namics of valproic acid have led to the
Oxcarbazepine. Chemically, oxcarbazepine hypothesis of an active metabolite: (1)the an-
is 10,ll-dihydro-10-oxocarbamazepine(121, ticonvulsant activity of valproic acid corre-
and is similar to carbamazepine in having the lates poorly with steady-state valproic serum
dibenzazepine nucleus with the 5-carboxam- concentrations; and (2) the time course of an-
ide substitution; however, it is different at the ticonvulsant effect differs from that predicted
l0,ll-bridge position and thereby differs from from the pharmacokinetics of valproate, in
carbamazepine in its metabolic disposition that protection against seizures is not maxi-
(Fig. 6.3). After oral administration, oxcarba- mal until some time after steady-state concen-
zepine is completely absorbed and extensively trations of valproate are achieved and persists
metabolized to the active enantiomeric sec- long after the parent drug has been cleared
ondary alcohols (Fig. 6.3) (24). There is a de- from the systemic circulation (2830). Al-
creased incidence of allergic skin reactions though (E)-2-ene VPA does show anticonvul-
with oxcarbazepine compared to carbamaz- sant activity, it was the only metabolite found
epine (25). For patients on carbamazepine, re- in the brain after valproate therapy. More-
placement with oxcarbazepine requires no ta- over, it was cleared from the brain and plasma
pering off from the carbamazepine, which may more slowly than the parent agent, and was
be withdrawn at once (25). An additional ad- shown to provide relatively slow washout ki-
vantage of oxcarbazepine is its reduced ten- netics compared to that of valproate (31-33);
dency to induce oxidative metabolism, espe- the opposing view argues that this agent is
cially in polytherapy, because it is easier to not an active metabolite. It is questionable
reach the therapeutic level of other antiepilep- whether the amount of (E)-2-eneVPA formed
tic agents during treatment with oxcarbaz- that has not been further biotransformed can
epine than with carbamazepine (26). account for the majority of the anticonvulsant
Table 6.4 Side Effects, Adverse Effects, Drug InteractionslContraindicationsof the Anticonvulsant Agents
- -

Anticonvulsant
kent Side Effects Adverse Effects Drua Interactions Contraindications
Phenytoin Drowsiness, dizziness, IV administration: Increased effects: Do not use in sinus
or blurred vision cardiovascular collapse," a. Inhibition of metabolism with bradycardia, sinoatrial block,
hypotension allopurinol, amiodarone, second- and third-degree AV
Oral administration: CNS: benzodiazepines, chloramphenicol, block, or in patients with
nystagrnus, ataxia, cimetidine, disulfiram, ethanol, Adams-Stokes syndrome.
slurred speech fluconazole, isoniazid, metronidazole,
Dermatologic: rash miconazole, omeprazole, phenacemide,
Endocrine: diabetes succinimides, sulfonamides,
insipidus, trimethoprim, valproic acida
hyperglycemia b. Plasma protein displacement with
Others: Gingival salicylates," tricyclic antidepressants,
hyperplasia," valproic acida
thrombocytopenia, c. Unknown mechanism:
agranulocytosis, chlorpheniramine, ibuprofen,
tinnitus, diplopia phenothiazines
Decreased effects:
a. Increased metabolism with
barbiturates," carbamazepine,"
diazoxide, ethanol, rifampin,
theophylline
b. Decreased absorption with antacids,
charcoal, sucralfate
c. Unknown mechanism: antineoplastics,
folic acid," influenza virus vaccine,"
loxapine, nitrofurantoin, pyridoxine
Carbamazepine Drowsiness, dizziness, Hematologic: aplastic Increased effects (P450 3A4 inhibitors): History of bone marrow
or blurred vision anemia, leukopenia, cimetidine, danazol, diltiazem, depression; hypersensitivity
agranulocytosis, bone erythromycin, troleandomycin, to carbamazepine and
marrow depression clarithromycin, fluoxetine, isoniazid, tricyclic antidepressants;
CNS: dizziness, niacinamide, nicotinamide, concomitant use of
drowsiness, propoxyphene, ketoconazole, monoamine oxidase (MAO)
unsteadiness itraconazole, verapami1,and valproate inhibitors. Discontinue MA0
Other: nausea, vomiting Decreased effects (P450 3A4 inducers): inhibitors for 214 days
cisplatin, doxorubicin, felbamate, before carbamazepine
rifampin, phenobarbital, phenytoin, administration.
primidone, theophylline
Valproic acid Dizziness, suicide CNS: asthenia, Increased effects with chlorpromazine, Hepatic disease;
ideation, somnolence, dizziness, cimetidine, erythromycin, felbamate, hypersensitivity to valproate;
hyperammonemia, tremor salicylates pregnancy (FDA category D);
nausea GI: nausea, vomiting, Decreased effects with rifampin, children < 2 years (especially
abdominal pain carbamazepine, cholestyramine, those on multiple
Hematologic: phenytoin, lamotrigine, phenobarbital antiwnvulsant therapy,
thrombocytopenia those with congenital
Respiratory: infection metabolic disorders, those
Other: alopecia, headache with severe seizure
disorders, and those with
organic brain disease);
panmeatitis.
Clorazepate Drowsiness, ataxia, Hypersensitivity to
dipotassium and confusion benzodiazepines.
Diazepam Drowsiness, ataxia, IV administration: Hypersensitivity to
and confusion cardiovascular collapse benzodiazepines; psychoses;
CNS: sedation and acute narrow-angle
sleepiness glaucoma; children < 6
h)
years; lactation; concomitant
V alcohol administration.
V
Clonazepam Drowsiness, ataxia, Decreased effects with phenytoin Hypersensitivity to
and confusion benzodiazepines; clinical or
biochemical evidence of
significant liver disease.
Clobazam Drowsiness, hangover None reported Hypersensitivity to
effects, dizziness, benzodiazepines.
weakness, and
lightheadedness
Nitrazepam Fatigue, dizziness, None reported Hypersensitivity to
lightheadedness, benzodiazepines.
drowsiness,
lethargy, mental
confusion, ataxia
Ethosuximide Drowsiness, ataxia GI: nausea, vomiting Ethosuximide increases phenytoin levels Hypersensitivity to
Ethosuximide decreases primidone and succinimides.
phenobarbital levels
Table 6.4 (Continued)
Anticonvulsant
kent Side Effects Adverse Effects Drug Interactions Contraindications
Phenobarbital Drowsiness, ataxia Somnolence Increased effect with MA0 inhibitors, Barbiturate sensitivity;
valproic acid alcohol; pregnancy (FDA
Decreased effect with chloramphenicol, category Dl;manifest or
rifampin latent porphyria; severe
respiratory disease when
dyspnea or obstruction is
evident; nephritic patients.
Primidone Drowsiness, dizziness, CNS: ataxia and vertigo Increased effect with isoniazid, Lactation; pregnancy;
GI upset, GI: nausea, anorexia, nicotinamide, phenytoin porphyria; hypersensitivity
vomiting Decreased effect with carbamazepine, to phenobarbital.
ethosuximide
Trimethadione Drowsiness, dizziness, Systemic lupus Hypersensitivity to
sore throat, blurred erythematosus; skin oxazolidinediones; pregnancy
vision rash (leading to (FDA category D);
exfoliative dermatitis or photosensitivity.
severe erythema
multiforme); fatal
aplastic anemia; fatal
nephrosis has occurred
Vigabatrin None reported in 75% Somnolence, fatigue Decreases phenytoin levels Dose-dependent field effects."
of patients tested (adults); agitation,
insomnia (children)
Gabapentin Drowsiness, dizziness, Somnolence, dizziness, Increased effect with cimetidine Hypersensitivity to the drug;
headache, viral ataxia, fatigue, and Decreased effect with antacids patients > 12 years of age;
infection, nausea, nystagrnus pregnancy (FDA category C).
vomiting
Felbamate Lymphadenopathy, Aplastic anemia, liver Decreased effect with phenytoin, Hypersensitivity to the drug or
leukopenia, failure, carcinogenic (in phenobarbital, carbamazepine other carbamates; avoid
agitation, animal studies)," prolonged exposure to
tachycardia sunlight or sunlamps; may
cause photosensitivity;
history of blood dyscrasias or
hepatic dysfunction;
pregnancy (FDA category C).
Lamotrigine Dizziness, diplopia, Rash, dizziness, headache Increased effect with folate inhibitors, Hypersensitivity to the drug;
ataxia, blurred valproic acid dizziness; pregnancy (FDA
vision," nausea, and Decreased effect with acetaminophen, category C); children < 16
vomiting primidone, phenobarbital, phenytoin, years; renal andlor hepatic
carbamazepine function impaired patients.
Oxcarbazepine Psychomotor slowing; Cross sensitivity from Decreased effect with (P450 3A4 Hypersensitivity to the drug
dizziness and carbamazepine, inducers): carbamazepine, phenytoin, and to carbamazepine,
somnolence hyponatremia and phenobarbital, also decreased with alcohol. Recommend
verapamil and valproic acid additional nonhormonal
forms of contraception.
Zonisamide Somnolence, anorexia, Pruritus, vomiting, Decreased effect with (P450 3A4 Hypersensitivity to
dizziness, headache, amblyopia, tinnitus, inducers): carbamazepine, phenytoin, sulfonamides or zonisamide;
nausea, agitation1 asthenia, kidney stones and phenobarbital skin rash; pregnancy (FDA
irritability category C); sudden back
pain; abdominal pain; or
blood in the urine." Not
approved for pediatric use.
Tiagabine Generalized weakness Dizziness, somnolence, None reported Hypersensitivity to the drug;
depression, confusion, pregnancy; lactation.
asthenia
Topiramate Psychomotor slowing; Fatigue, headache, injury, Increases the effect of alcohol and CNS Hypersensitivity to the drug;
somnolence anxiety, rash, depressants, carbonic anhydrase use in children has not been
palpitation, kidney inhibitors established.
stones Decreases the effect of oral
contraceptives, digoxin
Levetiracetam Dizziness Somnolence, asthenia, None reported Hypersensitivity to the drug;
infection, and dizzinessa pregnancy (FDA category C).
"For a full discussion, see Section 2.2. Data are from Ref. 18.
Table 6.5 Pharmacokinetic Properties of Antiepileptic Agentsa
Volume of
Generic Name (USP or Peak Plasma Levels Distribution Protein
Nonproprietary Name) Achieved (h) tm (h) w& Wkg) Metabolism/Excretion Binding (%)
Phenytoin sodium, Extended, (la) Liverkidney; <5% of 87-93
the unchanged drug
remaining
Phenytoin, Prompt, (la)
Mephenytoin, (lb) Liverkidney; -42% of No data
unchanged drug
remaining
Desmethyl metabolite (active) 150-200
Ethotoin, (lc) 2 3-9 Liverkidney No data
Carbamazepine, (2) 4-5 (tablets); -1.5 25-65 (initial); Liverkidney; 76
(suspension); -3- 3-24 (repeated metabolites are found
12 (extended administration) in the urine (72%)
release) and the feces (28%)
Epoxide metabolite (active)
Oxcarbazepine, (12) Liverkidney; >95%
found in the
Monohydroxy (MHD) metabolite urine, constituting 4 % 40
(active) of unchanged drug;
-80% as MHD, or
conjugates
Valproic acid, (3a) Liverjkidney 80-94
Clorazepate dipotassium, (4a) Liverkidney 97
Desmethyl metabolite (active) 55-100
Diazepam, (4c) 20-50
Clonazepam, (4b) 18-60
Nitrazepam, (4e) 2
Clobazam, (4d) 18
Desmethyl metabolite (active) -77
Ethosuximide, (5a) 30 (children);60 Liverkidney; 25% 0
(adults) excreted unchanged
in urine
Methsuximide, (5b) Liver; <1% excreted No data
Desmethyl metabolite (active) unchanged in urine
Phenobarbital, (6) 0.42-0.73 Liver; 25%excreted 40-60
unchanged in urine
Primidone, (7) 5-15 (primidone); Liverkidney; -40%is 20-25
53-140 excreted unchanged;
(phenobarbital); metabolized to
10-18 ( P E W ) phenobarbital and
P E W (both active)
Trimethadione, (17) 11-16
Desmethyl metabolite (active) 6-13 days
Gabapentin, (9) 5-7 0.65-1.04 Not appreciably <3
metabolized; excreted
in urine unchanged
Felbamate, (10) 0.84-0.76 Liverkidney; 40-50% 22-25
unchanged in urine;
40%as unidentified
metabolites and
t
4
conjugates
2 Lamotrigine, (11) 0.9-1.3 Liverkidney; 94% -55
excreted in urine as
conjugates, 2%in
feces
Zonisamide, (12) -63 (plasma); 105 -1.45 Liver; kidney -40%
(erythrocytes)
Tiagabine, (14) -45 min 5.4-8.0 Liver; kidney 96
Topiramate, (15) -2 21 Liverkidney; 70%of 13-17
unchanged drug in
urine
Levetiracetarn, (16) Liverkidney; 66%
unchanged drug
"Data are from Ref.18.
Anticonvulsants

activity after a relatively large dose of val- transformation to the 7-amino (43 and 7-acet-
proate. Levels of (E)-2-eneVPA in the cerebro- amido (4)derivatives. Abrupt withdrawal of
spinal fluid (CSF) (34) and the brain (35) in the drug has led to worsening of seizures with
humans were determined to be too low to pro- or without additional psychic symptoms such
vide effective anticonvulsant protection. as dysphoria, restlessness, or autonomic signs
Valproic acid is rapidly distributed and the (42).
plasma protein binding is concentration de- Nitrazepam. As indicated previously, ni-
pendent (18). As previously noted, valproic trazepam (4e), is similar in structure to clon-
acid is extensively metabolized, primarily in azepam. Absorption after oral administration
the liver, with about 30-50% of the drug ex- occurred within 1 h; however, in some cases
creted as the glucuronide (phase I1 metabo- relatively slow absorption (up to 4 h) has been
lism) in the urine, about 30-40% by the phase reported (43-48). Rectal administration pro-
I mitochondrial P-oxidation pathway, and vided more rapid absorption (median peak
about 10-20% by microsomal cytochrome time 18 min versus 38 min orally) (48). Al-
P450-mediated hydroxylation/dehydrogena- though a good correlation was apparent be-
tion of the side chain that provides the major tween the volume of distribution and elimina-
phase I metabolites (36). The metabolites of tion half-life, when comparing the young,
valproic acid have been thought to be the elderly, female, and male subjects, the differ-
cause of a rare, but fatal hepatotoxicity (35). ences observed in volume of distribution re-
The synthetic (El-2,Cdiene VPA has been lated to sex, age, and body weight seem to de-
shown to induce the same hepatic microve- pend on the relative proportion of body
sicular steatosis seen in patients, in chronic adipose tissue (49). The metabolic pattern of
administration studies in rats (36). The ulti- nitrazeparn is similar to that of clonazepam,
mate causative factorb) of hepatoxicity of val- with the principal formation of the inactive
proic acid currently remain undefined (28,29). 7-amino (41) and 7-acetamido (4m) com-
pounds.
2.3.4 Benzodiazepines Clobazam. Clobazam (4d) differs from the
Clorazepate Dipotassium. Clorazepate di- previous benzodiazepines, given that it is a
potassium is a prodrug that is rapidly and al- 1,5-benzodiazepine rather than a 1,4-deriva-
most quantitatively converted into the active tive. It was demonstrated that N-desmethyl-
decarboxylated analog, N-desmethyldiazepam clobazam (4k) possessed anticonvulsant activ-
[nordazepam (401 (37-40). ity (50, 51).
Diazepam. Like clorazepate, diazepam is
converted into nordazepam (40 by N-demeth- 2.3.5 Succinimides
ylation (Fig. 6.3) and to oxazepam (4g). Direct Ethosuximide. Ethosuximide (5a)is rapidly
hydroxylation produces N-methyl-oxazepam absorbed when administered orally (18). The
(4h).The low concentrations of (4g) and (4h) drug is extensively metabolized principally to
preclude their role as active anticonvulsants the inactive diasteromeric 2-(1-hydroxyethy1)-
(41). Unlike clorazepate, diazepam is bioac- 2-methylsuccinimide (5d) (Fig. 6.3) (52) and
tive. The transformation of diazepam to nor- the inactive 2-hydroxyethyl isostere. About
dazepam is less complete, in that 62-73% of 20% of the drug is excreted unchanged in the
diazepam is excreted in the urine and about urine.
10% is found in the feces (41). Diazepam is Methsuximide. Like ethosuximide, meth-
rapidly absorbed when taken orally (30-90 suximide (5b)is rapidly absorbed. The drug is
min) or rectally (10-60 min). also rapidly N-demethylated to N-desmethyl-
Clonazepam. Clonazepam, chemically 5-(2- methsuximide (5d), the active metabolite (53).
chloropheny1)-1,3-dihydro-7-nitro-2H-1,4- Less than 1% of unchanged methsuximide is
benzo-diazepin-2-one (4b),is closely related to found in the urine.
nitrazepam (4e), differing only at position 5
with the o-chloro substituent. Only 0.5% of 2.3.6 Barbiturate and 2-Desoxybarbiturate
the original drug is recovered unchanged in Phenobarbital. Phenobarbital (5-ethyl-5-
the urine after 24 h, indicating extensive bio- phenylbarbituric acid, 6) is relatively insolu-
2 Clinical Applications

S-(-)-5-(pHydroxyphenyl)
Phenytoin, (1) -5phenylhydantoin, Major (inactive)

I
Phenytoin sodium, (la)

R-isomeric Pathway

S-isomeric Pathway

OH
pHydroxymephenytoin Desmethylmephenytoin,
(inactive) Nirvanol (active)
Figure 6.3. Metabolism of anticonvulsants.

ble in water (1g i n 1000 mL), but readily sol- decreases resorption in the nephron and in-
uble as the sodium salt (1g i n 1 mL) (54). The creases clearance, whereas increasing urinary
drug is metabolized principally to the p- pH also increases excretion (59).
hydroxy metabolite (6a)(55). Absorption of Primidone. Primidone (2-desoxyphenobar-
the sodium salt is rapid and relatively com- bital, 7 ) is readily absorbed from the gastroin-
plete (80-100%)(56,57).It is distributed to all testinal tract. As seen in Fig. 6.3, primidone
body tissues (58). The elimination of pheno- undergoes two principal biotransformation
barbital follows fmt-order kinetics, and thus pathways: (1) C , oxidation to form pheno-
is independent of concentration (59). Al- barbital (6) and (2) C , ring cleavage to form
though the average half-life is not influenced phenylethylmalonamide (PEMA, 7a), both
by the route of administration, the rate of active. It has been shown that primidone is,
urine flow and urinary pH do influence the in fact, active and not a prodrug of pheno-
elimination rate (59). Increasing urine flow barbital (60).
Anticonvulsants

ture of R-(-)- and S-(+)-isomers, where the


R-(-)-isomer is inactive (62). In comparing
the absorption, time of peak effect, and t,,,
of the racemate and the separate enantiomerc
the following was obtained (63). As noted
in the following table, the peak plasma concen-
trations for both isomers were reached within
the same time range. The kinetics of the
S-(+)-isomer was not influenced by the R-(-)-
isomer, given that the data for the racemate
OH were similar to those of the S-(+)-isomer
Ethotoin, (lc) pHydroxyethotoin alone. It should be noted that. in contrast to
(inactive) other biologically active compounds wherein
the inactive isomer is considered to be an im-
purity that can influence the kinetics and the
action of the active isomer, with vigabatrin, the
toxic effects of the racemate are exclusively at-
tributed to the active S-(+)-isomer (63). This re-
sults from its mechanism of action as a GABA-T
inhibitor (62). As noted in the table, the drug is
rapidly absorbed and, because it is water solu-
ble, it is readily distributed to all parts of the
body. The volume of distribution in healthy vol-
5-Phenylhydantoin unteers is 0.8 L/kg (62). The metabolism and
(N-Desethylethotoin) protein binding of vigabatrin are negligible;
(inactive) there was no chiral inversion of the R-(-)-iso-
i.UNa mer to the active S-(+)-isomer (63).
rOH \
ONa
Pharmacokinetics of Vigabatrina
Peak t112
Enantiomer Concentration (h) (min)
Racemate 0.5-2 447b
s (+) 0.5-2 386
R (-) 0.5-2 485

Fosphenytoin, (1d) "Data are from Ref. 63.


bFor the S-(+)-isomer.
Figure 6.3. (Continued.)
Gabapentin. Gabapentin, chemically 1-(amino-
methyl)-cyclohexaneacetic acid (9), like viga-
2.3.7 Oxazolidinedione batrin, is neither metabolized nor protein
Trirnethadione. Trimethadione, chemically bound (64-66). Gabapentin exhibits dose-de-
3,5,5-trimethyloxazolidine-2,4-dione(17),is pendent bioavailability, in that the plasma
rapidly absorbed after oral administration and concentration of the drug is not directly pro-
is converted, through N-demethylation into portional to the dose throughout the thera-
the active dimethyldione (17a) (61). Tri- peutic range of dosage (67).
methadione is extensively metabolized, with
less than 5% appearing in the urine after oral 2.3.9 Carbarnate
administration (61). Felbamate. Felbamate, chemically 2-phe-
nyl-l,3-propanediol dicarbamate (lo),is well
2.3.8 CABA Analog absorbed after oral administration (68). Fel-
Vigabatrin. Vigabatrin, chemically Cami- bamate is distributed to all tissues and has
no-5-hexenoic acid (a),exists as a racemic mix- been metabolized by several pathways in ani-
2 Clinical Applications

0 4
NH2 NH2
Carbamazepine, (2) Carbamazepine-10 , l l -epoxide
(active)

Carbamazepine-lO,l1 -dihydrodiol Carbamazepine-10 , l l -dihydrodiol


(major, inactive)
I (minor, inactive)

Oxcarbazepine, (12) (S)-(+)-I


0-Hydroxycarbazepine (R)-(-)-1 0-Hydroxycarbazepine
(major,active) (minor, active)
Figure 6.3. (Continued.)

mals (Fig. 6.3): (1)ring hydroxylation to form 2.3.1 0 Triazine


p-hydroxyfelbamate (10a); (2) aliphatic hy- Larnotrigine. Lamotrigine, chemically 3,5-
droxylation to form 2-hydroxyfelbamate (lob); diamino-6-[2,3-dichlorophenyll-l,2, 4-triazine
and (3)hydrolysis to form the primary alcohol, ( l l ) , is rapidly and completely absorbed after
2-phenyl-1,3-diolmonocarbamate (l-hydroxy- oral administration with minimal first-pass
felbamate, 10c) and further to the carboxylic metabolism. Lamotrigine is metabolized pre-
acid (10d) (78). In humans, unchanged fel- dominantly by glucuronic acid conjugation to
bamate is found to the extent of 50% in the an inactive 2-N-glucuronide (1la) (76%),and
urine of male volunteers; the combined hy- the 5-N-glucuronide( l l b ) . Ten percent of un-
droxy metabolites (10a) and (lob) (10-15%) changed drug was recovered in the urine (18).
and the hydrolyzed (10c) (0.7-2.7%) consti- Following multiple administrations to healthy
tute the remainder. The propionic acid deriv- volunteers, lamotrigine induces its own me-
ative (10d) was not recovered. The metabo- tabolism, resulting in a 25% decrease (25.4 h)
lites are devoid of significant anticonvulsant in half-life and a 37% increase in plasma clear-
activity (68). ance at steady state. The clearance was 25%
Anticonvulsants

C02H
3-ene-VPA
(E)-and(Z)-isomers 4-Hydroxy-VPA 2-Propylsuccinic
acid

/' Valproic acid (VPA),


2,3'-diene-VPA 2-ene-VPA
(E,E)-and(E,Z)- (E)-and(Z)-isomers
isomers I I

H02C
/'
2-Propylglutaric
acid
Figure 6.3. (Continued.) (a) P-oxidation; (b) P450-dependent desaturation; (c) P450-dependent
w-hydroxylation; (d) P450-dependent (o-1)-hydroxylation;(e) P450-dependent (o-2)-hydroxylation).
The broken arrows indicate a metabolic route in which the details are not yet confirmed. (After Ref. 27.)

lower in non-whites than that in whites, but teins, resulting in an eightfold higher concen-
was not affected by gender (18). tration in red blood cells. It is excreted
primarily in the urine as:(1) unchanged drug
2.3.1 1 Oxcarbazepine. Oxcarbazepine (12) (35%); (2) inactive N-acetyl zonisamide (13a)
was previously discussed[see Carbamazepine (2)]. (15%); and (3) as the 0-glucuronide of the
ring-opened 2-sulfamoyl-acetyl phenol (SMAF',
2.3.1 2 Sulfonamide 13b)(50%) (18).
Zonisamide. Zonisamide(13)is chemically
1,2-benzisoxazole-3-methanesulfonamide.It 2.3.1 3 Nipecotic Acid Analog
should be noted that zonisamide binds exten- Tiagabine. Tiagabine, chemically (R)-(-)-
sively to erythrocytes as well as plasma pro- 1-[4,4-bis(3-methyl-thieny1)-3-butenyll-3-
i
i 2 Clinical Applications

H H3C H3C
\

CI -N

\
Clorazepate dipotassium, (4a) Diazepam, (4c) 3-Hydroxydiazepam
(N-Methyloxazepam), (4h)
- 0 H /N-Demethylatim H

Desmethyl diazepam Oxazepam, (4g)


(nordazepam, (4f) (active) (active)
H H H

Clonazepam, (4b) 7-Amino clonazepam, (4i) 7-Acetamido clonazepam, (4j)


(inactive) (inactive)
H

Clobazam, (4d) Desmethyl clobazam, (4k)


(active)
H

Nitrazepam, (4e) 7-Amino nitrazepam, (41) 7-Acetamido nitrazepam, (4m)


(inactive) (inactive)

Figure 6.3. (Continued.)


Anticonvulsants

Ethosuximide, (5a) 2-(1 -Hydroxyethyl)-2-


methylsuccinimide, (5d)
(inactive)
H

Methsuximide, (5b)

Phenobarbital, (6)
OH
gHydroxyphenobarbitaI, (6a)
H

Phenobarbital, (6)
(active)
\

Primidone, (7)

Phenylethylmalonamide
(PEMA), (7a) (active)
H3C

CH3 H
Trimethadione, (17) Diimethadione, (17a)

Figure 6.3. (Continued.)


2 Clinical Applications

Felbamate, (10) 2-Phenyl-l,3-diol


monocarbamate
.-. - (1 -Hydroxyfelbamate), (10c)

--
*
<
*<
*
B

0
)-NH~
0
3-Carbamoyloxy-2-phenyl-
propionic acid, (10d)
C02H

4
N-2 glucuronide, (1l a )
Lamotrigine, (11)

N-5 glucuronide, (11b)

Figure 6.3. (Continued.)


Anticonvulsants

A'
0 0 0 CH3
2-Sulfamoylacetyl phenol Zonisamide, (13) N-acetylzonisamide, (13a)
(SMAP),(13b) 0

.C02H

Tiagabine, (14) 5-0x0tiagabine, (14a)

Figure 6.3. (Continued.)

piperidinecarboxylic acid hydrochloride (14), pathways have been identified in humans: (1)
is rapidly and nearly completely absorbed thiophene ring oxidation, forming inactive iso-
(95%), with an absolute bioavailability of mers of 50x0 tiagabine (4-5% of the dose)
about 90% (18). The metabolism of tiagabine (14a);and (2) carboxylic acid glucuronidation
has not been fully elucidated, although two (69). Of the administered dose, 25% was ex-
3 Physiology and Pharmacology

Levetiracetam carboxylic Levetiracetam, (16) N-3-Hydroxypropionamido-


acid, (16a)
1 (2)
a-butanamide, (16c)

NH2

OH
3-Hydroxy levetiracetam, (16b)
Figure 6.3. (Continued.)

creted in the urine, with 60% (- 14% of the dine acetamide (16). The drug is rapidly ab-
dose) identified as the isomers of (14a). The sorbed, with peak plasma concentrations oc-
remaining dose was recovered in the feces 3-5 curring in about 1 h after oral dosing (18).The
days after dosing (69). Two major, as yet un- oral bioavailability of the tablets is 100%. Le-
identified metabolites were present in the fe- vetiracetam produces one major metabolite,
ces, and accounted for >60% of the fecal resi- levetiracetam carboxylic acid (16a) (Fig. 6.3)
due. The mean half-life of the drug in healthy in humans. The inactive carboxylic acid (16a)
volunteers was independent of the adminis- constitutes 24% of the dose. Two minor inac-
tered dose, indicating linear elimination ki- tive metabolites, the diastereomeric 3-hy-
netics (69). droxy levetiracetam (16b) (2%of the dose) and
the ring-opened butanamide (16c) (1%of the
2.3.1 4 Sulfamate dose) were also isolated. There was no enan-
Topiramate. Topiramate, chemically 2,3: tiomeric interconversion of levetiracetam or
4,5-bis-0-(l-methylethylidene)-/3-~-fructopyr-its major metabolite (18). The plasma half-life
anose sulfamate (15), is rapidly absorbed. The of the drug in adults is 7 5 1 h and is elimi-
relative bioavailability of the tablet is about nated by renal excretion of unchanged drug
80% of that of the solution (18).Metabolism of (66%).The mechanism of excretion is glomer-
the drug is not extensive and -70% of the ad- ular filtration, with subsequent partial tubu-
ministered dose is found in the urine. The me- lar reabsorption; the carboxylic acid metabo-
tabolites (Fig. 6.3) result from w-oxidation, lite (16a) is excreted by glomerular filtration
that is, di- (15a) and mono-hydroxymethyl and active tubular secretion.
(15c) derivatives of the isopropylidene car-
bons and ring cleavage (15b)as well as glucu-
ronidation (81). None of the metabolites pos- 3 PHYSIOLOGY AND PHARMACOLOGY
sessed significant activity. There is evidence of
renal tubular reabsorption of topiramate. As stated in the previous edition (8), seizures
in humans and laboratory animals result in
2.3.1 5 Pyrrolidinone Acetamide rapid voltage changes in their EEG patterns.
Levetiracetam. Levetiracetam is a single These changes are accompanied by an extra-
enantiomer, (-)-(S)-a-ethyl-2-0x0-1-pyrroli- cellular depolarizing shift caused by a large
Anticonvulsants

excitatory postsynaptic potential. The exact slow off-rate caused by- anticonvulsants that
biochemical mechanisms leading to these dis- act as sodium channel blocking agents pro-
charges and the resultant epileptic attack are vides an accumulated block after repeated de-
still unknown. Several events, however, are polarization (termed use-dependency). Thus,
known to occur. The EEG changes relate to in seizures, the sodium channel-blocking
the opening of specific ion channels in the neu- agents are effective only if the depolarization
ronal membrane. At the onset of the hyper- lasts for at least 5 s. These agents normally do
synchronous discharge, the extracellular Ca2+ not interfere with the normal action potential
concentration falls and the extracellular K+ or excitatory synaptic potentials that typically
concentration rises (3). Further, the excessive last less than 200 ms (86).
neuronal discharge may release large amounts As noted in Tables 6.6 and 6.7, several first-
of excitatory neurotransmitters at synapses generation and second-generation agents act
that may result in an avalanche of stimula- by blockade of voltage-dependent Na+ chan-
tion. The current proposed cellular mecha- nels; however, there are problems in explain-
nisms by which the anticonvulsants exert ing the clinical and experimental facts con-
their effect are indicated for the "first-gener- cerning these agents. As an example,
ation" and "second-generation" agents in Ta- carbamazepine and phenytoin are listed as
bles 6.5 and 6.6, respectively. These mecha- Na+ channel-blocking agents (80); however,
nisms are summarized below. in the clinic, an epileptic patient found to be
3.1 Ion Channels resistant to one of these agents may respond
favorably to alternative treatment with the
As noted in Tables 6.6 and 6.7, there is evi- other of the two drugs, pointing out that these
dence that some classes of the older and newer agents may act by more than one mechanism
anticonvulsants interact with voltage-depen- (87). Furthermore, in a subgroup of rats found
dent sodium channels (82-85). Voltage-gated resistant to phenytoin, they have responded
sodium channels are responsible for the gen- well to carbamazepine (88, 89). Of the newer
eration of action potentials of nerve fibers agents, lamotrigine, as noted in Table 6.1, is a
through fast, selective transport of sodium broad-acting anticonvulsant acting against a
ions across the cell membrane, leading to the variety of seizure types; however, as noted in
rapid depolarization of the cell network (85). Table 6.7, it does not effect either GABAergic
The Hodgkins and Huxley model for the func- potentiation or blockade of thalamic T-type
tion of the sodium channel postulates that Ca2+ channels, thus providing further doubt
they exist in at least three different states, as of these agents acting by a single mechanism.
shown in Fig. 6.4(86). These states are: (1) the This problem was caused by the classical
resting (closed) or nonconducting state; (2) method of animal testing of anticonvulsants
the activation state resulting from changes in for generalized tonic-clonic seizures [i.e., the
the resting potential of the channel, which in- maximal electroshock seizure (MES) test].
creases the ability of the channel to inwardly This method was developed by Goodman and
conduct Na+ across the cell membrane until coworkers in 1944 and is still employed today
an action potential is elicited; and (3) this open (8,90-96). The MES test has been found to be
channel state exists for a short period and particularly sensitive to Nat channel blockers
closes rapidly to the inactivated state, which (97).
terminates inward flow of Na+ and the result-
ing voltage change. The reactivation to the
3.2 GABAergic Mechanisms
resting state is membrane potential depen-
dent, given that repeated depolarizations de- GABA, y-or 4-aminobutyric acid (19),formed
lay the transformation back to the resting by the decarboxylation reaction shown in Fig.
state (86). 6.5, is present within a large proportion of the
Drugs that interact with sodium channels central nervous system, where it is the major
to block ion flux cause the channels to inacti- inhibitory neurotransmitter controlling syn-
vate to a greater degree and with smaller de- aptic transmission and neuronal excitability
polarizations than normal (86). The relatively (98, 99).
Table 6.6 Proposed Cellular Mechanisms of the "First-Generation" Agentsa
- -

Blockade of Voltage1 Potentiation of Blockade of Thalamic Blockade of


Anticonvulsant Dependent Na+ GABAergic T-type Ca+2 Glutamatergic
Seizure Type Agent Channels Mechanisms Channels Mechanisms
A. Generalized tonic-clonic Phenytoin NE ?
N
bn and partial seizures Carbarnazepine ? +
-
W
Phenobarbital NE +
B. Broad spectrum Valproate NE 5
Benzodiazepines NE NE
C. Absence seizures Ethosuximide + NE
"Effect is indicated by +. + +, effective; 2,inconsistent data; NE, not effective in therapeutically relevant concentrations;?, no data available (or found). Data are from Refs. 76,
77.
Table 6.7 Proposed Cellular Mechanisms of the "Second-Generation"Agentsa
Blockade of Voltage- Potentiation of Blockade of Thalamic Blockade of
Anticonvulsant Dependent Na+ GABAergic T-type Ca+' Glutamatergic
Seizure Type Agent Channels Mechanisms Channels Mechanisms
A. Generalized tonic-clonic Vigabatrin
and partial seizures Tiagabine
N Gabapentin
rD
fr B. Broad spectrum Lamotrigine
Oxcarbazepine
Topiramate
Felbamate
Zonisamide
C. Absence seizures -
"Effect is indicated by +. ++, effective; +, inconsistent data; NE, not effective in therapeutically relevant concentrations; ?, no data available (or found). Data are from Refs.
78-86.
3 Physiology and Pharmacology

/[ 2:;ed 17 Inactivation
Fast
Depolarized
4

/ Slow
Inactivation
( +'
Closed but
can be Inactivated v
activated Polarized
u
Figure 6.4. Relationship between open, closed, and resting state of Naf channels. (After Ref. 86.)

There are at present three known classes bles 6.6 and 6.7, the older agents (i.e., pheno-
of GABA receptors, GABAA, GABA,, and barbital, valproate, and the benzodiazepines)
GAB&, with distinctive binding properties act through this mechanism, whereas the
and different functional responses to GABA, newer agents (i.e., topiramate, felbamate, vi-
although each is involved with inhibition of gabatrin, tiagabine, and gabapentin) are also
the CNS (100). All GABA receptors are found GABAergic agonists, although by different
as pre- and postsynaptic receptors, and as au- mechanisms (105, 106). Topiramate, in addi-
toreceptors (100). tion to potentiating GABA, also prolongs inac-
tivation of sodium channels. Felbamate, also a
3.2.1 CABA, Receptors. Of the three, the GABA agonist, like topiramate, also blocks
postsynaptic receptors are responsible for in- the (RS)-2-amino-3-(3-hydroxy-5-methyl-4-
hibiting neuronal excitability (101, 102). isoxazolyl)propionic acid (AMPA, 25) as well
GABA, receptors (Table 6.8) are major GABA
receptors that are linked to chloride channels
and are activated by isoguvacine (21) (Fig.
6.6), modulated by barbiturates and the ben-
zodiazepines, and antagonized by bicuculline
(101, 102). This receptor is termed a hetero-
oligomeric complex and is composed of at least
four types of multiple allosterically interact-
ing binding sites (GABA, benzodiazepine, bar-
biturate, and picrotoxin sites), together with
an intrinsic chloride ion channel (103). Each
of the allosteric binding sites is thought to be as the N-methyl-D-aspartate (NMDA, 26) re-
physically distinct, and can be occupied simul- ceptors (these latter compounds are discussed
taneously to induce their individual pharma- later) (107).
cological effects through allosteric interaction. Vigabatrin acts by blocking GABA-T, the
It is established that the GABA, receptor com- enzyme responsible for the breakdown of
plex plays a significant role in the action of GABA (Fig. 6.5); tiagabine acts by inhibit-
anticonvulsant agents (104). As noted in Ta- ing the reuptake of the neurotransmitter,

H2N LC02H
Glutarnic acid, (18)
-GAD
-CO,
--
H2N -CO~H
GABA, (19)
GABA-T
-----'
-NHq ~U
H C02H
Succinic sernialdehyde
(20)

Figure 6.5. Major pathway for the synthesis and degradation of GABA. GABA, y-aminobutyricacid;
GAD, glutamic acid decarboxylase; GABA-T, GABA transaminase.
296 Anticonvulsants

Table 6.8 The GABA Receptor Subtypes


GABA
Receptor Response to
Subtype Linked Activated Modulated Bicuculline
GABA, Chloride channel Isoguvacine, (21) Barbiturates; Bicuculline-
benzodiazepines sensitive
GABA, Calcium or potassium (-)-Badofen, (22) Protein kinase C Bicuculline-
channels insensitive
GAB& Chloride channel cis-4-Aminocrotonic acid
(CACA, 23); cis-2-
(Aminomethyl)-cyclo-
propane-carboxylic
acid (CAMP, 24)

some animal models, but not yet in humans


(112). Several phosphinic acid analogs (27) of
GABA have been synthesized and found to be
selective, orally active GABA, agonists in an-
imals (113); however, they have not been ad-
(26) NMDA vanced to the market.

whereas gabapentin presumably acts by acti-


vation of GAD (1081, with the resultant in-
crease in GABA levels in patients (109). It
should also be noted that gabapentin (see Ta-
ble 6.7) exerts several other cellular actions
(27) Phosphinic acid analogs
not related to GABA (see Table 6.7 and Ref. R = CzH5;n-C3H7;CH2C6H5;CH2C6Hll
110).
The GABABagonist baclofen (22) has been
3.2.2 CABA, Receptors. In theory, drug
shown to prolong spike-and-wave discharges
that depresses GABA, receptor-mediated in-
in animal models, thus enhancing the amount
hibition should also be effective anticonvul-
of GABA available to the receptor, and GABAB
sants (111).This has been demonstrated in
antagonists block them (112, 114-117).

3.3 Glutamate Receptors


(S)-Glutamic acid (18) the main excitatory
neurotransmitter in the central nervous sys-
tem and other excitatory amino acids operate
I through four different classes of receptors
H (118). In addition to the three heterogeneous
Isoguvacine, (21) classes of ionotropic excitatory amino acids
(iGluRs) [i.e., AMPA (25), NMDA (26), and
kainic acid (28) receptors (119-12311, a heter-
ogeneous class of G-protein-coupled excitatory
H2N amino acid receptors (mGluRs) has been
cis-2-(Aminomethyl)- shown to have an important function in neu-
cis-4-Aminocrotonic cyclopropanecarboxylic ronal signaling processes (124, 125). It is now
acid (CACA, 23) acid (CAMP, 24) generally understood that both iGluRs and
mGluRs play important roles in health and
Figure 6.6. GABA activators. disease processes including epilepsy (119). It
4 History

(28) Kainic acid 0CH3


(29) Verapamil

was previously noted that several of the re-


cently marketed anticonvulsant agents act by
new mechanisms (80). In this respect, inhibition
of glutamatergic excitation, particularly medi-
ated by the NMDA and non-NMDA type of glu-
tamate receptors, has been suggested to play a
significant role (80). As noted in Table 6.7, there
is indeed evidence for an anti-glutamatergic ac-
tion for the newer agents, whereas in Table 6.6,
there is also evidence that the older drugs act
through this mechanism as well.

3.4 T-Type Ca2+ Channels


Calcium channels have been classified into L-,
N-, T-, P/Q-, and R-types on the basis of their
pharmacological and/or electrophysiological
properties (126, 127). The classification of
F
voltage-dependent calcium channels divides (30) Flunarizine
these channels into three groups: high volt-
age-activated, which includes L-, N-, P-, and
Q-types, intermediate R-type; and low volt-
age-activated, T-type (128). These channels
are composed of a, P, and y-subunits whose
sequences are known (128, 129). The a,-sub-
unit of voltage-sensitive Ca2+ channels has a
secondary structure similar to that of the
a-subunit of Na+ channels as well as some se-
quence homology (127, 129). Because of the
homology between these two relevant sites,
some Ca2+ channel-blockers, such as vera-
pamil (29), flunarizine (30), nifedipine (311, (31) Nifedipine
and diltiazem (32), also act on Na+ channels
RWJ 37868,33) have been synthesized, which
(130). These agents, however, showed only low
act by blocking Ca2+ influx into cerebellar
i or absent anticonvulsant activity in controlled
cells (131).
trials (78). These were all L-type channel
blockers. In addition to T-type Ca2+ channel
E blockers on the market [i.e., ethosuximide 4 HISTORY
L
1
(5a), zonisamide (13), and trimethadione
(17a) (78)], a new series of anticonvulsant The history of anticonvulsants has been based
I
: aroyl(aminoacyl)pyrroles (lead compound on serendipity (8). Table 6.9 indicates the rel-
Anticonvulsants

Table 6.9 Historical Development of Anticonvulsant Drugs


Anticonvulsant Agent Yeark) Scientist(s) Reference(s)
Phenytoin, (1) Introduced by Merritt and Putnam
Synthesized by Biltz
Carbamazepine, (2) Schindler
Initial synthesis by Thiel and Holzinger
Valproic acid, (3) Introduced by Meunier et al.
Synthesized by Burton
Diazepam, (412) Found to be effective in seizure models by:
LHernandez-Peon et al.
2.Kopeloff and Chusid
Ethosuximide, (5a) Antiepileptic properties described by:
1.Vossen
2.Zimmerman and Burgmeister
Phenobarbital, (6) Introduced by Hauptman
Primidone, (7) Introduced by Handley and Stewart
Synthesized by Bogue and Carrington
Trimethadione, (17) Introduced by Everett and Richards
Synthesized by Spielman
Vigabatrin, ( 8 ) Synthesized by Jung et al.
Gabapentin, (9) Synthesized by Satzinger and Hartenstein
Felbamate, (10) Synthesized by Berger, Ludwig et al.
Introduced by Brodie
Lamotrigine, (11 Developed by the Wellcome Research
Laboratories, Beckenham, Kent
Initial clinical trial Cohen et al.
Oxcarbazepine, ( Developed by Ciba-Geigy Ltd., Basel,
Switzerland
Initial clinical trial Meinardi et al.
Zonisamide, (13) 1976 Discovered by Dainippon Research
Laboratories, Japan; Clinical studies in
the United States sponsored by Warner-
LambertParke-Davis
Synthesized by Uno et al.
Tiagabine, (14) 1990 Developed by Novo Nordisk AIS, Denmark
Synthesized by Braestmp et al.
Topiramate, (15) - 1980 Developed by R.W. Johnson
Pharmaceutical Research Institute
Synthesized by Matyanoff et al.
Levetiracetam, (16) 1992 Developed by UCB S.A. Pharma Sector,
Belgium

evant scientists involved in the development


of these agents.
As indicated previously (8), the classical re-
search on epilepsy began with the work by
John Hughlings Jackson (1621, who found
that experimental seizures, analogous to the
clinical manifestations, could be replicated in
laboratory animals by electroshock and a vari-
ety of naturally occurring chemicals (163).
The following chronology (Table 6.10) evolved
(32) Diltiazem from that time.
4 History

Table 6.10 Historical Development of Drug Testing


Year Event (Reference)
Convulsions were induced in dogs and rabbits with absinthe (164).
Seizures were produced in animals by excessive electrical stimulation of the brain (165).
Picrotoxin, a component of Anamirta cocculus and A. paniculata, was first used as a
convulsant (166).
Albertoni tested a variety of agents against electrically induced convulsions in dogs (167).
Pentylenetetrazol(34) was synthesized by Schmidt (168); Hildebrant reported its
convulsant activity (169).
Putnam and Merritt reported a method for determining the anticonvulsant property of
chemical compounds and led to the discovery of phenytoin (1)(122).
Richards and Everett reported on the anticonvulsant activity of trimethadione (17),
originally synthesized as an analgesic), in seizures induced by pentylenetetrazol in rats
(148).
Goodman and coworkers (90-96) provided standards in the evaluation of potential
anticonvulsant candidates. These included the maximal electroshock seizure (MES)
test and the subcutaneous pentylenetetrazol (scMet, or scPTZ) test, two standards for
drug evaluation used today.
Establishment of the Epilepsy Branch within the National Institute of Neurological
Disorders and Stroke (NINDS), a pharmacological testing service for academia and
industry (170-173).

1. Enhancement of inhibitory (principally


GABA-mediated) processes
2. Reduction of excitatory (principally gluta-
mate-mediated) processes
3. Modulation of membrane cation conduc-
tance (Na+, Ca2+,or Kt)

A review of the second-generation anticon-


vulsants reveals that screening or serendipity
led to the development of felbamate (lo),lam-
otrigine (ll),zonisamide (131, topiramate
(33) RWJ 37868
(15), and levetiracetam (16); on the other
hand, clobazam (4d) and oxcarbazepine (12)
were developed by structural variation of
Of the compounds listed in Table 6.9, only a known agents (78). Only three, vigabatrin (€41,
few anticonvulsant agents were synthesized gabapentin (9), and tiagabine (14),were devel-
with a.definite plan of attack. This is particu- oped by mechanism-based rational develop-
larly true with the "first-generation" drugs, ment (78).
which were found by serendipity or screening
(random screening of newly synthesized com- Vigabatrin. In recognition of the role of
pounds of diverse structure, or structural vari- GABA-mediated mechanisms in the patho-
ation of known anticonvulsant agents) (2, 8). genesis of epilepsy, vigabatrin (y-GABA, 8)
Although the growing trend is toward rational was designed as an irreversible inhibitor of
drug design, the mechanisms of action for sev- GABA-T as seen previously in Fig. 6.5 (175).
eral of the newer agents remain obscure (174). As noted in Fig. 6.5, blockade of GABA-T, the
As related earlier in this chapter, three princi- major pathway for the degradation of GAEiA,
pal mechanisms of action are seen for the sec- would lead to an elevation of GABA. This was
ond-generation agents: found to be true in rodents (153); further, the
Anticonvulsants

@C
, -H

COO
Vigabatrin, (8)

Figure 6.7. Proposed mechanism of action of vigabatrin (8)(after Ref. 175). B, base in enzyme active
site; Nu, nucleophilic residue in enzyme active site.

increase occurred preferentially in the neuro-


nal GABA-T sites (176). The proposed mecha-
nism of vigabatrin is shown in Fig. 6.7 and is
adapted from Jung et al. (175). GABA-T is a
pyridoxal phosphate enzyme that forms a (35) Aspartic acid
Schiff s base with the active site (K,); the en-
zyme abstracts a proton from C4, forming an
aldimine-ketimine equilibrium (Kat-Kp2). ever, the hypothesis of a direct GABA-mimetic
The reactive C5, C6 unsaturated ketimine un- action was contradicted in a series of biochem-
dergoes a Michael addition with a nucleophilic ical studies (179). It has subsequently been
residue of the active site before it dissociates shown that gabapentin limits Nat-dependent
from the enzyme surface (175). action potentials of cultured mouse neurons in
Although the action of vigabatrin is pri- a manner that develops slowly with sustained
marily by augmentation of GABA-mediated exposure to the agent (174). This blockade is
function, another mechanism has been sug- both voltage and frequency dependent and oc-
gested; that is, a decrease in brain levels of the curs at clinically effective concentrations of
excitatory amino acids glutamate (18)and as- the drug. It is, however, not a sodium-channel
partate (35) may also play a part (177). blocker in the same manner as that previously
Gabapentin. Like vigabatrin, gabapentin noted with phenytoin and carbamazepine, but
[(I-aminomethyl)cyclohexaneacetic acid, (9)l instead acts at a distinct site or indirectly
was designed as a lipid-soluble GABA analog, (180). Further, gabapentin was found to in-
which would cross the blood-brain barrier, crease GABA accumulation in discrete regions
while retaining much of the chemical and in rat brain, in a time course that parallels
physical properties of GABA (8, 178). How- the anticonvulsant effect (181). There has
4 History

Excitatory nerve
terminal
1
Stimulus Carbamazepine
Phenytoin
Valproate
~amotri~ine
Gabapentin(?)
I
Felbamate (?)
Oxcarbazepine
Zonisamide

)larlzarlon 1 Voltage-dependent Na+channel

J
Glutamate

/ Glycine

Glutamate / 1 /

Postsynaptic
Zn2+ neuron

Mg2+
Felbamate (?)
Zonisamide

NMDA
receptor
Figure 6.8. Possible sites of interaction of antiepileptic drugs on glutamate-mediated transmission
(after Ref. 174). The NMDA receptor is associated with an ion channel permeable to Na+ and Ca2+,
and is associated with a number of modulatory sites, including a strychnine-insensitive glycine-
binding site. Glycine is an absolute requirement for the receptor-channel complex to enter the open
state.

recently been found a specific binding site for sant activity, whereas the R-(-) enantiomer
a [3H]gabapentin (182). It is localized in (36b)was less active in each evaluation (185).
discrete areas in the brain of rats that are as- These data support the conclusion that there
sociated with excitatory input (183, 184). is an association between the ability of gabap-
S-(+)-3-Isobutyl-GABA (364 displaces entin to interact with its binding site and the
[3H]gabapentin binding and has anticonvul- anticonvulsant effects (174).
Anticonvulsants

the result of the observations of Reynolds and


coworkers that chronic anticonvulsant treat-
ment with phenytoin (I), phenobarbital (6),
and primidone (7)led, in many instances, to a
disturbance in folate metabolism and that
there may be a relation between the antifolate
effects of these drugs and their therapeutic
actions (190). It was subsequently shown that
folic acid and other folates were convulsant in
laboratory animals when injected directly into
the brain or after massive p a r e n t e d doses
(191). However, lamotrigine has been shown
to be a potent anticonvulsant, with only weak
antifolate activity (8). Currently, it has been
shown that lamotrigine primarily acts by sta-
bilizing presynaptic neuronal membranes
through a blockade of voltage-dependent Na+
channels, thus preventing the release of exci-
Felbamate. In a recent report, it was noted tatory neurotransmitters, principally gluta-
that felbamate (2-phenyl-1,3-propanediol di- mate (see Fig. 6.8) (192). Although this block-
carbarnate, 10) can reduce sustained repeti- ade is similar to that elicited by phenytoin and
tive firing of spinal cord neurons at therapeu- carbamazepine (193, 1941, it differed in also
tic concentrations (186). This provides blocking electrically and visually evoked after-
indirect evidence of a blocking effect on volt- discharge tests, where only lamotrigine pro-
age-dependent Na+ channels as a mechanism vided protection (191). This latter test is used
of action (187). However, felbamate also has as a model of local (partial) seizures and is
been found to exert action on other systems as useful in identifying drugs such as ethosuxim-
well. The NMDA site has been postulated as ide (191). It is therefore of interest to note
an additional target for felbamate. Felbamate that, although lamotrigine demonstrates an
has been shown to interact with strychnine- effect similar to that of phenytoin and carbam-
insensitive glycine-bindingsites in concentra- azepine in blocking Na+ channels [useful in
tions within the therapeutic range (188).Fur- protection against tonic-clonic seizures and
ther, it was shown that glycine can selectively some partial seizures (77, 174)], it should be
reverse the anticonvulsant effects of felbam- noted that lamotrigine provides broader sei-
ate in rodents and provides evidence that fel- zure protection as well.
bamate acts as an antagonist a t the NMDA- Oxcarbazepine. Oxcarbazepine (10,ll-di-
associated glycine-binding site (189). The hydro- 10-0x0-5H-dibenz[b,flazepine-5-car-
result would be a reduction in excitatory boxamide or 10,11,dihydro-10-0x0carbamaz-
amino acid transmission (174). Additional re- epine, 12) was designed to avoid the dose-
search has shown that felbamate can block dependent side effects noted in some patients
NMDA responses in a low affinity noncompet- (e.g., nausea, headache, dizziness, ataxia, dip-
itive, or open channel manner (i.e., the ion lopia) and to minimize enzyme induction and
channel has been previously opened by gluta- drug-drug interactions displayed by carbam-
mate, or other agonist). These actions are azepine (195, 196). As shown previously (Fig.
summarized in Fig. 6.8. An additional study 6.3), the change in structure results in a dif-
showed that felbamate can enhance GABA, ference in metabolism. Although both car-
receptor-mediated responses in therapeutic bamazepine and oxcarbazepine are ultimately
concentrations (189).Thus, it is clear that fel- converted to the inactive trans diol, oxcarbaz-
bamate exerts multiple effects as an anticon- epine does not form the active l0,ll-epoxide
vulsant. intermediate, but does form the active 10-
Lamotrigine. Lamotrigine [3,5-diamino-6- hydroxy metabolite MHD (197). The mecha-
(2,3-dichloropheny1)-1,2,4-triazine( l l ) ] was nism of action of oxcarbazepine is very similar
4 History

(37a)Tryptophan

(37) Indole

(37b)Serotonin

to that of carbamazepine (i.e., MHD blocks


voltage-dependent Na+ channels), but unlike
carbamazepine, produces a reversible, dose-
dependent decrease in high voltage-activated
Ca2+ channels, an effect not antagonized by
nifedipine, and reduces glutamatergic trans-
mission (198). (38) Nipecotic acid
Zonisamide. Zonisamide (1,2-benisoxazole-
3-methanesulfonamide,13) was developed be- however, because of its polar nature it could not
cause of its isosteric similarity to indole (371,a permeate the blood-brain barrier (8, 198).
structural skeleton of tryptophan (37a) and Tiagabine was thus designed using the nipecotic
serotonin (3%)(8,157). Zonisamide prevents acid nucleus with the polar nitrogen atom at-
repetitive neuronal firing by blockade of volt- tached to a bis lipophilicthienyl carrier linked by
age-sensitive Na+ channels. It also reduces an aliphatic chain (8, 198). These modifications
voltage-dependent T-type Ca2+ channels, fa- permitted rapid brain penetration, where it ef-
cilitates dopaminergic and seratoninergic fectively inhibits GABA reuptake. Tiagabine
neurotransmission, weakly inhibits carbonic possesses an anticonvulsant effect, which paral-
anhydrase, and may protect neurons from lels elevation of GABA levels. Whether this is
free-radical damage, thus stabilizing neuronal the only anticonvulsant mechanism awaits fur-
membranes (199). Zonisamide does not poten- ther investigation (201).
tiate the synaptic activity of GABA (198). Topiramate. Topiramate (15), a unique sul-
Tiagabine. Tiagabine {(R)-(-)-1-[4,4-bis(3- famate-substituted sugar moiety, possesses
methyl-thieny1)-3-butenyll-3-piperidinecar- multiple proposed mechanisms of action: ( I )
boxylic acid or R-(-)-N-[4,4-di(3-methylthien-2- blockade of voltage-activated sodium chan-
y1)but-3-enyl]nipecoticacid) (14) was designed nels; (2) enhancement of GABA acting at the
specifically as a GABA reuptake inhibitor, oper- benzodiazepine-insensitive GABA, receptor;
ating through a high affinity, sodium-dependent and (3) modest blocking action at the AMPA
transport system (200).Earlier, it was observed glutamate receptors (196). There are no re-
that nipecotic acid (3-piperidinecarboxylic acid, ported effects at NMDA receptors. Although
38) possessed GABA reuptake blockade in vitro; the agent possesses weak carbonic anhydrase
Anticonvulsants

(39) Piracetam (16) Levetiracetam

inhibitory activity, this action, as it relates to placement of [3H]levetiracetam binding oc-


anticonvulsant activity, remains problematic. curred with amiloride, a T-type Ca2+
However, it can explain the appearance of kid- antagonist; however, levetiracetam is inactive in
ney stones in some patients resulting from the the T-channel assay (208). Thus, the mecha-
formation of the insoluble N-acetyl metabolite nism of action remains unknown (198).
(Fig. 6.3), a phenomenon known for the sul- Of interest is the structural interrelation-
fonamides. ship between levetiracetam (16) and its
Levetiracetam. Levetiracetam [(-)-@)-a- precursor piracetam (39) (207). Both are
ethyl-2-0x0-1-pyrrolidineacetamide (16)l is 2-pyrrolidinones; however, the chirality of le-
unique in that it failed the two primary evalua- vetiracetam allows for a wider range of thera-
tion screens, that is, the MES and the scMet peutic activity as noted above. These actions1
(scPTZ) tests (198). In contrast, levetiracetam inactions are shown in Table 6.11 (208).
possesses strong seizure protection in animal
models (i.e., genetic models and kindled rodent
5 STRUCTURE-ACTIVITY RELATIONSHIPS
models), which are more indicative of the
chronic disease state (201,202).Research on the
5.1 Hydantoins
mechanism of action has been ongoing and re-
veals the following: (1)the results on the GABA In addition to an extensive summary provided
system lead to conflicting results; one laboratory previously on this moiety (8), Brouillette et al.
reported that it is unlikely that the anticonvul- (209) employed comparative molecular field
sant action is mediated by action on the analysis (CoMFA), a three-dimensional struc-
GABAergic system (203), whereas another lab- ture-activity technique, to provide a new
oratory reported that its action may in part be potential anticonvulsant, 2-hydroxy-2-phe-
attributed to potentiation of GABAergic inhibi- nylnonanamide (40), whose Na+ channel inhi-
tion (204); (2) it is the first drug to demonstrate bition (IC,, = 9 p M ) compared favorably to 40
antiepileptogenic activity, which provides sei- p M for phenytoin (1). This study suggested
zure protection long &er termination of treat- that the hydantoin ring system is not neces-
ment (205); (3) a stereospecific binding site for sary in Na+ channel binding. Research on wa-
[3H]levetiracetamexists that is not displaced by ter-soluble prodrugs of phenytoin has contin-
phenytoin, carbamazepine, valproate, pheno- ued since the work by Stella, which led to the
barbital, or benzodiazepines (206); (4) the dis- synthesis of fosphenytoin (Id)(8,209-215).A

Table 6.11 2-F'y-rrolidinones


Effect Levetiracetam Piracetam
Brain-specific stereoselective Yes No
binding site
Improvement in learning Less effective Excellent
and memory
Seizure prevention Excellent Poor
Therapeutic indication Epilepsy (partial; possibly Age-related cognitive disturbances;
generalized and myoclonus) poststroke aphasia
5 Structure-Activity Relationships

activity as well as for activity in trigeminal


series of N-benzyloxycarbonyl-aminoacid pro- neuralgia (218). Two compounds, (43a) (X=
drugs of phenytoin, synthesized by Scriba and Cl, R = CONH,) and (43b) (X = H, R =
Lambert, led to (41), which provided a de- CONH,), were compared to carbamazepine
(2). In the oral MES evaluation (43a) and
(43b) provided ED,, values of 14 and 29 mg/
kg, respectively, compared to 19 mg/kg for car-
bamazepine. The three compounds were com-
pared for their ability to reduce the evoked
thalamic or trigeminal potentials in the cat. In
these studies, (43b) was equipotent to car-
bamazepine, whereas (43a) was less potent
than carbamazepine; however, both oxaz-
epines possessed a longer duration of action,
were less toxic, and provided a more selective
effect on the trigeminal sensory system than
creased median effective dose (ED,,) in the that of carbamazepine.
MES test and an increased median toxic dose A series of alkylamino-5,6-dihydro-6-0~0-
(TD,,) compared to that of phenytoin (216). morphanthridinones (chemically, dihydrod-
The piperazine prodrug (42), prepared by ibenz[b,e]azepines, 44) were synthesized and

evaluated for anticonvulsant activity by War-


Bosch and coworkers, was hydrolyzed more ing and Whittle (219). The most active com-
rapidly than fosphenytoin under the same in pound, (44a) (R, = R, = CH,; MES ED,, = 42
vitro conditions (96.52 ? 7.15% at 2 min for 42 mg/kg; scMet ED,, = 38 mg/kg), was advanced
versus 11.63 f 1.8% for fosphenytoin) (217). to clinical trial in epileptic patients.
Research on derivatives of oxcarbazepine
5.2 lminostilbenes
(12) has evolved. Soares-da-Silvaand cowork-
Several structure-activity studies were de- ers provided data from two studies. As indi-
scribed. Yale synthesized a series of 5,ll-dihy- cated previously (Fig. 6.3) oxcarbazepine (12)
dro[b,e] [1,4]oxazepine-5-carboxamides(43) is rapidly and extensively metabolized to a
and tested these analogs for anticonvulsant mixture of the active metabolites, the (105')-
Anticonvulsants

alcohol (45a) and its (10R)-enantiomer (45b), statistically significant different IC,, of 138 t
both appearing in plasma (220) and urine 32 a, compared to that of carbamazepine
(221) in an approximately 4:l ratio. The first (210 + 15 and provided 95.6 t 2.6% inhi-
study (222) evaluated the esters of the mono- bition of sodium uptake at 300 $4 (carbamaz-
epine 64.8 2 3.0% at 300 pM). In a follow-up
study, they indicated that acetates (45) appear
to be preferable to oxcarbazepine because they
provide a clearer metabolic pathway (223).
Therapeutically, acetate (45a) was found to be
more appropriate as the R-( -)-isomer, which
has a greater propensity to undergo inactiva-
tion to the trans-diol (45c) (222). The bio-
transformation of the esters is shown in Fig.
6.9. The predominant pathway is indicated
with the heavy arrow.
The quadracyclic (*)-5-aminocarbonyl-
10,ll-dihydro-5H-dibenzo[a,d]cyclohepten-
5,lO-imine(ADCI, 47), results from the fusion
of two active anticonvulsant compounds, MK
801 (dizocilpine, 46), a potent noncompetitive
NMDA antagonist (224, 225) and carbamaz-
epine (2). The compound acts as a selective,
low affinity channel blocker of the NMDA re-
ceptor and also possesses Naf channel-block-
ing activity (226). ADCI is devoid of the ten-
dency to cause behavioral impairment as MK
801. ADCI is a racemate, although the (+)-
enantiomer displays a four- to fivefold greater
potency at the NMDA receptor and a greater
than twofold potency for seizure models inan-
imals. There was no enantioselectivity in the
hydroxy derivatives and it noted that the ace- Nat channel evaluation, however. The (+)-
tates (R = COCH,) were the most active com- enantiomer (SGB-017)is currently in Phase I1
pounds. Of further interest was the fact that of clinical development.
the acetate of (45a) was active in its own right
and not a prodrug in the true sense. Compar- 5.3 Barbiturates
ative data are provided in Table 6.12. As
noted, whereas carbamazepine was the most Of renewed interest is the emergence of etero-
active, the acetate of (45a) was as active as barb (N,Nr-dimethoxymethyl phenobarbital,
oxcarbazepine. In addition, blockade of volt- 6b) (200). This agent possesses attenuated
age-sensitive sodium channels was also evalu- sedative and hypnotic properties compared
ated, revealing that the acetate of (45a) had a to those of phenobarbital (6). Although

Table 6.12 Comparative Data of Carbamazepine (2), Oxcarbazepine (12), and Acetate of 45a
and 45ba
Compound % Protection MES (mglkg) TD5,( m g k ) Protective Indexb
Carbamazepine, (2) *
100 0.0 *
3.4 0.1 *
27.4 0.1 8.1
Oxcarbazepine, (12) 68.3 5 20.3 6.1 t 0.1 40.1 t 1.2 6.6
Acetate of (4Sa) 100 t 0.0 6.3 t 0.1 78.6 t 4.2 12.5
Acetate of (45b) 5.9 t 1.8 18.0 t 0.1 134.9 t 3.5 7.5
"Values are means 2 SEM of 5-8 ratslgroup.
bProtediveindex = TD,,,IED,o.
5 Structure-Activity Relationships

0
NH2
(45a) acetate; S(+) (45b) acetate; R(-)

(45a) alcohol S(+) (45b) alcohol; R(-) (45c) Trans-diol


f

Oxcarbazepine (12)
Figure 6.9. Proposed metabolism of acetates o)foxcarbazepine (12). Dark arrows are the preferred
pathway.

eterobarb is completely converted to pheno- binding site (8).The anticonvulsant activity of


barbital, N-monomethoxymethyl phenobarbi- these agents in vivo was directly correlated to
tal (MMP, 6c),the first step in the metabolism their in vitro binding effect (227-229). Of the
occurs more rapidly than the final step. Etero- drugs currently in the market, the anticonvul-
barb does not enter the brain and may be sant 1,4-benzodiazepines (48a) are composed
considered a prodrug for MMP and phenobar- of clorazepate dipotassium (R, = R, = H, R, =
bital, both active anticonvulsants (200). Et- CO,K, R4 = C1,4a), clonazepam (R, = R, = H,
erobarb has the advantage of lacking sedative R, = 2-C1, R4 = NO,, 4b), diazepam (R, =
activity, a prominent side effect with pheno- CH,, R, = R, = H, R, = C1, 4c), and nitraz-
barbital. The metabolic conversion and inter- epam (R, = R, = R, = H, R4 = NO,, 4e);
actions are shown below. whereas clobazam [4d (R, = CH,, R, = R, =
H, R, = Cl)] possesses the isosteric 1,5-ben-
5.4 Benzodiazepines zodiazepine system (48b). Talampanel
Benzodiazepines act by potentiating the (LY300164,49)is the most potent in a series of
GABAergic receptor, a high affinity, saturable 5H, 2,3-benzodiazepines(230).The compound
Anticonvulsants

(46) Dizocilpine (MK 801) (2) Carbamazepine

(6) Phenobarbital
5 Structure-Activity Relationships

(231). The nitro, chloro, iodo, and proteo de-


rivatives were found to be inactive in the MES
model.
In a related study by Grasso et al., it was
shown that 1-(4-aminopheny1)-3,5-dihydro-3-
methylcarbamoyl-7,8-methylenedioxy-4H-
benzodiazepin-4-one (50)was the most potent

in a series of analogs (232). Because of its long


duration of MES and kainic acid-induced sei-
zure protection, (50)may become a useful tool
is a selective, noncompetitive antagonist of the in the mapping of the AMPA/kainicacid recep-
AMPA receptor. From analysis of the meta- tor. The Grasso group synthesized a novel se-
bolic products, it was observed that the C1 an- ries of 4-aryl-6,7-methylenedioxyphthalazin-
iline moiety would lend itself to modification, l(Wi)ones, the most active of which was (51);
given that the N-acetyl functionality was the however, (51a) and (51b) were less active
primary route of metabolism in monkeys than (49a) (233).
Anticonvulsants

5.5 Valproate m a g ; scMet ED,,, 127 mg/kg; TD,,, 369 mg/


In a study to evaluate the structure-pharma- kg), compared to valproate (3a) (MES ED,,,
cokinetic-pharmacodynamicrelationships of a 272 mg/kg; scMet ED,,, 149 mgkg; TD,,, 426
series of N-alkyl and N,N-dialkyl derivatives mg/kg) (234,235). The drug combined glycine,
of valproic acid (52), N-valproyl glycinamide a neuroinhibitory transmitter, as an amide, to
(valrocemide, TV 1901, 52a) emerged as the valproate, an anticonvulsant. The polar na-
most promising candidate (MES ED,,, 152 ture of glycine would not permit it to pene-
6 Recent Developments

trate the blood-brain barrier; however, the 6 RECENT DEVELOPMENTS


conjugate product (52a) could serve as a
chemical drug-delivery system for glycine or, The following are drugs in development.
alternatively, the combination could act as a
drug on its own. It was found that the intact 6.1 AWD 131-138
(52a) did, in fact, exert anticonvulsant activ- Chemically, AWD 131-138 is 1-(Cchlorophe-
ity. As expected, the major metabolic product ny1)-Cmorpholinoimidazolin-2-one (54). This
was the carboxylic acid, valproyl glycine, and
this compound was devoid of anticonvulsant
activity. Only a small amount of valproate was
detected in animals. Valrocemide is currently
undergoing phase I1 clinical trials (198).
In another study, a series of phosphatidyl
choline analogs (53) containing valproate
were prepared. The agents were developed
based on targeted drug-delivery technology
and were directed toward delivering therapeu-
tic levels of valproate in the vicinity of the ep-
ileptic focus (198). In theory, this process
would limit the drug to a restricted area, thus compound is currently in Phase I clinical de-
limiting the overall systemic and side effects. velopment (198). It possesses a broad spec-
The most active, DP-VPA (DP 16,53a) is com- trum of anticonvulsant activity as well as an-
xiolytic action. Its mechanism of action is by
posed of phosphatidylcholine linked to val-
proic acid as an ester. This linkage renders the blockade of the voltage-activated Ca2+ chan-
nel in a dose-dependent manner. The Ca2+
molecule inactive. The cleavage of DP-VPA
and local release of active valproic acid occurs channel subtype is currently unclear. AWD
131-138 is rapidly absorbed in rats and dogs
selectively in response to epileptic activity in
the brain signaled by elevation of phospho- and displays a high metabolic stability under
lipase A,. Once the neurons return to their in vitro human liver slices (228).
normal state and enzymatic hyperactivity
6.2 Harkoseride
subsides, drug activation ceases, thus provid-
ing dual control over drug action (198). The Chemically, harkoseride is (R)-2-acetamido-
drug has completed phase I studies and phase N-benzyl-3-methoxypropionamide (55a),part
I1 studies are being planned. of a class of functionalized amino acid deriva-
Anticonvulsants

tives developed by Kohn and coworkers (236, aqueous media and readily diffuses through
237) and Paruszewski (238,239). Harkoseride biological membranes. It is thus rapidly ab-
shows excellent anticonvulsant activity in sev- sorbed and extensively distributed through-
eral animal models, including two models of out body water. It is not bound to plasma pro-
status epilepticus. It also provides neuropro- teins, but is extensively metabolized, with
tective effects in rat models of focal ischemia about 50% excreted in the urine of rats as the
(198). It is currently undergoing phase I1 clin- w (i.e., 4-hydroxy), and w-1 (i.e., 3-hydroxy)
ical evaluation. It was found to be rapidly and oxidation products.
completely absorbed, was less than 1% plasma The drug has successfully completed Phase
bound, and possessed a half-life of about I clinical trials (198).
12 h. The drug is eliminated primarily by
renal excretion and the metabolites have not 6.5 NW-1015
been identified. Preliminary data indicate
Chemically, NW-1015 is (S)(+)-2-[4-(3-fluoro-
that harkoseride does not affect the blood
benzyloxy)benzylamino]propanamide (57)
levels of carbamazepine, phenytoin, or val-
proate (198).

LY 300164 was previously discussed (see Ben-


zodiazepines, Section 5.4).

6.4 NPS 1776


Chemically, NPS 1776 is 3-methylbutana-
mide, or isovaleramide (561, a branched-

(241). The compound combines frequency and


use-dependent blockade of Nat channels,
Ca2+channel modulation, inhibition of gluta-
mate release, and monoamine oxidase B inhi-
bition. A study in human volunteers was suc-
cessfully completed. The findings of MAO-B
inhibition at the dosages tested indicate the
chained aliphatic amide that possesses a broad
possibility of the potential use in Parkinson's
spectrum of activity similar to that of val-
disease.
proate (240). The mechanism of action is un-
known; it was inactive in in vitro neurotrans-
6.6 Pregabalin (CI-1008)
mitter binding or uptake assays (198). This
suggests that its mechanism does not involve a This agent was previously discussed under
direct receptor-mediated action. Being a gabapentin. As noted, pregabalin is the S-(+I-
small, neutral molecule, it is easily soluble in enantiomer of 3-aminomethyl-5-methylhex-
6 Recent Developments

anoic acid (36a).The mechanism of action is protective potential, trials have also been
unknown, but it is likely to differ from that of conducted for other indications, including
other anticonvulsants. Pregabalin does not Parkinson's disease and Huntington's dis-
appear to have any direct action at Na+ and ease. A phase 111study in a monotherapy trial
Ca2+ channels, and it does not seem to affect with carbamazepine, however, indicated that
transmitter responses to glutamate, NMDA, the efficacy of remacemide was inferior to that
or GABA. Additionally, it does not change of carbamazepine (198).
neurotransmitter uptake e . , glutamate,
GABA, monoamine, adenosine, cholinergic, or 6.8 Retigabine (D-23129)
opiate receptors). Pregabalin, however, in- Chemically, retigabine (D-23129) is ethyl
creases GABA content in neuronal tissues,
N-(2-amino-4-(4-fluorobenz1amino)phenyl-
binds to the a218 subunit of the Ca2+channels, carbamate (59), and is structurally unrelated
and enhances glutamic acid decarboxylase ac-
tivity (185).Pregabalin is not significantly me-
tabolized in humans. Studies in healthy volun-
teers indicate the drug has a 90% oral
bioavailability and is not bound to plasma pro-
teins. In clinical studies, pregabalin provided
positive results against partial seizures. Addi-
tional studies are planned to evaluate its use
as monotherapy and in pediatric patients
(198).

6.7 Remacemide to currently marketed anticonvulsant agents.


Remacemide, which chemically is (?)-2-ami- It shows a unique mode of action by increasing
no-N-(1-methyl-l,2-diphenylethy1)acetamide K+conductance in neuronal cells (198).Phase
(58),and its principal active desglycinyl me- I and I1 studies have shown good tolerability
tabolite (58a), are low-affinity, noncompeti- and efficacy trials are ongoing.
tive NMDA receptor blockers and Na+ fast-
6.9 Rufinamide (CGP 33101)
channel blockers (242). Remacemide is rapidly
absorbed on oral administration and achieves Chemically, rufinamide (CGP 33101) is 1-(2,6-
a peak plasma level in 1 h, whereas the active difluorobenzyl)-1H-l,2,3-triazolo-4-carbox-
metabolite (58a)takes 2-3 h. The parent has a amide (60), which interacts with the inacti-
half-life of 3-4 h, compared to 12-15 k for the vated state of the Na+ channel, limiting high
active metabolite (243). Comedication with frequency firing of action potentials in neu-
enzyme-inducing anticonvulsants (i.e., phe- rons. It does not significantly interact with the
nytoin, carbamazepine, and phenobarbital) following neurotransmitter systems: GABA,
induces the metabolism of both remacemide adenosine; NMDA; monoaminergic; cholin-
and (58a),thus reducing their plasma concen- ergic binding sites; and other excitatory amino
tration. The agent has been studied for its an- acid binding sites (244). Based on the broad-
ticonvulsant effect, and because of its neuro- spectrum preclinical profile, favorable clinical
Anticonvulsants

When the individual isomers are given sepa-


rately, the apparent oral clearance of the (-)-
enantiomer is >10 times that of the (+)-enan-
tiomer. Losigamone is eliminated primarily by
oxidation. Biotransformation is stereoselec-
tive, with the (-)-enantiomer undergoing
greater first-pass metabolism compared to
that of the other isomer. It has undergone one
clinical trial with no serious adverse events
reported (226).

pharmacological characteristics, and efficacy 6.1 1 Stiripentol


and safety results from early clinical trials,
phase I11 development procedures are being Chemically, stiripentol is 4,4-dimethyl-1-
undertaken (198). [(3,4-methy1enedioxy)phenyll-1-penten-3-01
(62). This agent is limited by its extensive me-
6.1 0 Losigamone (AO-33)
Chemically, losigamone (AO-33) is (+)-5(R,S),
a-(S&)-5-[(2-chlorophenyl)hydroxymethyl)]-
4-methoxy(5H)-furanone (61), and belongs to

tabolism (245). Phase I1 trials in Europe have


demonstrated its efficacy in hard-to-treat p&-
tial epilepsies. Its effectiveness in partial sei-
zures, however, is lower than that of the cur-
rently available agents (246).
the group of p-methoxy-butenolides, which is
found in a large number of natural products
6.1 2 Canaxolone (CCD 1042)
[e.g., the piperolides obtained from Piper sanc-
tum (244)l. Losigamone exists as a racemic This steroid is a member of a novel class of
mixture of two threo enantiomers. There is neuroactive steroids, termed epalons, that al-
evidence that the two isomers differ in anti- losterically modulate the GABA, receptor
convulsant activity; the (+)-isomer (AO-242) complex through a unique recognition site
is more potent than the (-)-isomer (AO-294), (226). This compound was developed after ob-
but the reverse may be true depending on the servations that endogengenously occurring
animal model (226). The toxicity profiles, how- metabolites of progesterone (63a)had signifi-
ever, are identical (244). The mechanism of cant anticonvulsant effects in animals. Al-
action of losigamone is unclear at present. The though chemically related to progesterone, ga-
agent is rapidly absorbed, with peak plasma naxolone possesses no hormonal activity. The
concentrations occurring 2-3 h after an oral agent was successful in phase I and phase I1
dose. It is bound to plasma proteins to the ex- studies in refractor infantile spasms. The
tent of 6O%,and has a half-life of 4 h. Although safety and tolerability was generally good. Be-
the preceding data refer to the racemate, there cause of extensive first-pass metabolism, the
are data that an enantioselective difference development of a suppository dosage form is
exist in the pharmacokinetics of the drug. underway.
7 Things to Come

6.1 3 Soretolide (D 291 6)


Chemically, soretolide (D 2916) is N45-
methyl-3-isoxazoly1)-2,6-dimethylbenzamide
(641,a compound similar to carbamazepine in
its activity profile (229). It was noted that the
active hydroxymethyl metabolite, (64a), was
formed preferentially in female rats; however,
it is uncertain whether this species-specific ef-
fed is noted in humans (247). It is currently
undergoing a multicenter study in refractory
partial epilepsy (229).

7 THINGS TO COME Of further interest was the model Dim-


mock employed in determining the structure-
7.1 (Ary1oxy)Aryl Semicarbazones activity relationship among the compounds in
Dimmock et al. have prepared an extensive this series. This model is shown in Fig. 6.10
(251, 253).
series of semicarbazones (248-261). The lead
compound among the (ary1oxy)aryl semicar-
bazones is 4-(4'-fluorophenoxy)benzaldehyde
semicarbazone (65). Preclinical evaluations Evolved from a series of N-phosphonoalkyl-5-
have been completed and an IND has been aminomethylquinoxaline-2,3-diones(262),
filed. The compound is a potent sodium chan- AMP397A (66) has emerged. This compound
nel blocker and it is planned to be developed is an orally active, potent competitive AMPA
for the treatment of neuropathic pain. Phase I receptor antagonist active in a broad spectrum
clinical trials are scheduled in the near future. of anticonvulsant tests. AMP397A combines a
31 6 Anticonvulsant!

Proximal aryl ring Distal aryl ring

. . -
.
Hydrogen j bonds
bonds

1 1
Proximal ring
I
Distal ring
Hydrogen bonding area bonding area bonding area

Figure 6.10. Postulated interaction of compound (65)at a binding site. (After Ref. 251.)

Ca2'-induced seizures (264). The drug is


structurally related to a K-opioidagonist, al-
though it shows no binding affinity to this re-
ceptor. Its primary effect is with sodium chan-
nels; it blocks NlE-115 mouse neuroblastoma
cells in a voltage- and use-dependent manner
(265). The compound was found to be a long-
acting anticonvulsant, but its brain levels
could not account for its extended time course
(266). It was found that two active metabo-
lites, cis-N-(2-aminocyclohexy1)-3,4-dichloro-
high affinity for native human AMPA recep- benzamide (67a) and cis-N-(2-methylamino-
tors (IC,, = 11 nM) with moderate affinity for cyclohexy1)-3,4-dichlorobenzamide (67b)
the competitive site of NMDA receptors (IC,, were formed, each of which was an active an-
= 420 nM). The NMDA component does not
ticonvulsant (263). The individual enanti-
contribute significantly to its antiepileptic omers were recently evaluated and the (-)-
properties. In addition to its broad anticonvul- isomer was metabolized to a lesser extent than
sant spectrum (MES, pentylenetetrazol, the (+)-isomer, which had a lower oral bio-
strychnine, and picrotoxin), it strongly de- availability as well (267). Fischer et al. inde-
creases burst activities in genetically epilepsy- pendently evaluated U-54494A (268). It waf
prone rats with absence-type seizures, sup- observed in this study that there was consid-
presses kindling development, and decreases erable evidence to suggest that the stimula-
the severity of behavioral syndromes in kin- tion of K-receptors reduces the entry of Ca2+
dled rats. As a result of preclinical results, it is into neurons or nerve terminals, which may be
expected to be active in patients with partial, related to the closure of N-type Ca2+channels.
generalized tonic-clonic, and myoclonic/ab- This action can result in a decrease of neuro-
sence type seizures (198). nal excitability and a reduction of transmitter
release (269-271). Fischer concluded that it
was thus difficult to draw definitive conclu-
sions regarding the involvement of central
U-594494A, chemically (?)-cis-3,4-dichloro- K-opioid receptor mechanisms in the anticon-
N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]- vulsant actions of U-54494A (268).
benzamide (67), is a potent, long-acting anti-
convulsant without sedative or analgesic ef-
fects (263). It is not only effective in antago-
nism of electroshock seizures, but also Chemically, (+)- (3R,4S) trans-4-(fluorobenz-
effective against excitatory amino acids and amido)-6-acetyl-3,4-dihydro-2H-benzo[b]
7 Things to Come

pyran-3-ol(68),SB-204269 showed good anti- SB compound library in the [3HlSB-204269


convulsant activity in the MES evaluation and binding assay and led to the following series of
is currently undergoing clinical evaluation of active 1,2,3,4-tetrahydroisoquinolinylbenz-
epilepsy and has progressed to Phase I1 of clin- amides (68a)(276).
ical development (272-275). The stereochem- Data for the active compounds are pre-
istry was found to be necessary with the sented in Table 6.13. As seen from the data,
trans4S configuration essential for activity. the structure-activity studies have led to a re-
As with levetiracetam (16), this series were finement of the original pharmacophore
discovered with aunique [3HlSB-204269bind- model (272). It should also be noted that these
ing site assay (275). In a subsequent study, a structures bear a close structural resemblance
series of alternative structural classes were to (- )-levcromakalim (69), an antihyperten-
prepared by high throughput screening of the sive ATP-sensitive potassium channel opener;

Table 6.13 Active 1,2,3,4-TetrahydroisoquinolinylBenzamides (68a)(276)


Mouse MES Data (% Increase
[3HlSB-204269 in Seizure Threshold at
Compound R Binding, pKi 10 mgkg po 1 h Postdose)
Anticonvulsants

(277). Wherease several anticonvulsant


agents act by blocking T-type Ca2+ channels,
Hu and coworkers investigated the N-type
VSCCs (278,279). Based on a high throughput
screening, PD 151307 (70a) was synthesized,
which possessed significant N-type antagonis-
tic activity (IC,, = 0.32 CLM) in IMR-32 human
neuroblastoma cells (279). Unfavorable phys-
icochemical properties (i.e., high C log P and
poor aqueous solubility) led to the synthesis of
the amide (70b) (PD 1673411, with similar
however, the 3S,4R stereochemistry abolished Ca2+ blocking activity (IC,, = 0.59 @),but
anticonvulsant activity (273). with improved lipophilic and solubility prop-
erties. Modification of (70b) included: (1)plat-
7.5 N-Channel CaZ+ Blockers ing the (4-0-benzy1)-phenylgroup on the k!-
Excessive calcium entry into depolarized neu- terminal end; (2) replacing the tert-butyl
rons contributes significantly to neuronal amide with a 3-methyl-2-butyenylamine to
injury. Voltage-sensitive calcium channels generate structure (71) (S)-2-amino-144-
(VSCCs) regulate, among other functions, cel- [(4-benzyloxypheny1)-(3-methylbut-2-eny1)-
lular excitability and neurosecretory activity, amino]-piperidine-1-y1)-4-methyl-pentan-1-
functions implicit in epileptogenic events one (280), a potent N-type Ca2+ antagonist
7 Things to Come

7.6 Models of the Anticonvulsant Receptor


Several authors have provided insight into the
putative MES receptor based on their struc-
ture-activity data. As noted by Unverferth et
al. (281), there have been several attempts to
postulate a general pharmacophore for the dif-
ferent anticonvulsant classes, all of which are
anti-MES in animal studies and are, or have
H-A ' HAD
the potential to be, effective in generalized
tonic-clonic seizures. These include: benzodi-
Figure 6.11. Suggested pharmacophore model for azepines (282); barbiturates (283);triazolines
anticonvulsants acting at the voltage-dependent so- (284); semicarbazones (248-261); and enami-
dium channel on the basis of molecular dynamics simu- nones (285-2881, respectively; and for differ-
lations on phenytoin (11,carbamazepine (21, lamotrigine ent compounds with similar anticonvulsant
(ll),zonisamide (131, and rufinamide (60).Rema-
profiles (289-292). The Unverferth model
cemide (58)is discussed in the text. (After Ref. 281.)
(Fig. 6.11) provides an excellent representa-
tion of the current anticonvulsants phenytoin
(IC,, = 0.67 f l ,with anticonvulsant activity (11, carbamazepine (2), lamotrigine (111, zoni-
(ED,, = 6 mg/kg) in the audiogenic seizure samide (13), and rufinamide (60). Remace-
model (8) as well as possessing significant an- mide (58) is also included as a possible candi-
algesic activity. date (Fig. 6.12).

I
CI
N 3

1 : HAD

HAD

Figure 6.12. Selected anticonvulsants for the development of a pharmacophore model. The essen-
tial structural elements are indicated by dotted rectangles. 1 = phenytoin; 2 = carbamazepine; 11 =
lamotrigine; 13 = zonisamide; 60 = rufinamide; inset, 58 = remacemide. R, hydrophobic unit; D,
electron-donor group; HAD, hydrogen donor/acceptor unit. (After Ref. 281.)
Anticonvulsants

Features of commonalitv " include: ( 1 ) at More data in animal models with focal epi-
least one aryl ring (R);(2)one electron donor lepsy are needed to determine long-term appli-
atom (D);and (3)a second donor atom in close cability (198).
proximity to the N-H group, forming a hydro-
gen bond acceptor/donor (HAD). In the struc- 7.8 A New Causative Agent for Epilepsy
tures listed in Fig. 6.12, the moieties are indi-
A recent report indicated that cryptogenic ep-
cated with either a bracket or a dotted
ilepsy, the group of epilepsy syndromes for
rectangle. Through molecular modeling tech-
which an etiology is unknown, consisting of
niques, each structure was minimized and su-
about 20% of all epilepsy syndromes, may be
perimposed (281). The deviation was <0.7 A.
caused by Toxoplasm gondii (299). A statisti-
In the case of remacemide (581, it contains the
cally significant elevation of T. gondii antibod-
HAD function as the amide, but not at the
ies was found compared to that of controls,
correct position. Taking the carbonyl oxygen
suggesting that T. gondii infection with brain
as the donor atom (D), the hydrogen-bond
cysts may be a cause of the disease.
function would be represented by the m i n e
function, which was different in the previous
compounds. This model is not all inclusive and 8 WEB SITE ADDRESSES AND
deviated from that proposed by Brouillette et RECOMMENDED READING FOR FURTHER
al. (209, 293-295), in that the orientation of INFORMATION
the aromatic ring was not in a specific confor-
mation (the rings are rotated in relation to the 8.1 For Information on Anticonvulsant
R-D-HAD plane by 10-40"). Needless to say, Evaluations
research in this area is sorely needed. This
problem is complicated by the fact that the 0 NINDS ADD Program Webpage: http://
three-dimensional structure of the sodium www.ninds.nih.gov/asp.htm
channel is unknown, and as stated by Madge
et al. (75), it is likely to be many years before 8.2 For Information on Epilepsy
high resolution structures are available for
these channels. 0 Epilepsy Foundation of America Webpage:
7.7 Porcine Embryonic GABAergic Cell http://www.e fa.org/
Transplants 0 Society for Neuroscience Webpage: http://
www.sfn.org/
Historically, transplantation of fetal neurons
American Epilepsy Society: http://www.
and glia have been demonstrated to survive,
aesnet.org/
integrate, and reduce functional deficits in
animal models of Parkinson's disease and University of Pennsylvania: http://www.
Huntington's disease (296, 297). In addition, med.upenn.edu/health/hi -files/neurology/
surgical implants in humans have been suc- epilepsy/ep-seizures-.html
cessfully performed in pilot studies (298). An
FDA-approved safety and feasibility study of 8.3 References on Animal Procedures
transplantation of embryonic porcine lateral
ganglionic eminence cells (NeuroCellTMFE, 0 The Neuronal Microenvironment (Neuro-
Diacrin, Inc.) into epileptogenic tissue in pa- methods Series, Vol. 91, A. A. Boulton, G. B.
tients with surgically amenable temporal or Baker, and W. Walz. Humana Press, To-
frontal lobe onset seizures was initiated (198). towa, NJ, 1988.
Before transplantation, the cells were treated 0 Check the previous edition of this chapter
with anti-MHC I monoclonal antibodies, thus also.
removing the need for treatment with the im-
munosuppressant cyclosporine. Preliminary 8.4 Sodium Channels
evaluation in three patients with medically re-
fractory partial-onset seizures have shown 0 The study reported by Madge et al. (75) is
that the procedure is safe and well tolerated. the most current on the topic.
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290. G. L. Jones and D. M. Woodbury in D. M. and P. Brundin, Neuroscience, 74, 959-970
Woodbury, J. K. Penry, and C. E. Pippenger, (1996).
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1982,pp. 83-109. Quota, J. Dinsmore, P. K. Dempsey, A. J. Fis-
291. P. W. Codding, N. E. Duke, L. J. Aha, L. Y. chman, C. Thomas, R. G. Feldman, S. Kassis-
Palmer, D. K. McClurg, andM. B. Szkaradzinska sieh, R. Raineri, C. Manhart, D. Penney, J. S.
in E. Bugg and M. Ealick, Eds., Crystallographic Fink, and 0. Isacsson, Neurology, 54, 1042-
Modeling and Methods: Molecular Design (Pa- 1050 (2000).
pers Symposium), Meeting Date 1989, Springer- 299. E. W. Stommel, R. Seguin, V. M. Thadani, J. D.
Verlag, New York, 1989,pp. 151-160. Schwartzman, K. Gilvert, K. A. Ryan, T. D.
292. M. G. Wong, J. A. Defina, and P. R. Andrews, Tosteson, and L. H. Kasper, Epilepsia, 42,
J. Med. Chem., 29,562472(1986). 436-438(2001).
CHAPTER SEVEN

Narcotic Analgesics
JANE V. ALDRICH
SANDRA C. VIGIL-CRUZ
Department of Medicinal Chemistry
School of Pharmacy
University of Kansas
Lawrence, Kansas

Contents
1 Introduction, 331
2 Clinical Use of Agents, 332
2.1 Current Drugs on the Market, 333
2.2 Side Effects, Adverse Effects, Drug
Interactions/Contraindications,333
2.2.1 Central Side Effects, 335
2.2.1.1 Respiratory Depression, 335
2.2.1.2 Tolerance, Dependence, and
Addiction Liability, 336
2.2.1.3Sedation and Cognitive
Impairment, 337
2.2.1.4 Nausea and Vomiting, 337
2.2.2 Other Side Effects, 337
2.2.2.1 Constipation, 337
2.2.2.2 Itching, 338
2.2.3 Contraindications,338
2.2.4 Drug Interactions, 338
2.2.4.1Interactions with Cytochrome
P,,, Enzymes, 338
2.3 Absorption, Distribution, Metabolism,
Elimination, 339
2.3.1 Absorption and Distribution, 339
2.3.2 Metabolism and Elimination of
Morphine and Derivatives, 340
2.3.3 Metabolism and Elimination of Other
Opioid Agents, 341
3 Physiology and Pharmacology, 341
3.1 Opioid Effects in the Central Nervous
System and the Periphery, 341
3.2 Multiple Opioid Receptor Types, 341
3.2.1 Discovery of Multiple Opioid Receptor
Types and Current Nomenclature, 341
3.2.2 Signal Transduction Mechanisms, 342
Burger's Medicinal Chemistry and Drug Discovery 3.2.3 Characterization of Opioid Receptors,
Sixth Edition, Volume 6: Nervous System Agents 343
Edited by Donald J. Abraham 3.2.3.1 Ligands Used to Characterize
ISBN 0-471-27401-1 0 2003 John Wiley & Sons, Inc. Opioid Receptors, 343
Narcotic Analgesics

3.2.3.2 Radioligand Binding Assays, 5.12 Miscellaneous Nonpeptide Opiates, 407


344 6 Opioid Peptide Analogs, 407
3.2.3.3 in Vitro Assays for Efficacy, 347 6.1 Introduction, 407
3.2.3.4 in Vivo Evaluation of Opioids, 6.1.1 Opioid Peptides from Amphibian Skin,
349 409
3.2.4 Opioid Receptor Structure and 6.2 Enkephalin Analogs, 410
Molecular Biology, 350 6.2.1 Mu-Selective Enkephalin Analogs, 410
3.2.4.1 Mutagenesis Studies of Opioid 6.2.1.1 Linear Analogs, 410
Receptors, 351 6.2.1.2 Conformationally Constrained
3.2.4.2 Computational Models of Analogs, 411
Opioid Receptors, 352 6.2.2 Delta-Selective Enkephalin Analogs, 412
3.2.4.3 Receptor Subtypes, Splice 6.2.2.1 Linear Analogs, 412
Variants, and Receptor 6.2.2.2 Conformationally Constrained
Dimerization, 352 Analogs, 414
3.3 Physiology of Non-p Opioid Receptors, 354 6.2.2.3 Enkephalin Analogs with
3.3.1 Delta Receptors, 354 Antagonist Activity a t 6
3.3.2 Kappa Receptors, 355 Receptors, 416
3.4 Endogenous Opioid Peptides, 356 6.2.3 Dimeric Enkephalin Analogs, 417
4 History: Identification of Morphine and Early 6.3 Dynorphin Analogs, 418
Analogs, 358 6.3.1 Linear Analogs, 418
5 Structure-Activity Relationships of Nonpeptide 6.3.2 Conformationally Constrained Analogs,
Opioid Ligands, 360 420
5.1 Introduction, 360 6.3.3 Dynorphin A Analogs with Antagonist
5.2 4,5a-Epoxymorphinans: Morphine Activity, 421
and Derivatives, 361 6.4 Opioid Peptides with the Tyr-Pro-Phe
5.2.1 Morphine and Alkaloids from Opium, Sequence, 422
361 6.4.1 p-Casomorphin Analogs and the
5.2.2 Morphine Derivatives, 362 Endomorphins, 422
5.3 N-Substituted 4,5a-Epoxymorphinans: 6.4.2 TIPP and Related Peptides, 425
Opioid Antagonists, 364 6.5 Opioid Peptides with the Tyr-D-aa-Phe
5.3.1 Introduction, 364 Sequence, 428
5.3.2 Kappa-Receptor Selective Antagonists, 6.5.1 Dermorphin Analogs and Related p-
365 Selective Peptides, 428
5.3.3 Delta-Receptor Selective Antagonists 6.5.1.1 Linear Analogs, 428
and Related Compounds, 367 6.5.1.2 Conformationally Constrained
5.4 Diels-Alder Adducts, 370 Analogs, 430
5.5 Morphinans, 372 6.5.2 Deltorphin Analogs and Related
5.6 Benzomorphans, 373 Peptides, 432
5.7 Piperidine Derivatives, 376 6.5.2.1 Linear Analogs, 432
5.7.1 4-Arylpiperidines with a Carbon 6.5.2.2 Conformationally Constrained
Substituent a t C,, 377 Analogs, 435
5.7.2 4-Arylpiperidines with an Oxygen 6.6 Other Peptides with High Affinity for Opioid
Substituent at C,, 380 Receptors, 437
5.7.3 4-Anilidopiperidines, 381 6.6.1 Mu-Receptor Antagonists Derived from
5.8 Acyclic Analgesics, 385 Somatostatin, 437
5.9 Kappa-Selective Agonists, 387 6.6.2 Peptides and Peptidomimetics from
5.9.1 Centrally Acting Agonists, 387 Combinatorial Libraries, 438
5.9.2 Peripherally Acting Agonists, 393 6.7 Peptide Affinity Label Derivatives, 440
5.10 Delta-Selective Agonists, 395 6.8 Peptidase Inhibitors, 440
5.10.1 BW373U86, SNC 80, and Analogs, 7 Recent Developments, 443
395 7.1 Opioid Receptor Structure: Receptor
5.10.2 Other &Receptor Agonists, 399 Dimerization, 443
5.11 Nonpeptide Affinity Labels Used to Study 7.2 Opioid-Receptor-Like 1 (ORL1) Receptor and
Opioid Receptors, 400 Its Endogenous Ligand Orphanin
5.11.1 Morphine and Naltrexone FQ/Nociceptin (OFQ/N), 444
Derivatives, 403 7.2.1 Physiological and Pharmacological
5.11.2 Other Nonpeptide Amnity Labels, 405 Effects, 445
1 Introduction 331

7.2.2 Structure-Activity Relationships of 9.2.2 Dimerization of Opioid and Other


OFQ/N and Other Peptidic Ligands for G-Protein-Coupled Receptors, 451
the ORLl Receptor, 446 9.3 SAR of Classical Nonpeptide Opiates, 451
7.2.3 Nonpeptide Ligands for the ORLl 9.4 Delta and Kappa Opioid Receptors and
Receptor, 447 Selective Ligands, 451
8 Things to Come, 448 9.4.1 Delta Opioid Receptor Pharmacology
9 Web Addresses and Recommended Reading for and &Receptor-Selective Ligands, 451
Further Information, 450 9.4.2 Kappa-Receptor-Selective Ligands, 451
9.1 Clinically Used Agents, 450 9.5 Opioid Peptides, 451
9.2 Pharmacology, 450 9.6 ORLl Receptor and Orphanin
9.2.1 Opioid Receptor Structure and FQ/Nociceptin, 451
Molecular Biology, 450 10 Acknowledgments, 452

1 INTRODUCTION ing to separate analgesic activity from the


undesired side effects associated with mor-
Although treatment of mild to moderate pain phine and other opioid analgesics. At the same
can typically be accomplished with nonnar- time the search for endogenous ligands for opi-
cotic analgesics such as acetaminophen or as- oid receptors led to the discovery of peptides
pirin, treatment of severe pain often requires with opiate-like activity. The first peptides
use of an opioid analgesic such as morphine. identified were the pentapeptides leucine and
These drugs methionine enkephalin (3and 4) (71, followed
- are associated with serious side
effects, however, most notably addiction lia- by the longer peptides dynorphin and p-endor-
bility and respiratory depression, which limit phin. Because these peptides are structurally
their clinical usefulness. Therefore there has distinct from the alkaloid opiates, the term
been an intensive effort to find new analgesics o ~ i o i dwas introduced to describe all com-
that retain the effectiveness of morphine, but pounds, both nonpeptide and peptide, with
do not have the undesired side effects. AS a opiate-like activity. To understand the inter-
result, a wide variety of compounds with opi- actions of opioids with their receptors at a mo-
oid activity have been identified and signifi- lecular level, knowledge of receptor structure
cant strides have been made in understanding- was still needed. A major breakthough camk
the mechanisms of opioid action. when first the delta (6) opioid receptors (8,9),
The effects of opium, from which morphine followed shortly thereafter by the mu ( p ) (10)
(1,Fig. 7.1) is isolated, have been known for and kappa ( K ) (11)receptors, were sucessfully
thousands of years, but it is only within the cloned in the early 1990s.
twentieth century, and really within the last
25 years, that we have begun to understand Leucine enkephalin (3) Tyr-Gly-Gly-Phe-Leu
the effects of opioid analgesics at a molecular Methionine enkephalin (4)
level. Beckett and Casy in 1954 proposed that
opiate effects were receptor mediated (I),but Tyr-Gly-Gly-Phe-Met
it was not until the early 1970s that the ste-
reospecific binding of opiates to specific recep- The focus of this c h a* ~ t eis
r on recent devel-
tors was demonstrated in mammalian brain opments in the opioid field, with summaries of
tissue (2-4). In the mid-1970s two other dis- key features of the structure-activity relation-
coveries revolutionized our understanding of ships (SAR) of older compounds. Much of the
opioid analgesics and how they produce their early opioid SAR is discussed in detail in two
effects. The characterization and classifica- comprehensive books on opioid analgesics
tion of three different types of opioid receptors published in 1986 (12, 13). Specific areas in
by Martin and coworkers in the mid-1970s (5, which there has been considerable research in
6 ) formed the foundation of our current un- the last decade and which are discussed in this
derstanding of opioid pharmacology. This dis- chapter include: the molecular biology of opi-
covery sparked renewed interest in attempt- oid receptors (see Section 3.2.4), the design
Narcotic Analgesics

R=H (1) Morphine R=H,X=H (5) Hydromorphone


R = CH3 (2) Codeine R = C H ~x, = OH (6) Oxycodone

(7) Meperidine (8) Fentanyl

(9) Methadone (10) Propoxyphene

Figure 7.1. Structures of the most commonly used clinical agents.

and synthesis of agonists and antagonists se- American Academy of Pain MedicirLe and the
lective for the different receptor types (Sec- American Pain Society also advocate the pru-
tions 5.3, 5.9, and 5.10), the design and syn- dent use of narcotic analgesics for the treat-
thesis of opioid peptide analogs (Section 61, ment of chronic pain (15,16). The widespread
and the recent characterization of the related use of opioids in chronic, nonmalignant pain,
opioid-receptor like (ORL1) receptor and its however, is still somewhat controversial be-
endogenous ligand orphanin FQ/nociceptin cause of the lack of substantial evidence from
(Section 7.2). Before describing the different long-term controlled studies demonstrating
classes of nonpeptide analgesics and opioid effectiveness in this setting (17). The clinical
peptides, the clinical use of analgesic agents use of opioids in different types of pain and in
(Section 2), opioid receptors, and the methods different clinical settings has been reviewed in
used to characterize the opioid activity of com-
detail in a recent book (18).
pounds (Section 3) are discussed.
The World Health Organization (WHO) in-
troduced a three-tiered approach for the treat-
2 CLINICAL USE OF AGENTS ment of cancer pain (19) that also serves as a
model for the management of acute and
Opioid analgesics are indispensable drugs in chronic pain. In this model, the first tier con-
the management of cancer pain (141, and the sists of acetaminophen (APAP) or a nonsteroi-
2 Clinical Use of Agents

dal anti-inflammatory agent [e.g., aspirin Pentazocine is a prototype for the mixed ago-
(MA)or ibuprofen] for mild to moderate pain. nistlantagonist class and acts as an agonist at
If the pain persists or increases, then treat- K opioid receptors generating analgesia (see
ment progresses to the second tier, where a Section 3.2); its antagonist activity at p opioid
narcotic analgesic is added to the regimen. receptors significantly decreases or eliminates
Frequently, this is accomplished by use of a the potential for respiratory depression and
combination product such as ASA plus codeine addiction liability generated through p recep-
that combines an opioid with a nonnarcotic tor activation. The mixed agonistslantago-
analgesic. The third tier is reached when the nists shown in Table 7.3 find limited clinical
pain escalates from moderate to severe. At this utility, despite the analgesia resulting from
level the opioid may be used as a single agent, activating K opioid receptors. The analgesic ef-
given that opioids do not have a ceiling to their fect produced reaches a maximum despite in-
analgesic effect as do the nonnarcotic analge- creased drug dose (analgesic ceiling). Further,
sics such as ASA and MAP (20). Adjuvant these drugs exhibit a different side-effect pro-
drugs, such as tricyclic antidepressants or an- file, including dysphoria and hallucinations,
ticonvulsants, may be added to opioid therapy which also appears to be a result of K-agonist
as a means to enhance the efficacy of opioids activity (23).
for pain relief (17, 21). Opioid agonists also have an antitussive ef-
For continuous pain, analgesic agents are fect attributed to the depression of the cough
generally prescribed for use on a regular, reflex. Thus some opioids, typically codeine or
around-the-clock basis by use of a long-acting one of its derivatives, are used for their anti-
analog. For acute pain or pain after surgery, tussive activity, predominantly in combina-
often an immediate-release, short-acting opi- tion products. The antitussive effect is in part
oid is used. In addition, short-acting opioids the result of the interaction with opioid recep-
with rapid onset are used for "rescue" doses tors at the cough center in the brain (23). The
when breakthrough pain is problematic (21, dose required for antitussive activity, how-
22). ever, is lower than that required for analgesia;
the opioid receptors involved in blocking the
2.1 Current Drugs on the Market
cough reflex are less sensitive to naloxone
The structures for the most commonly used than those responsible for analgesia (23). .
clinical agents are shown in Fig. 7.1. Some of Opioid antagonists (Table 7.4), predomi-
the opioid agonists used clinically (Table 7.1) nantly naloxone, are used clinically to reverse
such as morphine may be used as the sole the effects of opiates in overdose or postoper-
agent for analgesia. Because of their rapid on- ative sedation. Naltrexone, which has oral bio-
set and short duration of action, fentanyl and availability, is used for the treatment of nar-
other 4-anilidopiperidines have been used ex- cotic addiction and alcohol dependence. As
tensively as adjuncts to anesthesia, whereas discussed below (Section 2.2.2.1), peripherally
methadone and its analog levomethadyl ace- selective antagonists are being evaluated for
tate (LAAM) are used as maintenance agents treatment of constipation and other gastroin-
for individuals who are addicted to narcotics. testinal side effects associated with opioid ag-
Other agents such as loperamide or diphe- onist use.
noxylate are used primarily for their consti- 2.2 Side Effects, Adverse Effects, Drug
pating side effect to treat diarrhea. Some Interactions/Contraindications
drugs are used extensively in combination
products (Table 7.2) for treatment of pain. In addition to analgesia, clinically used opioids
Most of the clinically used agents are agonists display a plethera of biological effects. The
at p opioid receptors. In contrast, mixed ago- most common sideladverse effects involve al-
nists/antagonists generally interact with two terations of the nervous, respiratory, gastro-
distinct opioid receptors to provide analgesic intestional, and integument systems (see Refs.
activity while exhibiting decreased potential 23, 25 and references cited therein for more
for serious side effects such as respiratory de- detailed discussions). The most serious side
pression and addiction (see Section 2.2 below). effects associated with the majority of opioid
Table 7.1 Opioid Agonists Used Clinically"
Equal
. Aanalgesic
Dose (mg)b
Chemical Class Generic Name Trade Name (manufacturer) Route of Administration
-

4,5p-Epoxymorphinans Morphine (1) Available as generic p.o., i.v., i.m., s.c., rectal
Codeine (2) Available as generic p.o., i.v., i.m., s.c.
Hydromorphone (5) Dilaudid (Knoll), also available as generic p.o., i.v., i.m., s.c., rectal
Hydrocodonec
Oxymorphone Numorphan (Endo Laboratories) i.v., i.m., s.c., rectal
Oxycodone (6) OxyContin (Purdue Pharma LP), also p.0.
available as generic
Morphinans Levorphanol Levo-Dromoran (ICN), also available as
generic
Phenylpiperidines Meperidine (7) Demerol (Sanofi-Synthelabo) also available as
generic
Lomotil (Searle), also available as generic
Motofen (Carnrick)
Imodium A-D (McNeil-CPC), also available as
generic
Sublimaze (Taylor) i.v.
Fentanyl Oralet (Abbott) Lozenges
Actiq (Abbott) Lozenges on a stick
Duragesic (Janssen) Transdermal patches
Alfentanil Alfenta (Taylor) i.v. with individualized dosing
Remifentanil Ultiva (Abbott) i.v. with individualized dosing
Sufentanil Sulfentanil citrate (ESI Lederle), Sufenta i.v. with individualized dosing
(Taylor)
Acyclic analgesics Methadone (9) Available as generic i.m., s.c., p.0. with
individualized dosing
Levomethadyl Orlaam (Roxane) p.0. with individualized
acetate dosing
Propoxyphene (10) Darvon-N (napsylate) (Eli Lilly), available a s p.0.
generic (HC1)
"Agents currently marketed in the United States. Unless otherwise noted these drugs are Class-I1 controlled substances. From Ref. 24.
bBased on short-term use for acute pain.
"Used only as an antitussive produd.
dRectaladministration.
'Class V narcotic available only by prescription for treatment of diarrhea.
fClass IV narcotic available only by prescription for treatment of diarrhea.
gA noncontrolled substance available both by prescription and over the counter for treatment of diarrhea.
hi.v. dose.
2 Clinical Use of Agents 335

Table 7.2 Examples of Narcotic Agonists Currently Marketed as Oral Combination Products
for Painasb
Trade or Common Name Nonnarcotic
(manufacturer) Narcotic Component Component
APAP with codeine (generic) Codeine MAP
ASA with codeine (generic) Codeine ASA
DHC Plus (Purdue Frederick) Dihydrocodeine APAP, caffeinec
Synalgos-DC (Wyeth-Ayerst) Dihydrocodeine ASA, caffeine
Vicodin (Knoll) Hydrocodone APAP
APAP with hydrocodone (generic)
Alor 51500 (Atley) Hydrocodone ASA
Vicoprofen (Knoll) Hydrocodone Ibuprofen
Percocet (DuPont) Oxycodone APAP
N A P with oxycodone (generic)
Percodan (Du Pont) Oxycodone ASA
I,
ASA with oxycodone (generic)
Mepergan Fortis (Wyeth-Ayerst) Meperidine Promethazined
Darvocet-N (Eli Lilly) Propoxyphene sapsylate APAP
I,
APAP with propoxyphene (generic)
Wygesic (Wyeth-Ayerst) Propoxyphene HCl APAP
APAP with propoxyphene (generic) ,
Darvon Propoxyphene HC1 ASA, caffeinec
"Products currently marketed in the United States. From Ref. 24.
%odeine, hydrocodone, and hydromorphone are used in combination products as antitussives.
"May be beneficial in vascular headaches.
dUsed for sedative effect.

analgesics are respiratory depression, addic- ing in one of the most serious adverse effects
tion liability, and constipation that are associ- (22). Respiratory depression is caused at least
ated with their agonist activity at p opioid re- in part by interaction of opioids with the respi-
ceptors. ratory center in the brain stem, causing a de-
creased response to carbon dioxide and thus
2.2.1 Central Side Effects depression of breathing rate (23). Respiratory
2.2.1.1 Respiratory Depression. Mu opi- depression can occur at doses far lower than
oids used for analgesia slow breathing, result- those that affect consciousness and increases

Table 7.3 Narcotic Agonist-Antagonistsa


Controlled
Trade Name Substance Route of Equivalent
Chemical Class Generic Name (manufacturer) Class Administration Dose (mgIb
6,14-Endoetheno Buprenorphine Buprenex (Reckitt & C-V i.v., i.m. 0.3
opiates Colman)
4,5a-Epoq- Nalbuphine Nubain (DuPont) NAc i.v., i.m., s.c. 10
morphinans
Morphinans Butorphanol Stadol (Mead Johnson) C-IV i.v., i.m., nasal 2.5
spray
Benzomorphans pentazocined Talwin (Sanofi C-IV i.v., i.m., s.c. 30
Winthrop)
Aminotetralin Dezocine Dalgan (Astra) NAc i.v., i.m., s.c. 10
"Agents currently marketed in the United States. From Ref. 24.
bParenteral dose equivalent to 10 mg morphine.
'Not applicable.
dAlso available as oral combination products with ASA (Talwin Compound), APAP (Talacen), or naloxone (Talwin NX)
(Sanofi Winthrop).
336 Narcotic Analgesics

Table 7.4 Narcotic Antagonistsa American Academy of Pain Medicine, the


Generic Trade Name Route of American Pain Society, and the American So-
Name (manufacturer) Administration ciety of Addiction Medicine have written a
Naloxone Narcan i.v., i.m., or s.c.
consensus document that clearly outlines the
(DuPont) recommended definitions for addiction, physi-
Naltrexone ReVia (DuPont) p.0. cal dependence, and tolerance related to the
Depade use of opioids for the treatment of pain (26).
(Mallinckrodt) According to the consensus document defini-
Nalmefene Revex (Ohmeda) i.v., i.m., or s.c. tions, addiction is "a primary, chronic, neuro-
aAgentscurrently marketed in the United States. From biologic disease, with genetic,' psychosocial,
Ref. 24. and environmental factors influencing its de-
velopment and manifestations. It is character-
progressively with increasing drug dose (23). ized by behaviors that include one or more or
Mortality from opioid overdose is almost al- the following: impaired control over drug use,
ways a result of respiratory arrest. Of impor- compulsive use, continued use despite harm,
tant note is that the respiratory effects of and craving." Physical dependence is defined
sleep, which often accompanies pain relief, are as "a state of adaptation that is manifested by
additive with the depressant effects of the opi- a drug class specific withdrawal syndrome
oid analgesic on respiration (23). The most that can be produced by abrupt cessation,
profound respiratory depression occurs within rapid dose reduction, decreasing blood level of
5-10 min postintravenous (i.v.1 administra- the drug, and/or administration of an antago-
tion of morphine, and this effect occurs more nist" (26). There is, however, a very low addic-
rapidly as the lipophilicity of the narcotic an- tion potential for opioids used for pain man-
algesic increases (23). agement (271, on the order of only 3 cases per
Opioid-naive patients with severe pain who 10,000 patients (see Ref. 22 and references
require high doses of opioids are at highest cited therein). In the pain management pa-
risk for respiratory depression, whereas pa- tient it is important to distinguish between
tients receiving chronic opioid therapy rarely addiction andpseudoaddiction (22),which re-
experience this problem (20). Fortunately, the late to the motivation for obtaining the narcot-
occurrence of respiratory depression can often ics. In pseudoaddiction uncontrolled pain is
be circumvented with appropriate titration of the motivating factor for the drug-seeking be-
opioid dose (22) unless there is underlyingpul-
havior that stops once relief is obtained (22).
monary dysfunction such as emphysema or se-
Pseudoaddiction may be attributed to toler-
vere obesity (23).
ance or pseudotolerance where an increase in
2.2.1.2 Tolerance, Dependence, and Addic-
tion Liability. Patients treated with long-term
dosage needs results from other factors such
opioid therapy often develop tolerance and as disease progression, a new disease process,
usually become physically dependent on nar- or drug interactions (28).
cotic analgesics as well. Tolerance results The pharmacological mechanisms respon-
when exposure to a drug results in its de- sible for the euphoria and rewarding behavior
creased effectiveness with time and larger associated with p opioid analgesics and addic-
doses are required to achieve the same re- tion liability remain uncertain (23). These ef-
sponse (26). Physical dependence is also an fects are distinct from analgesia (29). Consid-
adaptive state that is characterized by a spe- erable evidence suggests that the rewarding
cific constellation of withdrawal symptoms effects result from interaction of the opioid
that occur upon abrupt cessation or significant with dopaminergic pathways, particularly in
reduction in the dose of the opioid or adminis- the nucleus accumbens (23).Activation of p or
tration of an opioid antagonist (26).Addiction, 6 opioid receptors results in the release of do-
however, is distinct from physical dependence, pamine, which results in the motivational ef-
and "the term addiction should never be used fect (30). In contrast, agonists interacting
when physical dependence is meant" (22). The with K opioid receptors, naloxone, and p-selec-
2 Clinical Use of Agents

tive antagonists inhibit dopamine release (311, digestion in the small intestine and decrease
producing aversion rather than motivation in peristaltic waves in the large intestine, re-
(32). sulting in the retention of bowel contents.
2.2.1.3 Sedation and Cognitive Impairment. This is compounded by the enhanced tone of
The initiation or dose escalation of narcotic the anal sphincter and the reduction of the
analgesics may cause drowsiness and impair reflex relaxation in response to rectal disten-
cognitive function. Tolerance usually develops sion. Tolerance does not usually develop to
fairly quickly to these side effects, but other this side effect, and the patient on long-term
medications that induce somnolence will opioid therapy remains chronically consti-
produce an additive effect when taken con- pated.
comitantly. If sedation remains problematic, Patients are generally started prophylacti-
in order to achieve adequate analgesia a psy- cally on a regimen including a laxative such as
chostimulant such as caffeine, dexamphet- bisacodyl or senna that increases bowel motil-
amine, or methylphenidate may be added to ity plus a stool softener like docusate (20,221.
counteract the side effect (22). In patients refractory to laxatives, oral nalox-
2.2.1.4 Nausea and Vomiting. The most one (22) has been successfully used as a ther-
bothersome and unpleasant side effects for pa- apeutic alternative for constipation without
tients receiving opioids for pain are often the loss of analgesia (37). Because of its central
nausea and vomiting that have been associ- activity, however, higher doses of naloxone
ated with all clinically used p agonists. Emesis can decrease the analgesic effectiveness of the
predominantly results from direct stimulation opiate and precipitate opioid withdrawal in
of the chemoreceptor trigger zone, yet the de- some patients (37). Peripherally selective an-
gree of effect depends on the individual (23). tagonists offer the advantage of reversing the
Nausea and vomiting related to narcotic anal- gastrointestinal and other peripheral side ef-
gesics occur in 10-40% of patients (33). Toler- fects of narcotic analgesics without the poten-
ance often develops to these side effects, how- tial for decreasing their central analgesic ac-
ever, and they often vanish with long-term use tivity. Two peripherally selective antagonists,
(22). Nausea and vomiting can be treated by the quaternary derivative of naltrexone
use of a variety of drugs such as transdermal N-methylnaltrexone bromide (methylnaltrex-
scopolamine, hydroxyzine, or a phenothiazine one, see Section 5.3.1) and the phenylpipe~i-
for movement-induced nausea (201, or meto- dine alvimopan (ADL 8-2698, LY246736; see
clopramide or cisapride for patients with nau- Section 5.7. I), are undergoing clinical trials
sea and vomiting stemming from delayed gas- for opioid-induced constipation (34-36, 38).
tric emptying. If the nausea and vomiting After both i.v. and oral administration meth-
persist, steroid therapy with dexamethasone ylnaltrexone reverses the opioid-induced de-
may be initiated or a 5-HT, antagonist such as lay in GI transit ( 3 4 3 6 ) and is effective in
ondansetron may be used (22). Another alter- individuals receiving chronic opioid treatment
native is to try a different opioid, given that (methadone users) as well as in healthy volun-
there is significant individual variability in teers (34,36). In clinical trials oral alvimopan
this side effect (20). reverses the delay in GI transit after the ad-
ministration of exogenous opioids to both opi-
2.2.2 Other Side Effects oid naive individuals and patients receiving
2.2.2.1 Constipation. The most common chronic opioid treatment (both pain patients
side effect of long-term narcotic analgesia is and individuals taking methadone for opioid
constipation plus other gastrointestinal (GI) addiction) (38, 39); in addition it has been
effects collectively referred to as opioid bowel shown to speed the recovery of bowel function
dysfunction. The frequency of these side ef- after abdominal surgery (40).
fects is very high [40-50% or more in patients The constipating effect of orally adminis-
receiving opioids (34-36)] and can become the tered opiates can be used for the treatment of
limiting factor in opioid use. These effects are diarrhea, as with camphorated tincture of
mediated predominantly by p receptors in the opium (Paregoric or Parepectolin, which is a
bowel (23).The effects begin with delayed food paragoric plus kaolin as an adsorbent and pec-
Narcotic Analgesics

tin as a demulcent) (24). Two phenylpiperi- may induce or exacerbate asthmatic attacks;
dine derivatives are used solely as antidiar- hence, fentanyl may be a better choice in asth-
rheal agents. Diphenoxylate, which is a matic patients (23). Other relative contraindi-
congener of meperidine, is available only in cations to the use of narcotics also exist with
combination with atropine, which has anti- respect to the potential for drug abuse (17).
spasmodic activity in the intestine. At thera- Although a history of substance abuse does
peutic doses diphenoxylate does not show any not definitely preclude the use of opioids, it
central nervous system (CNS) effects, but at does necessitate careful vigilance. If the epi-
high doses it displays the typical opioid profile sode of abuse is active or recent, then another
including euphoria. The carboxylic acid me- pain management strategy may be prudent.
tabolite, difenoxylic acid (Motofen; Table 7.1) Consideration of the social network also re-
has activity similar to that of the parent (23). quires consideration, especially if the patient
Unlike diphenoxylate, the second opioid used lives with a substance abuser or has a home
for diarrhea, loperamide, does not exhibit life conducive to enabling abuse.
pleasurable CNS effects even at large doses
(23); loperamide is a substrate for P-glycopro- 2.2.4 Drug Interactions. The pharmacolog-
tein in the blood-brain barrier, which excludes ical activity of opioids can be affected by a
this drug from the CNS (41,421. number of other drugs, including amphet-
2.2.2.2 Itching. After administration of amines, antihistamines, antidepressants, and
opioids there may be urticaria at the injection antipsychotics (see Ref. 23). Small doses of
site or generalized itching because of degran- amphetamine significantly enhance the anal-
ulation of mast cells, resulting in histamine gesic activity and euphoric effects of morphine
release. The itching is a common side effect and may counteract sedation. Diphenhydra-
and often one that results in severe patient mine and hydroxyzine are antihistamines that
distress (23). The histamine release may also exhibit modest analgesic activity themselves,
be partially responsible for the pruritus and and hydroxyzine has been shown to enhance
sweating after drug administration as well as the analgesic effects of low doses of narcotic
flushing resulting from blood vessel dilation of analgesics (47).The depressant effects of some
the skin (23). Antihistamines may be used to opioids may be exaggerated and prolonged by
combat the discomfort (20) or patients can be monoamine oxidase inhibitors, tricyclic anti-
switched to either fentanyl or oxymorphone depressants, and phenothiazines; the exact
(43),which do not tend to cause histamine re- mechanism of action is not fully - understood,
lease. Opioid antagonists such as naloxone are but may involve metabolic or neurotransmit-
effective in controlling the pruritus and can be ter alteration (23). The antidepressants des-
used at low doses without loss of pain control ipramine (48) and nefazodone (49) appear to
(34,44); the peripherally selective antagonist enhance morphine-induced analgesia. The
methylnaltrexone exhibits antipruritic effi- phenothiazine antipsychotics can potentiate
cacy without the potential to reverse mor- the analgesic effect of opioids, but also in-
phine analgesia (45). crease respiratory depression and sedation
(23).
2.2.3 Contraindications. Contraindications 2.2.4.1 Interactions with Cytochrome P,,,
include hypersensitivity to opioids, head Enzymes. Drug interactions with opioid anal-
trauma or increased intracranial pressure, se- gesics can also result from their interaction
vere respiratory depression or compromised with cyctochrome P,,, (CYF') isozymes, specif-
respiratory function, and potentially, liver or ically 3A4 and 2D6 (Table 7.5) (50).
renal insufficiency (46). Whether morphine or The CYP3A4 isozyme is responsible for the
other opioids are used depends on the severity metabolism of a large number of endogenous
of the contraindication, and the potential ben- compounds as well as a wide range of drugs
efits must be weighed relative to the risk. Ana- (50). Fentanyl, alfentanil, and sufentanil are
phylactoid reactions have been reported after substrates for CYP3A4, and therefore drugs
morphine or codeine administered i.v., al- that inhibit this enzyme, such as erythromy-
though the reactions are rare (23). Morphine cin, HIV protease inhibitors, or cimetidine,
2 Clinical Use of Agents

Table 7.5 Cytochrome P,,, Isozymes and 2.3 Absorption, Distribution, Metabolism,
Opioid Substrates and Inhibitors Elimination
P450
Isozyme Substrate Inhibitor 2.3.1 Absorption and Distribution. Opioid
analgesics are available for administration by
1A2 Methadone
2D6 Codeine Codeine
a variety of routes, including by subcutaneous
Hydrocodone Methadone (s.c.) and intramuscular (i.m.) injections and
Meperidine Propoxyphene rectal suppositories as well as by oral and in-
Methadone travenous (i.v.1 administration (see Tables
Morphine 7.1,7.3, and 7.4). The least invasive and safest
Propoxyphene route that provides adequate analgesia should
3A4 Alfentanil Dextropropoxyphene be chosen (22). Opioids are absorbed from the
Fentanyl Propoxyphene gastrointestional tract or the rectal mucosa
Sufentanil and are also readily absorbed into the blood-
stream after s . ~ or
. i.m. iniection.
" Some nar-
cotics with increased lipophilicity may be ab-
sorbed through the nasal or buccal mucosa
may result in oversedation or increased respi- (butorphanol nasal spray and fentanyl loz-
ratory depression as well as prolonged dura- enges, respectively). Fentanyl is sufficiently li-
tion of action of the opioid (51). Conversely, pophilic to be absorbed through the skin (fen-
more rapid metabolism of alfentanil or fenta- tanyl transdermal patch) (23,241.
nyl may result when these agents are used in Intravenous administration of opioids re-
combination with rifampin, which is an in- sults in a rapid onset of action. The more li-
ducer of 3A4 (51). pophilic drugs show more rapid onset of action
Genetic polymorphism in CYP2D6 results after S.C.administration because of differing
in varied drug metabolism (52), with the lack rates of absorption and penetration into the
of this isoenzyme affecting between 5 and 10% CNS across the blood-brain barrier (23).. . In-
of Caucasians and 1-3% of African-Americans traspinal administration produces long-last-
and Asians (52). Individuals lacking 2D6 may ing analgesia, but the hydrophilicity of mor-
display a larger response to some drugs and be phine can result in rostral spread of the drug
at greater risk for toxicity because of their in- in the spinal fluid. This may be problematic,
ability to metabolize certain drugs. Several given that respiratory depression can occur up
opioids such as morphine, meperidine, and to 24 h after the last administered dose as a
methadone are metabolized by 2D6 (Table result of the drug reaching the respiratory
7.5), and interactions with drugs that induce control center in the brain (23). Fentanyl and
"

2D6 result in loss of opioid activity. Thus ri- hydromorphone are highly lipophilic and are
fampin, phenytoin, phenobarbital, prima- rapidly absorbed by spinal tissue, and thus the
done, and carbamazepine can all result in a rostral spread is significantly reduced, result-
significant reduction in opioid concentrations ing in a localized analgesic effect (23).
and concomitant use may require increasing The binding of opioids to serum proteins is
the opioid dose. This genetic defect is also of considerable importance, given that it influ-
problematic when metabolism to an active me- ences the distribution of the drug as well as
tabolite occurs. Because CYP2D6 can convert metabolism and excretion (53). The protein
codeine to morphine (see Section 2.3.2 below), binding of morphine is low (35%), moderate
2D6 inhibitors, especially quinidine, can sig- with meperidine (70%), and high for metha-
nificantly diminish the analgesic effects of co- done (90%)(54). The high human plasma pro-
deine (51). Ritonavir and cimetidine also in- tein binding of methadone is well known (55);
hibit metabolism by 2D6 and therefore can the highest binding is to p-globulin I11 (56)
significantly increase the concentration of opi- and albumin (53, 56). The extensive protein
oids metabolized by 2D6 (Table 7.5), including binding of methadone is an important factor
meperidine, methadone, and propoxyphene, because it significantly affects the amount of
which may result in toxicity (51). drug available in the plasma for penetration
Narcotic Analgesics

cause of the accumulation of M6G (59). M3G


has very low affinity for opioid receptors and
/ does not contribute to analgesia, but it may
H3C OR' (11) R = glucuronide
contribute to neuroexcitatory side effects such
as allodynia (60). M3G has been reported to
antagonize morphine (61), but this effect has
not been consistently observed (62). Metabo-
lism by N-demethylation to normorphine is a
glucuronide = HO-HO minor metabolic pathway for morphine,
whereas N-dealkylation is important to the
metabolism of some morphine congeners (see
Figure 7.2. Major metabolites of morphine.
Ref. 63 and references cited therein for an
excellent overview of morphine metabolism
and elimination). Codeine, levorphanol, oxy-
across the blood-brain barrier. The extensive codone, and methadone have a high oral to
protein binding may provide a reservoir for parenteral potency ratio attributed to de-
methadone to replenish the drug to the blood creased first-pass hepatic metabolism (23).
(57). It has been suggested that the high pro- A small but significant amount of codeine
tein binding of methadone accounts for its (-10%) is metabolized to morphine through
mild but extended withdrawal symptoms (23). 0-demethylation by the 2D6 isozyme of he-
It is also fairly common for drug abusers (50% patic cytochrome P,,, (64).The resulting mor-
for heroin addicts) to have serum protein ab- phine is thought to be responsible for the an-
normalities, including elevated globulin and algesic activity because codeine has very low
albumin levels, which may further complicate affmity for opioid receptors (23). Patients
addiction treatment (57). In addition, there lacking CYP2D6, because of a genetic poly-
may also be liver dysfunction or disease stem- morphism, are unable to metabolize codeine to
ming from concomitant alcohol abuse that morphine (51). As noted above, there also ap-
may account, in part, for the abnormal serum pears to be variation in metabolic efficiency
protein levels (57). depending on ethnicity (65). The predominant
metabolite of codeine is the 6-glucuronide
2.3.2 Metabolism and Elimination of Mor- (C6G), which is renally excreted. One contro-
phine and Derivatives. Most opioids are sub- versial report suggests that codeine analgesia
jected to significant first-past hepatic metabo- is a result of C6G and not the morphine me-
lism (see Ref. 23). Thus oral morphine has tabolite (66). Hydrocodone is also metabolized
only approximately one-quarter bioavailabil- to hydromorphone and oxymorphone is a mi-
ity compared to that of a parenteral dose. The nor active metabolite of oxycodone through
major route of metabolism is through glucu- hepatic P,,, 2D6 metabolism.
ronic acid conjugation. Two major metabolites Naloxone undergoes extensive hepatic
are formed with the conjugation of the glucu- first-pass metabolism through glucuronida-
ronic acid to either position 3 (M3G, 11, Fig. tion. Naltrexone is metabolized to the active
7.2) (50%) or 6 (M6G, 12) (5-15%) of mor- metabolite 6-naltrexol, which is less potent
phine, whereas only small amounts of the di- but has a prolonged half-life compared to that
glucuronide are formed (23, 25). M6G has of the parent drug.
pharmacological actions indistinguishable from The opioids are predominantly excreted re-
those of morphine, yet it is twice as potent and nally (23). Morphine is eliminated by glomer-
is present in higher concentrations in plasma ular filtration from the kidney, predominantly
than in morphine (58). It has been suggested as M3G or M6G (23).The majority of excretion
that M6G accounts for a significant portion of (>go%) takes place on the first day, but a
morphine's analgesic activity, especially with small amount of enterohepatic circulation ac-
chronic use (59). Dose adjustment is not re- counts for the presence of small amounts of
quired in mild hepatic disease, but excessive morphine and metabolites for several days af-
sedation can occur in cirrhotic patients be- ter the last drug dose of drug is given (23).
3 Physiology and Pharmacology

Both the free and conjugated forms of codeine tors have also been implicated in analgesia,
are excreted in the urine (23). particularly in cases of inflammation (see
Refs. 71-74 for reviews). Readers are referred
2.3.3 Metabolism and Elimination of Other to a comprehensive two-volume series on opi-
Opioid Agents. Meperidine is also metabo- oids (75, 76) plus more recent reviews (18, 77,
lized in the liver. It is either hydrolyzed di- 78) for detailed reviews of opioid pharmacol-
rectly to meperidinic acid or N-demethylated ogy and physiology.
to normeperidine and then hydrolyzed to
normeperidinic acid. The acid forms are con- 3.2 Multiple Opioid Receptor Types
jugated, then excreted (23).
Fentanyl is also hepatically metabolized 3.2.1 Discovery of Multiple Opioid Recep-
and renally excreted. However, the congener tor Types and Current Nomenclature. Our un-
remifentanil is metabolically distinct when derstanding of opioid receptors has expanded
compared to other members in its chemical or considerably from the early assumption of a
pharmacological class. Remifentanil is metab- single opioid binding site to the characteriza-
olized by plasma esterases to remifentanil tion of multiple types of opioid receptors (see
acid, which is approximately 3000-fold less po- Refs. 79-81 for reviews). The initial proposal
tent than the parent opioid (67). of opioid receptors by Beckett and Casy in
Methadone undergoes significant hepatic 1954 (1)assumed a single opioid binding site.
metabolism by N-demethylation and cycliza- Multiple opioid receptors were postulated as
tion to form pyrrolidines and pyrroline (23). early as the 1960s by both Portoghese (82) and
Propoxyphene is also hepatically metabolized Martin (83), but it was behavioral studies in
predominantly by N-demethylation and re- the chronic spinal dog by Martin and cowork-
nally eliminated. The metabolite norpropoxy- ers in the mid-1970s (5,6) that led to the clas-
phene is cardiotoxic and produces arrhyth- sification of multiple opioid receptors. On the
mias and pulmonary edema that have led to basis of the pharmacological profile of a vari-
reports of cardiac arrest and death (59). This ety of opioids, Martin proposed three types of
is especially problematic because of the long opioid receptors, p, K, and a receptors, with
half-life of norpropoxyphene that accumulates morphine (1, Fig. 7.1), ketocyclazocine (13),
with repeated doses of the parent drug. Meth- and SKF-10,047 (N-allylnorcyclazocine, 141,
adone is excreted in the urine but also in the respectively, as the prototypical ligands (Fig.'
bile (23). 7.3). The discovery of the enkephalins led to
the proposal of a distinct opioid receptor type,
the 6 receptor, for these opioid peptides (84).
3 PHYSIOLOGY AND PHARMACOLOGY
The existence of three distinct opioid receptor
types, the p, K, and S receptors, has now been
3.1 Opioid Effects in the Central Nervous
clearly established and these receptors have
System and the Periphery
been cloned (see below). Sigma (m) receptors,
Opioid receptors are found in both the CNS however, are not considered opioid receptors
and in the periphery. In the CNS different because effects associated with this receptor
types of opioid receptors (p, K, and 6 receptors; are not reversed by opioid antagonists such as
see below) exhibit distinct anatomical distri- naloxone (see Ref. 85). Other opioid receptor
butions (see Refs. 68-70 for reviews), and types have also been proposed (see Ref. 86),
there is considerable species variation in both but these receptor types are not universally
relative receptor density and receptor distri- accepted.
bution. Peripheral receptors mediate some ef- During attempts to clone the opioid recep-
fects of opioids, such as inhibition of gut mo- tors (see Section 3.2.4 below), a related recep-
tility, and for a number of years receptors tor with high sequence homology was identi-
from tissues such as the guinea pig ileum fied by several research groups (see Refs.
(GPI) formed the basis of standard bioassays 87-90 for recent reviews). This receptor, re-
used to assess compounds for opioid activity ferred to by Mollereau et al. as opioid-recep-
(see Section 3.2.3.3 below). Peripheral recep- tor-like 1 (ORL1) receptor (91), does not dis-
Narcotic Analgesics

(13) Ketocyclazocine (14) SKF 10,047


(N-allylnormetazocine)
Figure 7.3. Agonists used by Martin and coworkers (5,6) to define K and a receptors. Morphine (1)
was the prototypical ligand used to characterize p receptors.

play affinity for classical opioid ligands, tion of opioid and other receptors with a vari-
including naloxone. Although distinctly differ- ety of effector systems, including adenylyl cy-
ent from opioid receptors, the ORLl receptor clase and ion channels. Numerous forms of
interacts with the opioid receptor system in G-proteins have been identified, including Gi
the regulation of analgesia and other physio- and Go that inhibit adenylyl cyclase and G,
logical effects. Details concerning the pharma- that stimulates adenylyl cyclase. Pertussis
cology of the ORLl receptor and its endoge- toxin inhibits Gi and Go by ADP-ribosylation
nous ligand orphanin FQ/nociceptin (OFQIN) of the a-subunit, whereas cholera toxin persis-
(92,93) are discussed below under Recent De- tently activates G,. Thus sensitivity to pertus-
velopments (Section 7.2). sis toxin is an indication of the involvement of
In 1996 the International Union of Phar- Gi (or Go) in the transduction mechanism,
macology (IUPHAR) recommended that OP1, whereas sensitivity to cholera toxin is an indi-
0P2, and 0 P 3 be used as the accepted names cation of involvement of G,.
for 6, K, and p receptors, respectively, (94) to Of the effector systems that have been im-
replace the DOR, KOR, and MOR nomencla- plicated in the transduction mechanisms for
ture typically used in the literature; 0 P 4 was opioid receptors, the best studied is opioid in-
the proposed name for the related ORLl re- hibition of adenylyl cyclase (see Refs. 69,
ceptor. This nomenclature has not gained 97-99 for reviews). Thus binding of an agonist
widespread acceptance, however, and in 2000 to opioid receptors inhibits the activity of ad-
the International Narcotic Research Confer- enylyl cyclase and decreases intracellular
ence (95) recommended a modified nomencla- CAMPin a number of different tissues. Pertus-
ture DOP, KOP, MOP, and NOP for 6, K, p, sis toxin sensitivity of opioid inhibition of ad-
and ORLl receptors, respectively, which is enylyl cyclase has been demonstrated in many
consistent with the nomenclature require- systems, indicating the involvement of either
ments of IUPHAR. Gi or Go in the transduction mechanism. Ago-
nist activation of all three types of cloned opi-
3.2.2 Signal Transduction Mechanisms. oid receptors to inhibit adenyl cyclase has
There is considerable evidence that opioid re- been demonstrated (see Ref. 100 and refer-
ceptors are coupled to G-proteins and produce ences cited therein). There is also some evi-
their effects through these proteins (see Refs. dence that p and S opioid receptors can stim-
96, 97 for reviews of opioid receptors and G- ulate adenylyl cyclase in certain tissues (see
proteins). The structure of cloned opioid re- Refs. 69,97 for reviews). There are conflicting
ceptors is consistent with their belonging to reports on whether K opioid receptors stimu-
this receptor superfamily (see below). G-pro- late or inhibit phosphatidylinositol turnover
teins are heterotrimers, consisting of a, p, and in some tissues (see Ref. 100); S and p recep-
y subunits, which bind guanine nucleotides to tors, however, do not appear to be coupled to
their a-subunit and catalyze the hydrolysis of phosphatidylinositol turnover in neuroblas-
GTP to GDP. G-proteins mediate the interac- toma cell lines NG108-15 and SK-N-SH (101).
3 Physiology and Pharmacology

Opioid receptors can also be coupled to ion (MVD), have been routinely used to assess opi-
channels through G-proteins (see Refs. 69,98, oid activity. Radioligand binding assays for
99, 102 for reviews). All three receptor types each of the opioid receptor types have been
can decrease voltage-dependent Ca+ cur- + instrumental in the identification of selective
rent. The coupling of opioid receptors to cal- opioids. With the cloning of the opioid recep-
cium channels involves a G-protein, and the tors, assays for both opioid receptor affinity
actions of opioids on Ca++current are blocked and efficacy can now be routinely performed
by pertussis toxin, indicating involvement of by use of these cells that express only a single
Gi or Go. Activation of p and 6 receptors can receptor type, greatly simplifying the inter-
also increase Kt conductance. Similar to the pretation of the results of the assays. Each of
results found for calcium channels, potassium these types of assays and their utilization in
channel coupling to opioid receptors appears characterizing compounds for opioid activity
to involve a G-protein and is sensitive to per- are discussed below.
tussis toxin. Considerable evidence suggests 3.2.3.1 Ligands Used to Characterize Opi-
that the effects on ion currents are attributed oid Receptors. Since the identification of mul-
to direct coupling of opioid receptors to ion tiple opioid receptor types, considerable effort
channels through G-proteins and are not re- has focused on developing more selective li-
lated to inhibiton of adenylyl cyclase (see Ref. gands for each of the receptor types (see Figs.
102). 7.4-7.6 and Sections 5.3, 5.9, 5.10, and 6 be-
Agonist binding to opioid receptors also ap- low). Ligands commonly used to study the dif-
pears to activate the extracellular signal regu- ferent receptor types include both nonpep-
lated kinase (ERK) cascade, which consists of tides and peptides (see Table 7.6). Morphinans
three intracellular kinases: a mitogen-acti- such as morphine and the antagonists nalox-
vated protein kinase (MAPK) kinase kinase, a one (16), naltrexone (17), and cyprodime (18)
MAPK kinase, and a MAPK homolog (see Ref. (104) are used to study p receptors (Fig. 7.4);
100). This activation appears to be through naloxone and naltrexone retain significant af-
G,or Go (see Ref. 100 and references cited finity for 6 and K receptors and therefore at
therein) higher concentrations these compounds will
antagonize all three receptor types. Several
3.2.3 Characterization of Opioid Recep- peptides, including the enkephalin analog
tors. Early evaluation of compounds for opioid DAMGO ([D-Ala2,MeNPhe4,glyol]enkephalin,
activity relied on testing for antinociceptive 15),and CTOP and CTAP (19 and 20), soma-
activity in vivo. These pharmacological assays tostatin analogs that antagonize p receptors
are often predictive of analgesic activity in hu- (105), are also used to characterize p recep-
mans, but the activity of compounds observed tors. Early studies of 6 opioid receptors used
in these assays is affected by a variety of fac- the enkephalin analog DADLE ( [ D - A ~ ~ ~ , D -
tors, including the route of administration of Leu5]enkephalin, 21), but several more 6-se-
the compound, the ability of the compound to lective enkephalin analogs, including DSLET
cross the blood-brain barrier into the CNS, the and DTLET ( [ ~ - S e r ~ , L e u ~ , T h r22
~ ] -and
,
2 5 6
susceptability of the compound to metabolism [D-Thr ,Leu ,Thr ]enkephalin, 23) and par-
and pharmacokinetics, the choice of noxious ticularly the cyclic analog DPDPE (cyclo[~-
stimulus, and the animal species and strain Pen2,~-Pen5]enkephalin,24) (Fig. 7.51, are
used for the assay (see Ref. 103). The results of now used routinely to characterize 6 recep-
in vitro assays are not influenced by many of tors; the naturally occurring deltorphins (e.g.,
these factors that complicate in vivo assays. 25), peptides isolated from frog skin (106),ex-
The pharmacological activity of opioids in hibit marked 6-receptor selectivity. The non-
vitro can still be complex, however, because peptide agonists BW373U86 (26),SNC 80 (27)
more than one opioid receptor type is present (107), and TAN 67 (28) (108,109) also exhibit
in many tissues. Opioid receptors are present very high selective for 6 receptors and are used
in a variety of peripheral tissues, and isolated frequently to study these receptors. Delta-re-
tissue preparations, particularly the guinea ceptor antagonists include the peptides ICI
pig ileum (GPI) and mouse vas deferens 174,864 (29) (110), TIPP (Tyr-Tic-Phe-Phe
Narcotic Analgesics

Agonist K-selective antagonist norbinaltorphimine


(norBNI, 39) (119, 120)) are now available.
.D-Ala-Gly-MeNPhe-NHCH2CH20H
Recently, Portoghese and coworkers described
(15) DAMGO GNTI (41) (121-123), which is a more K-selec-
Antagonists tive antagonist than norBNI, and which
should be a useful pharmacological tool to
OH study K receptors. The structure-activity rela-
I

tionships of these compounds are discussed in


more detail in the sections below.
3.2.3.2 Radioligand Binding Assays. The
demonstration of stereospecific binding of tri-
tiated ligands to opioid receptors in the early
1970s (2-4) paved the way for the subsequent
development of radioligand binding assays for
R = CH2CH=CH2 (16) Naloxone each of the opioid receptor types, which have
been instrumental in the identification of se-
R= (17) Naltrexone lective opioids. Early studies often used non-
selective ligands such as I3H1etorphine ([3Hl-
42) or [3Hlnaloxone,which labeled all types of

(18) Cyprodime

(42) Etorphine
(Pen = penicillarnine)
X = Orn (19) CTOP
X = Arg (20) CTAP

Figure 7.4. Ligands used to characterize p opioid


receptors.

OH, 30) (Ill), and TIPP[*] (Tyr-Tic*


[CH,NH]Phe-PheOH, 31) (112),and the non-
peptide naltrindole (32) (113). Recently, how-
ever, TIPP has been reported to exhibit
(43) Diprenorphine
agonist activity in adenylyl cyclase assays
(114). Early studies of K receptors used benzo-
morphans such as ethylketocyclazocine (EKC, opioid receptors, but today tritiated ligands
33), a close analog of ketocyclazocine, and selective for each receptor type are available
bremazocine (34) (Fig. 7.6), but the selectivity (see Table 7.7 and Refs. 69, 94). [3H]DAMG0
of these ligands for K receptors is very low (see ([3H]-15) is most often used for the radioli-
Table 7.8 below). Kappa-selective agonists gand binding assays for p opioid receptors.
such as U50,488 (35) (1151, U69,593 (36) [3H]DADLE ([3H]-21)was often used in early
(116), and CI-977 (37) (117, 118), and the binding studies examining S opioid receptors,
3 Physiology and Pharmacology

Agonists
Tyr-D-Ala-Gly-Phe-D-Leu 0
(21) DADLE
(CH3CH2)2N
Tyr-X-Gly-Phe-Leu-Thr
X = D-Ser (22) DSLET -

X = D-Thr (23) DTLET

R=H (26) (k)BW373U86


R = CH3 (27) (+) SNC 80

(24) DPDPE
0 OH

Tyr-D-Ala-Phe-GIu-Val-Val-GlyNH2 (28) TAN 67


(25) [D-Ala2]deltorphin II
Antagonists

yNpt
HO
( y-~ib-~ib- he-~eu
(Aib = -NHC(CH&CO-)
(29) ICI 174,864
- +H3N 0 N
H
0
N
--
C02-

X ==0 (30) TlPP


X =Hz (31) TIPP[Y]
OH
(32) Naltrindole (NTI)

Figure 7.5. Ligands used to characterize 6 opioid receptors.


Narcotic Analgesics

Agonists

(33) Ethylketocyclazocine (34) Bremazocine


(EW
CH3
I

(38) Dynorphin A

Antagonists

OH
R= H (39) norBNl (41) GNTl
R = CH3 (40) BNI

Figure 7.6. Ligands used t o characterize K opioid receptors.

but studies now commonly use the more 6-se- 34) in the presence of unlabeled p- and 6-se-
lective ligand [3H]DPDPE ([3H]-24). Early lective ligands such as DAMGO and DPDPE to
binding studies of K opioid receptors were block p and 6 receptors in the tissue prepara-
hampered by the low K selectivity of available tion. Because the highly K-selective ligand
tritiated ligands and the low levels of K recep- U69,593 ([3H]-36)is now available in tritiated
tors in rat brain (see below). One solution was form (116), it is routinely used in K-receptor
to examine the binding of ligands such as binding assays; the K-selective ligand CI-977
[3H]EKC ([3H]-33)or [3H]bremazocine ([3H]- (37) (117, 118) is also available in tritiated
3 Physiology and Pharmacology 347

Table 7.6 Ligands Commonly Used to Study Different Opioid Receptor Typesa
Receptor Type Agonists Antagonists
P Morphine (1) (Naloxone, 16)
DAMGO (15) (Naltrexone, 17)
Cyprodime (18)
CTOP, CTAP (19,20)
6 DPDPE (24) TIPP (30)
DSLET, DTLET (22,231 TIPP[+I (31)
Deltorphins (25) ICI 174,864 (29)
(DADLE, 21) Naltrindole (32)
BW373U86 (26)
SNC 80 (27)
TAN 67 (28)
K U50,488 (35), U69,593 (36) norBNI (39)
CI-977 (37) GNTI (41)
(EKC, 33) (bremazocine, 34)
Dynorphin A (38) and derivatives
"Compounds with limited selectivity for a given receptor type are listed in parentheses (see Table 7.8 for affinities and
opioid activities of these agents). See Figs. 7.1 and 7.4-7.6 for structures of these agents.

form. The affinity of a variety of opioids in ing assays. In contrast the rabbit cerebellum
radioligand binding assays for p, 8, and K re- contains predominantly (>70%) p opioid re-
ceptors are given in Table 7.8. ceptors (127). Species differences also exist for
Prior to cloning of the opioid receptors, af- S receptors, with mouse brain exhibiting sub-
finity for these receptors was most commonly stantially higher 6-receptor density than rat
determined by the use of homogenates or brain (128). NG108-15 cells contain only 6 re-
membrane fractions from rat, guinea pig, or ceptors and therefore have been used in radio-
mouse brain, which contain all three types of ligand binding assays for these receptors
opioid receptors. The relative amounts of dif- (129). With the cloning of opioid receptors
ferent opioid receptor types vary between spe- (Section 3.2.4 below), binding assays are now
cies, however, particularly for K receptors. In typically performed using these cells that ex-
rat brain K opioid receptors constitute only press only a single receptor type.
about 10-15% of the total number of opioid 3.2.3.3 In Vitro Assays for Efficacy. Until
receptor sites (1241, whereas in species such as the cloning of the opioid receptors isolated tis-
guinea pig they represent approximately 30% sue preparations, particularly smooth muscle
of the total opioid receptor population (125). preparations, were used extensively to charac-
Over 80% of the opioid receptors in the guinea terize opioids (see Refs. 131, 132 for reviews).
pig cerebellum are K receptors (126), so this The electrically stimulated GPI myenteric
tissue was frequently used in K-receptor bind- plexus-longitudinal muscle and the MVD
Table 7.7 Commercially Available Tritiated Opioid Receptor Ligandsa
Receptor Type
Nonselective
P 6 K (or low selectivity)
Morphine (1) DPDPE (24) U69,593 (36) EKC (33)
DAMGO (15) [D-Ala21deltorphinI1 (25) CI-977 (37) Diprenorphine (43Ib
I1
[~-Ala~,IIe~~~]deltorphin (Bremazocine, 34) Naloxone (16Ib
Naltrindole (32Ib
(DADLE, 21)
"Compounds with limited selectivity for a given receptor type are listed in parentheses. Ligands commercially available
from PerkinElmer Life Sciences, Amersham Biosciences, or Tocris. Iodinated derivatives of @-endorphinand Met(0) en-
kephalin are also available.
bAntagonists
348 Narcotic Analgesics

Table 7.8 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of a Variety
of Opioid Ligands Commonly Used to Study Opioid Receptorsa
a. Agonists Ki (nM) KiRatio Ic50(nM)
Agonist P 6 K P/~/K GPI MVD
Nonselective agonists
Etorphine (42) 1.0 0.56
(-1-EKC (33) 1.0 5.5
Agonists preferentially interacting with p receptors
Morphine (1) 1.8 90
Meperidine (7) 385 4,350
Fentanyl(8) 7.0 150
Methadone (9) 4.5 15
DAMGO (15) 1.9 345
Agonists preferentially interacting with 6 receptors
BW373U86 (26)" 46d 0.92d
SNC 80 (27)" 2,470d l.Od
TAN 67 (28)' 2,320 1.1
DPDPE (24) 710 2.7
DSLET (22) 39 1.8
DADLE (21) 14 2.1
[D-Ala2]deltorphin11(25) 2,450 0.71
Agonists preferentially interacting with K receptors
(-)-Bremazocine (34) 0.62 0.78
U50,488 (35) 435 9,200
U69,593 (36) 2,350 19,700
CI-977 (37) 100 1,040
[D-ProlO]Dyn A-(1-11) 0.56 2.3
b. Antagonists Ki (nM) KiRatio K, (nM)
Antagonist P 6 K P/~/K p, (GPI) K (GPI) 6 (m)
Nonselective antagonists
Naloxone (16) 1.8 23 4.8 1/13/2.7
Naltrexone (17) 1.1 6.6 8.5 1/6.0/7.7
Diprenorphine (43) 0.24 1.0 0.14 1.7/7.1/1
Antagonists preferentially interacting with p receptors
Cyprodime (18) 9.4 356 176 1/38/19
CTOP (19) 1.7 >1,000 >1,000 1/>590/>590
Antagonists preferentially interacting with 6 receptors
Naltrindole (32) 11 0.12 18 92/1/150
ICI 174,864 (29) 29,600 190 65,400 155/1/345
TIPP (30Y 1,720 1.2 ND 1,43011
TIPP[JI] (3Uk 3,230 0.31 ND 10,500/1
Antagonists preferentially interacting with K receptors
NorBNI (39) 14 10 0.34 41/29/1
GNTI (41)' 22 46 0.18 125125711
"Data from Ref. 130 except where otherwise indicated.
bAntagonistat p and 6 receptors in the rat and hamster vas deferens, respectively.
"From Ref. 107.
dIC50.
'From Ref. 109.
fND, not determined.
BDetermined in the MVD.
hAgonist in the GPI (IC,, = 1.4 nM).
'NA, not active at indicated dose.
&om Ref. 111.
'From Ref. 112.
lFrom Ref. 122.
3 Physiology and Pharmacology

preparations have been the tissues used most cies have been used to examine the activity of
extensively. The predominant effect of opioids potential analgesics. Animal models for pain
is to inhibit smooth muscle contraction, gen- include models of acute pain (e.g., hot plate,
erally by inhibiting the release of neurotrans- tail flick, paw pressure, and writhing assays),
mitters; in the GPI and MVD acetylcholine persistent pain (e.g., the formalin test),
and norepinephrine, respectively, are the neu- chronic pain (e.g., adjuvant-induced arthritis),
rotransmitters effected (see Ref. 132). In con- and neuropathic pain (e.g., nerve ligation) (see
trast to radioligand binding assays, which Table 2.1 of Ref. 144). The different types of
measure only opioid affinity, these bioassays noxious stimuli commonly used in these an-
provide information on the intrinsic activity of tinociceptive assays include heat (e.g., hot -
the compounds tested. The activity of com- plate and tail flick assays), pressure (e.g., tail
pounds in these assays can be complex, how- pinch and paw pressure assays), chemical
ever, because both tissues contain more than (writhing or abdominal constriction assay and
one opioid receptor type. The GPI contains the formalin test), and electrical (tail shock
both p and K receptors, with little if any func- vocalization) stimuli. Among the most com-
tional 6 receptors, whereas the MVD contains monly used assays are the hot plate, tail flick,
all three opioid receptor types. The activity of and writhing assays. In the hot plate test, the
a variety of opioids in these tissues are given in latency to various behavioral responses (e.g.,
Table 7.8. GPI and MVD preparations en- forepaw or hindpaw licking) is measured when
riched in a single receptor population have the animal is placed on a hot plate, typically
been prepared by use of the affinity labels set at 55"C, whereas the tail flick assay mea-
p-chlornaltrexamine (p-CNA) and p-funal- sures the time for the animal to flick its tail
trexamine (p-FNA) (133, 134) (see Section away from radiant heat focused on the tail. In
5.11). Vas deferens from other species have the writhing or abdominal constriction assay
been used to characterize opioids and appear the animal is injected intraperitoneally (i.p.)
to contain predominantly a single receptor with an irritant (typically phenylquinone or
population. The rabbit vas deferens appears to acetic acid) and the dose of a test compound
contain only K receptors (1351, whereas the required to abolish the writhing syndrome de-
hamster vas deferens contains only 6 recep- termined. On the basis of a comparison of the
tors (136). In the rat vas deferens P-endorphin potencies of standard opioids in several pain
is a potent inhibitor, which led to the proposal models, it was concluded that the mouse ab-
that this tissue contains an additional type of dominal constriction assay (use of 0.4% acetic
opioid receptor, the E receptor (137-139). acid) was the most sensitive to opioids,
With the cloning of the opioid receptors, in whereas the mouse hot plate test (at 55°C) was
vitro functional assays that used these recep- the least sensitive; the rat tail flick test was
tors have been developed. These assays have intermediate (see Ref. 144). For a detailed dis-
used measurement of effects on signal trans- cussion of these antinociceptive assays, read-
duction systems to determine the efficacy and ers are referred to excellent recent reviews
potency of compounds being studied. Because (144, 145) that describe these procedures and
opioid receptors are G-protein-coupled recep- discuss methodological issues and recent
tors, measurement of the stimulation of bind- developments.
ing of the radiolabeled nonhydrolyzable ana- Activation of all three types of opioid recep-
log of GTP [35SlGTPyS(140, 141) following tors (p, 6, and K) can produce antinociception,
interaction of a compound with the receptor but there are significant differences in the ef-
can be used to determine the efficacy and po- fects of activating different receptor types, de-
tency. Inhibition of adenylyl cyclase has also pending on the noxious stimulus used and the
been used as a functional assay to evaluate the animal species (see Refs. 103,146 for excellent
efficacy and potency of opioid ligands at opioid reviews; see particularly Table 1 of Ref. 103
receptors (142,143). for a summary of supraspinal opioid receptor
3.2.3.4 in Vivo Evaluation of opioids. A va- involvement in antinociceptive assays). Al-
riety of antinociceptive assays that use differ- though p agonists are active against all types
ent noxious stimuli and different animal spe- of noxious stimuli, the activity of K agonists
350 Narcotic Analgesics

Figure 7.7. Schematic diagram of the protein structure of the three opioid receptors. Rectangles
indicate transmembrane helices and numbers indicate the percentage identical residues among the
three opioid receptors in that segment (from Ref. 100).

depends on the type of stimulus. Kappa ago- type of cloned opioid receptor and in knockout
nists are active against chemical and pressure mice lacking individual opioid receptors have
stimuli, but they are inactive against electrical confirmed the involvement of the cloned re-
stimulation and their efficacy against thermal ceptors in analgesia mediated by p, 6, and K
stimuli is dependent on the intensity (147). receptors (see Refs. 149,153,154 for reviews).
Delta agonists may be active against all four The opioid receptors belong to the family of
types of stimuli in mouse, depending on the G-protein-coupled receptors. On the basis of
route of administration (see Ref. 103), but the model for this family of receptors, the re-
there are species differences. It has been re- ceptors contain extracellular regions includ-
ported that while S agonists are effective in ing the N-terminus and extracellular loops,
both the tail flick and hot plate assays in mice, seven putative transmembrane (TM) regions,,
in rats they are active in the hot plate, but not and intracellular regions including the C-ter-
tail flick assays (148). minus and intracellular loops (Fig. 7.7). Com-
parison of the sequences (155) indicates the
3.2.4 Opioid Receptor Structure and Molec- highest sequence homology between the K, p,
ular Biology. The first successful cloning of and S receptors in TM2, TM3, and TM7 (Fig.
opioid receptors used a cDNA library from 7.7). TM2 and TM3 each contain a conserved
NG108-15 cells to clone S receptors (8,9).Af- Asp residue; the conserved Asp in TM3 is
ter expression of the cDNA library in COS thought to interact with protonated amine
cells, the cells were screened for L3H1 S-ligand groups on opioid ligands (see below). There
binding and the clone isolated. Yasuda et al. are also high similarities in the intracellular
subsequently reported cloning of both mouse loops; the third intracellular loop is thought to
brain K and 6 receptors while trying to isolate be involved in interactions with G-proteins.
cDNAs encoding somatostatin receptors (111, The second and third extracellular loop, TM1,
and Chen et al. reported cloning of rat p recep- and TM4-6 are less conserved. The largest
tor (10). Since then the cloning of all three structural diversity occurs in the extracellular
opioid receptor types from several different N-terminus. Potential sites for possible post-
species, including human, have been reported translational modification have been identi-
(see Refs. 79,80,94,149-152 for reviews). The fied on the receptors. Two potential glycosyla-
human p, 8, and K receptors exhibit 91-95% tion sites are located in the N-terminal
sequence homology to the corresponding type sequence. Two possible sites for protein ki-
of receptor from rat and mouse (79). Studies nase C phosphorylation are located in the C-
with antisense oligodeoxynucleotides to each terminus plus a third site is found in the third
3 Physiology and Pharmacology

intracellular loop; a possible palmitoylation contributes directly to the affmity of K recep-


site is also located in the C-terminus. Con- tors for the opioid peptide dynorphin A
served Cys residues in the first and second ex- through ionic interactions with basic residues
tracellular loops may be involved in a disulfide in the C-terminus of this peptide. Examina-
linkage. tion of both d p (167, 168) and ~ / (169)
6 chi-
3.2.4.1 Mutagenesis Studies of Opioid Re- meric receptors supported the importance of
ceptors. A variety of chimeric receptors be- EL2 for the high affinity of dynorphin A for K
tween different opioid receptor types have receptors. However, in a recent study in which
been prepared in attempts to identify regions three or four of the seven acidic residues in
of the receptors that are involved in ligand EL2 of K receptors were mutated to the corre-
recognition and receptor-type selectivity (see sponding amides, the mutant receptors still
Refs. 156, 157 for recent reviews). What has bound dynorphin A with high affinity, raising
emerged from these studies is a complex pic- questions about the role of these acidic resi-
ture of the possible roles of different regions of dues in dynorphin A affmity for K receptors
the receptors. It has been suggested that the (170). The study of chimeric receptors also
extracellular loops may play an exclusionary suggests that different domains of a receptor
role rather than a direct role in ligand binding, may be involved in interactions with different
acting as filters to prevent ligands selective for ligands. Thus, in contrast to dynorphin A, the
other receptor types from binding (158). How- K-selective nonpeptide agonists U50,488 and
ever, which loop serves this role can be differ- U69,593 appear to require the whole K recep-
ent for different receptors excluding the same tor except for EL2 (167, 168). U69,593 also
ligand. Thus the study of p/6 chimeric recep- appears to bind to K receptors differently than
tors suggested that the first extracellular loop does naloxone, suggesting that agonists and
(ELI) causes the loss of high affinity binding antagonists may bind differently to this recep-
of the p opioid agonist DAMGO to 6 receptors tor (171).
(159,160);subsequent site-directed mutagen- Site-directed mutagenesis has been used to
esis studies suggested that Lys108 in EL1 of examine the roles of individual residues [see
the 6 receptor was the residue responsible Refs. 156, 157 and the Center for Opioid Re-
(161). In contrast, results for p / chimeric
~ re- search website (http:Nwww.opioid.umn.edu)
ceptors suggest that EL3 may be responsible for a complete listing of opioid receptor muta- .
for the low binding affinity of DAMGO to K tions with references]. Thus the conserved
receptors (162, 163); site-directed mutagene- Asp in both TM2 and TM3 have been substi-
sis identified G ~ u ~ ' Ser310,
~, Tyr312, and tuted with neutral residues (172-174) to ex-
Tyr313 as the residues in the K receptor re- plore their roles in opioid ligand binding. Re-
sponsible for discriminating against DAMGO sults for the mutation of the Asp in TM2
(164). The involvement of different loops also suggested that agonists and antagonists may
appears to be ligand dependent (see Ref. 157). bind differently to their receptors. Substitu-
The major determinant for binding of the tion of the Asp in TM3 dramatically reduced
p-selective alkaloids appears to involve the re- the affinity of some, but not all, opioids (1741,
gion of TM5 through TM7 (160), and similar- raising the possibility that this is not a univer-
ily the binding of the &selective peptide sal counterion for opioid ligands. The His in
DPDPE (24) to 6 receptors appears to involve TM6 has also been implicated in the binding of
this region near the C-terminus of the recep- ligands to the p receptor (173), and this resi-
tor (160). EL3 also seems to be important for due is conserved across the three receptor
the selectivity of several other 6-selective com- types. Mutation of G ~ u at ~ the
' ~ top of TM6 in
pounds, both peptide and nonpeptide ligands, K receptors was used to demonstrate the im-
for 6 over p receptors (165, 166); point muta- portance of this residue for the K-receptor af-
tions indicated that Trp284,Val296,and Val297 finity and selectivity of the nonpeptide K-selec-
were the crucial residues in EL3 of the 6 recep- tive antagonist norBNI (175); conversely, the
tor for 6 selectivity (166). single mutation of the corresponding residue
Because of the number of acidic residues in Lys303in the p receptor to Glu imparts high af-
EL2, it has been suggested that this region finity for norBNI (121). Indeed, the close sirni-
Narcotic Analgesics

larity between the opioid and ORLl receptors ceptor (1821, arylacetamides to the K receptor
(see Section 7.2) has been clearly demonstrated (182, 183, 186), fentanyl analogs at the f i re-
by the ability to convert the ORLl receptor to an ceptor (182, 1871, and piperazine and piperi-
opioid receptor with the mutation of only four dine derivatives at 6 receptors (182, 188).
residues in TM6 and TM7 (176). Site-directed Modeling of the flexible opioid and opioid-like
mutagenesis has also been used to examine pos- peptides bound to their receptors is more chal-
sible points of attachment of the affinity label lenging, and therefore reports describing their
P-FNA (177) (see Section 5.11.1 below). receptor-binding modes have been more lim-
. and site-directed
Thus chimeric rece~tors ited. Models have been developed for the bind-
mutagenesis have provided tremendous in- ing of the conformationally constrained 6-se-
sight into receptor-structure and receptor-li- lective peptides JOM-13 (Tyr-cyclo[~-Cys-
gand interactions. However, the data from Phe-D-PenlOH) and DPDPE to 6 opioid
these studies must be intermeted with cau- receptors (182), and the extracellular loops
tion, particularly in cases involving loss of have been incorporated into computational
function (157). Changes in the primary se- models of K receptors (181) and ORLl recep-
quence of a receptor could have significant ef- tors (1891, so that possible binding modes of
fects on the protein secondary or tertiary Dyn A-(1-10) and OFQN-(1-13) to these re-
structure, which in turn could affect the af- ceptors could be examined. With the recent
finities of various ligands. Thus whether ob- report of the X-ray structure of rhodopsin
served changes in ligand affinity are attrib- (2.8-A resolution) (178), additional reports of
utable to the direct effect of the mutations or computational models of opioid receptors de-
indirect effects that result from altering the rived from this structure are beginning to ap-
tertiary structure of the protein is not pear in the literature (see Refs. 156, 190).
known. 3.2.4.3 Receptor Subtypes, Splice Variants,
These studies demonstrate the comdexi- - and Receptor Dimerization. Before cloning of
ties of ligand binding to opioid receptors and the opioid receptors, subtypes of each of the
indicate that more research is required to three opioid receptors were proposed on the
more fully understand, at the molecular level, basis of evidence from pharmacological assays
the interactions of different opioid ligands (see Refs. 69, 103 for excellent reviews), al-
with their receptors. though opioid receptors identified by cloning
3.2.4.2 Computational Models of Opioid have consistently represented only a single
Receptors. ~ e c a u s eG-protein-coupled recep- subtype for each receptor type. Currently,
tors are transmembrane proteins, until quite there is still considerable debate on the exis-
recently (178) structural information on these tence and nature of some of these receptor
receptors was limited to low resolution (6-9 A) subtypes.
structures from electron microscopy studies of There is considerable evidence from both
rhodopsins.
* With the deduced amino acid se- functional assays and binding studies support-
quences of the opioid receptors available, com- ing the existence of two types of 6 opioid recep-
putational models of the three-dimensional tors (see Refs. 69,191,192). A key factor in the
structures of opioid receptors were developed characterization of these &receptor subtypes
based initially on these low resolution struc- was the availability of ligands selective for
tures (166, 179-188). The rigid structures of each of the proposed subtypes (Fig. 7.8). The
many nonpeptide opioid ligands decreases the 6, subtype was characterized by its preferen-
possible degrees of conformational freedom, tial stimulation by the enkephalin analog
decreasing the complexity of docking these DPDPE (24) and DADLE (21) and selective
compounds to opioid receptor models, and antagonism by the naltrindole analog BNTX
therefore several of the reports have described (7-benzilidenenaltrexone, 44) (193) and the
possible binding modes for these compounds. affinity label (see below) DALCE (45) (194).
These include tifluadom-like benzodiazepine The 6, subtype was distinguished by its stim-
ligands at K opioid receptors (1791, naltrexone- ulation by [~-Ala~]deltor~hin 11 (25) and
derived antagonists at K and 6 receptors ( N O ) , DSLET (22) and antagonism by the benzofu-
morphinans including morphine to the p re- ran naltrindole analog naltriben (46) (195)
3 Physiology and Pharmacology

Delta receptor ligands:

Tyr-D-Ala-Gly-Phe-Leu-Cys
(45) DALCE

(44) BNTX

(46) Naltriben (47) Naltrindole isothiocyanate (NTII)


Mu receptor ligands: OH OH

(49) Naloxonazine
(48) Naloxazone OH

(50) Naloxone benzoylhydrazone


(Nal(Bzo)H)

Figure 7.8. Ligands used to characterize opioid receptor subtypes.

and the irreversible antagonist naltrindole ible ligands (see Section 5.11) FIT (198) or
isothiocyanate (NTII, 47) (196). Delta-recep- (+)-transSUPERFIT (199) to selectively acy-
tor subtypes were also proposed by Rothman late a,, receptors (200) and used the p-recep-
and coworkers which were differentiated by tor affinity label BIT (198) to deplete the mem-
whether they were associated with a p-6 re- branes of S, receptors (201). On the basis of
ceptor complex (S,,) or were not associated binding and pharmacological studies Roth-
with such a complex (S,,,) (see Ref. 197 for a man and coworkers proposed that the S,, and
review). These researchers used the irrevers- the S,, receptors corresponded to the 6, and 6,
Narcotic Analgesics

receptors, respectively (202, 203). Pharmaco- ria, are decreased in these animals). Mice de-
logical characterization of the cloned 6 opioid ficient in each of the opioid receptors and
receptor is consistent with classification as the animals lacking all three opioid receptors have
S,subtype (2041,and antisense oligonucleotides been examined for residual K, receptor bind-
differentially affect the two subtypes (205). In ingsites (216);all of the residual non-K, recep-
&receptor knockout mice binding of both [,HI- tor labeling could be accounted for by p and 6
DPDPE and [3H]-[~-Ala2]deltorphin I1 is ab- receptors, and the triple receptor deficient
sent (206), indicating that the proposed sub- mice exhibited no residual binding of
types are not due to different gene products; [3H]bremazocine, indicating that no other
however, selective 6 agonists still retain anal- gene product was involved in binding this opi-
gesic potency, suggesting the existence of a oid ligand. A third K-receptor subtype, K,, has
second 6-like analgesic system (206). also been proposed on the basis of studies that
Multiple types of p opioid receptors have used naloxone benzoylhydrazone, Nal(Bzo)H
been proposed by Pasternak and coworkers. (50) (217).
Two subtypes of p receptors, the p, site, which Recently, an alternative explanation for
was suggested to be a common high affinity opioid receptor subtypes, receptor dimeriza-
site for both nonpeptide opioids and opioid tion, has appeared in the literature that could
peptides, and the p2site, which was proposed explain why different gene products have not
to correspond to the "traditional" p-binding been identified for the proposed receptor sub-
site (2071, were initially postulated by these types in spite of the evidence from pharmaco-
researchers (see Refs. 69,208). The hydrazone logical assays for their existence. The details
derivative of naloxone, naloxazone (48) (209), of these studies are discussed under Recent
and its dimeric azine derivative naloxonazine Developments (Section 7.1) below.
(49) (210) have been used to study the puta-
3.3 Physiology of Non-p Opioid Receptors
tive p, receptors (see Ref. 691, which is
thought to represent about 20% of the specific Because of the side effects associated with an-
binding to rat brain membranes (208). Follow- algesics that interact with p opioid receptors,
ing the cloning of the opioid receptors, Paster- there has been considerable interest in devel-
nak and coworkers characterized multiple oping opioid ligands that interact with other
splice variants of the p receptor (see Refs. 211, opioid receptors. In addition to analgesic activ-
212 for reviews). ity, there are a number of other potential ther-
Three or more subtypes of K receptors have apeutic applications of ligands, both agonists
been postulated. In the early 1980s several and antagonists, for non-p opioid receptors.
groups reported differences between the bind-
ing of [,HIEKC and [3H]diprenorphine or 3.3.1 Delta Receptors. There has been con-
[,H1etorphine (after blockade of p and 6 recep- siderable interest in 6 opioid agonists because
tors), suggesting that there might be K-recep- they exhibit antinociceptive effects without
tor subtypes; there was considerable debate, the side effects associated with p opioid recep-
however, concerning the nature of these tor agonists. Antinociceptive activity was first
different binding sites (see Refs. 69, 213). demonstrated with 6-selective opioid peptides
Subsequently, the K-selective arylacetamides (see Ref. 218 for a review), and more recently
U50,488 and U69,593 helped to clarifjr the def- with nonpeptidic 6-selective agonists (see
inition of different K-receptor subtypes, and Refs. 219-222 for reviews). Of particular in-
two populations of binding sites, K , versus K,, terest is the activity of 6 agonists in inflamma-
were differentiated on the basis of their sensi- tory and neuropathic pain (220). Delta opioid
tivity and insensitivity, respectively, to these receptors also modulate p opioid receptors
arylacetamides (214). The cloned K receptors and, as discussed earlier, one classification of 6
appear to be the K, subtype on the basis of opioid receptor subtypes was based on their
pharmacological characterization (204) and association with p opioid receptors. There is
the analgesic activity of U50,488 is abolished now considerable evidence that interaction
in K-receptor knockout mice (215) (other ef- between the two receptor types can alter the
fects of U50,488, hypolocomotion and dyspho- activity of p opioid agonists. Delta agonists
3 Physiology and Pharmacology

can potentiate the analgesic activity of p ago- ences cited therein). There is considerable ev-
nists (223,224) and 6 antagonists can decrease idence that endogenous opioids and opioid
the development of tolerance and dependence receptors play important roles in the abuse of
to morphine (225, 226). Although the 6-selec- alcohol (235,236), and the opioid receptor an-
tive antagonist naltrindole can block the de- tagonist naltrexone has been used to treat al-
velopment of tolerance to the analgesic effects coholism. The involvement of 6 opioid recep-
of morphine (225), it does not block the bene- tors in alcohol abuse, however, remains
ficial development of tolerance to the respira- unclear. Delta-selective receptor antagonists
tory depressant effects of morphine (227). have been examined for their ability to de-
Delta ligands can also reverse the respiratory crease alcohol consumption in animal models,
depression caused by p agonists, and interest- but the results have been mixed, with some
ingly, 6 agonists as well as antagonists were studies reporting decreased alcohol consump-
reported to have similar effects on respiration tion, whereas others observed no effects (see
(228). Thus 6 receptor ligands, particularly 6 Refs. 222,236 for reviews). One possible expla-
antagonists, could have important therapeutic nation for this discrepancy could be differ-
applications to minimize the deleterious ef- ences in the genetic backgrounds of the ani-
fects of morphine. These findings have mals studied.
prompted the search for compounds that ex- Delta receptors are also involved in a num-
hibit both p agonist and 6 antagonist activity, ber of other biological effects, including both
and peptidic ligands with this mixed activity centrally and peripherally mediated effects
have been reported by Schiller to produce po- (see Refs. 219,220,222 for reviews). Delta ago-
tent analgesic effects without physical depen- nists are effective in learned helplessness ani-
dency and less tolerance than that of mor- mal models, suggesting a potential therapeu-
phine (229). Nonpeptide ligands with mixed tic application in depression (237).Convulsant
activity have also recently been reported (230) effects have been observed with nonpeptide 6
(see Section 5.3.3 below). agonists [particularly BW373U86 (see Section
Delta receptors may also modulate re- 5.10.11, however, which could prevent their
sponses to substances of abuse other than opi- clinical use unless these adverse effects can be
oids, includingcocaine, amphetamines, and al- separated from their desired action (e.g., an-
cohol (219, 220, 222). Several 6 agonists have tinociceptive activity; see Ref. 238). Opioids,
been reported to at least partially discriminate including 6 receptor ligands, have immuno-
for cocaine (see Ref. 222). There are numerous modulatory effects (239). Delta agonists have
reports that 6-receptor antagonists can atten- been reported to stimulate immune responses,
uate a number of the effects of cocaine (see whereas 6 antagonists can cause immunosup-
Refs. 219,220,222), and an antisense oligode- pression (see Refs. 219, 220). The immuno-
oxynucleotide to 6 opioid receptors blocks co- modulatory effects are still present in 6 recep-
caine-induced place preference in mice (231). tor knockout mice (240), however, indicating
Thus 6 antagonists could potentially be used that these effects are not mediated by these
in the treatment of cocaine abuse. One study, receptors.
however, found that the 6-receptor antagonist
naltrindole can potentiate the lethal effects of 3.3.2 Kappa Receptors. Like p and 6 recep-
cocaine; this was found only after intracister- tors, activation of K opioid receptors can
nal administration and not after i.v. adminis- produce antinociceptive effects. However, the
tration, so it is not clear whether this would effectiveness of K opioid agonists as antinoci-
limit the application of 6-receptor antagonists ceptive agents varies in different types of pain
in treatment of cocaine abuse (232). Similar (see Ref. 146),and K agonists are less effective
results have been found for 6 agonists and an- in thermal antinociceptive assays involving
tagonists in methamphetamine-induced place more intense stimuli.
preference (see Ref. 222); one important find- Kappa agonists can also produce antinoci-
ing was that the 6 agonist DADLE can protect ceptive effects in inflammatory pain through
against the neuronal damage caused by meth- interaction with peripheral K opioid receptors.
amphetamine (see Refs. 233, 234 and refer- Kappa agonists have been shown to have anti-
Narcotic Analgesics

arthritic activity (241, 2421, and to produce model, a K-receptor antagonist could be useful
antinociception in capsaicin-induced thermal to normalize this imbalance and treat opioid
allodynia through interaction with peripheral addiction (249).
K receptors (243, 244). Because many painful The effects of K opioid agonists on dopa-
conditions are associated with inflammation, mine levels also has implications for the
there is significant potential for the applica- treatment of cocaine abuse. Cocaine blocks
tion of K agonists as peripheral analgesics. Pe- reuptake of dopamine, and considerable evi-
ripheral K opioid receptors also appear to be dence suggests that cocaine's reinforcing effects
involved in visceral pain and the activity of K are mediated by these increases in extracellular
agonists is enhanced in the presence of chronic dopamine (see Refs. 250, 251 and references
inflammation of the viscera (245, 246), sug- cited therein). Because K agonists can decrease
gesting potential therapeutic applications of dopamine levels, they can ad as h d i o n a l an-
tagonists of cocaine (250, 251). Several K ago-
peripherally selective agents without the side
nists have been shown to decrease cocaine self-
effects (e.g., dysphoria) associated with many
administration (250-254; but see Ref. 255) and
centrally acting K agonists. K agonists can also attenuate many of the behav-
In many cases activation of central K opioid ioral effects of cocaine (see Ref. 250).
receptors opposes the activity of p opioid re- Central K opioid receptors also mediate
ceptors (see Ref. 247 for a recent review). Sev- other effects that could be therapeutically
eral studies have reported that K agonists at beneficial. Kappa agonists exhibit neuropro-
doses that do not affect the baseline pain tective effects in stroke (256);these effects are
threshold can antagonize the analgesic activ- observed in experimental models even several
ity of p opioid agonists (see Ref. 247). The hours after blood vessel occlusion (see Ref. 257
K-opioid peptide dynorphin A-(1-13) has been and references cited therein), which is partic-
reported to improve the memory impairment ularly promising for the potential therapeutic
induced by the p agonist DAMGO (248). use of K agonists in stroke. Dynorphin im-
Kappa agonists also reduce tolerance to mor- proves memory dysfunction in an animal
phine in a variety of antinociceptive tests, and model of amnesia (see Ref. 247). Kappa opioid
dynorphin can inhibit morphine withdrawal agonists have also been shown to cause down-
symptoms in morphine-dependent animals regulation of HIV expression in human micro-
(see Ref. 247 and references cited therein). glial cells (258) and CD4+ lymphocytes (259),
Kappa agonists generally lack reinforcing ef- which raises the intriguing possibility of using
K ligands as adjuvant therapy in HIV-infected
fects and can abolish the reinforcing effects of
morphine (see Ref. 247). This effect of K ago- individuals; whether this will have clinical ap-
plicability remains to be determined.
nists on morphine reward may be attributed
to the opposing modulation of the mesolimbic
dopamine system by p and K opioid receptors, 3.4 Endogenous Opioid Peptides
where p agonists increase dopamine levels During the mid-1970s the search for endoge-
while K agonists decrease dopamine levels. nous ligands for opioid receptors led to the
Kappa agonists also generally have opposite discovery of peptides with opiate-like activity.
subjective effects from p opioid agonists (dys- The first opioid peptides reported were the
phoria for K agonists versus euphoria for p pentapeptides leucine and methionine en-
agonists). Chronic administration of mor- kephalin (3and 4) (7), followed shortly there-
phine and other drugs with positive reinforc- after by dynorphin A (38) (260,261) and @en-
ing effects increases brain levels of the endog- dorphin (51)(262). Because these peptides are
enous K opioid peptide dynorphin (see Ref. 249 structurally distinct from the alkaloid opiates,
and references cited therein). It has been pro- the term opioid was introduced to describe all
posed (249) that this produces an imbalance in compounds, both nonpeptide and peptide,
abstinent p opioid-dependent individuals and with opiate-like activity. These mammalian
dysphoric mood states, which can result in the opioid peptides share a common N-terminal
desire to take p opioid agonists to normalize tetrapeptide sequence, but differ in their C-
mood. Thus on the basis of this " K overdrive" terminal residues (Fig. 7.9). They also differ in
3 Physiology and Pharmacology

Proenkephalin peptides
Leu-Enkephalin (3) Tyr-Gly-Gly-Phe-Leu
Met-Enkephalin (4) Tyr-Gly-Gly-Phe-Met
Met-enkephalin-Arge-Phe7 Tyr-Gly-Gly-Phe-Met-Arg-Phe

Met-enkephalin-Arg6-Phe7-Leu8 Tyr-Gly-Gly-Phe-Met-Arg-Gly-Leu

Prodynorphin peptides

Dynorphin A (38) Tyr-Gly-Gly-Phe-Leu-Arg-Arg-lle-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln

Dynorphin B Tyr-Gly-Gly-Phe-Leu-Arg-Arg-GIn-Phe-Lys-Val-Val-Thr

a-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Arg-Pro-Lys

p-Neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Arg-Pro

Pro-opiornelanocorlin peptides
&-endorphin (51) Tyr-Gly-Gly-Phe-Met-Thr-Ser-GIu-Lys-Ser-GIn-Thr-Pro-Leu-Val-Thr-Leu-
Phe-Lys-Asn-Ala-lle-lle-Lys-Asn-Ala-Tyr-Lys-Lys-Gly-Glu
Endornorphins

Orphanin FQJnociceptin and related peptides

Orphanin FW
Nociceptin (54) Phe-Gly-Gly-Phe-Thr-Gly-Ala-Arg-Lys-Ser-Ala-Arg-Lys-Leu-Ala-Asn-GIn

Orphanin FQ 2 Phe-Ser-Glu-Phe-Met-Arg-Gln-Tyr-Leu-Val-Leu-Ser-Met-GIn-Ser-Ser-Gln

Nocistatin Pro-Glu-Pro-Gly-Met-Glu-Glu-Ala-Gly-Glu-Met-Glu-Gln-Lys-Gln-Leu-Gln
(human)
Figure 7.9. Mammalian opioid peptides and orphanin FQ/nociceptin.

the receptor types with which they preferen- functioned as "address" components to direct
tially interact. Although the enkephalins ex- the peptides to particular opioid receptors.
hibit some preference for interacting with S Recently, a new class of opioid peptides, the
receptors (Table 7.9), the dynorphins prefer- endomorphins (52 and 53, Fig. 7.9), were dis-
entially interact with K receptors; p-endor- covered (264) that do not share the classical
phin possesses high affinity for both p and 6 "message" sequence with other mammalian
receptors. This led Goldstein to apply the opioid peptides. In contrast to other mamma-
"message-address" concept (see also Section lian opioid peptides, the endomorphins show
6.3) to the opioid peptides (263). In Goldstein's high selectivity for their preferential receptor,
proposal the common N-terminal tetrapeptide the receptor (Table 7.9). Since their discov-
sequence constituted the "message" sequence ery the pharmacology of these new mamma-
responsible for activating opioid receptors, lian opioid peptides has been studied exten-
whereas the unique C-terminal sequences sively (see Ref. 265 for a detailed review).
358 Narcotic Analgesics

Table 7.9 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Endogenous
Opioid Peptidesasb
Ki (nM) KiRatio IC5, (nM)
Peptide P 6 K ~ 1 6 1 ~ GPI MVD
Proenkephalin peptides
Leu-enkephalin (3)
Met-enkephalin (4)
Met-enkephalin-kg6-Phe7
Met-enkephalin-Arg6-Gly7-Leus
Prodynorphin peptides
Dynorphin A (38)
Dynorphin A-(1-8)
Dynorphin B
p-Neoendorphin
a-Neoendorphin
POMC peptide
&-Endorphin (51)
Endomorphins"
E n d o m o r p h -1 (52)
Endomorphin-2 (53)
"Data from Ref. 130 except where otherwise indicated.
bSeeSection 7.2 for data on orphanin FQlnociceptin.
'Data from Ref. 264.

After the identification of the ORLl recep- dues along with one copy of Leu-enkephalin.
tor, two groups isolated a 17-residue peptide In addition, extended Met-enkephalin deriva-
(54, Fig. 7.9) as the endogenous ligand for this tives Met-enkephalin-kg6-Phe7 and Met-en-
receptor (92,93). This peptide was referred to kephalin-kg6-Gly7-Leu8and longer peptides
as orphanin FQ by one group because it was (e.g., peptides E and F and BAM-20) are ob-
the ligand for the orphan receptor (FQ are the tained from proenkephalin A. The dynor-
N- and C-terminal residues, respectively, of phins, which contain a number of basic resi-
the peptide) (92) and named nociceptin by the dues in the C-terminus, are derived from
other group, since in the initial studies this prodynorphin (also called proenkephalin B;
peptide was reported to produce hyperalgesia see Ref. 269 for a review). In addition to dynor-
(93).Although the N-terminal tetrapeptide se- phins A and B, longer dynorphins (e.g., dynor-
quence of orphanin FQInociceptin (OFQ/N) is phin 32, which contains both dynorphin A and
similar to that of the classical opioid peptides, B) and a- and p-neoendorphins are obtained
the presence of Phe rather than Tyr in posi- from prodynorphin B. The precursor protein
tion 1 is an important factor in the peptide's of the endomorphins has yet to be identified.
high selectivity for ORLl over opioid receptors The OFQ/N precursor protein prepronocicep-
(see Section 7.2). tin (93) has been characterized and also con-
The classical mammalian opioid peptides tains additional biologically active peptides re-
are derived from three distinct precursor pro- lated to OFQ/N, orphanidnociceptin 2 (270)
teins (Fig. 7.10) (see Refs. 75,266 for reviews). and nocistatin (271) (Fig. 7.10).
Processing of the precursor proteins occurs at
pairs of basic residues. p-Endorphin is derived
from proopiomelanocortin (POMC), along 4 HISTORY: IDENTIFICATION OF
with ACTH, a-MSH, and p-lipotropin (see Ref. MORPHINE AND EARLY ANALOGS
267 for a review). The enkephalins are derived
from proenkephalin A (see Ref. 268 for a re- The effects of opium have been known for
view). This protein contains four copies of thousands of years, with written references
Met-enkephalin flanked by pairs of basic resi- dating as far back as the third century B.C.
listory: Identification of Morphine and Early Analogs 359

Proorphanin
Orphanin
a-neoendorphin
Prodynorphin Dynorphin A
I l l I

~ ~ n b r ~ hB' i n
Proenkephalin Peptide F Octapeptide Heptapeptide

POMC
II

Leu enkephalin B-LPH -


1 Met enkephalin
Figure 7.10. Peptide precursors and processing products (taken from Ref. 100).

~rphinewas first isolated from opium in somniferum in 1832. By the mid-1800s the pu-
15 by Sertiirner, who named it after Mor- rified alkaloids morphine and codeine began to
?us,the Greek god of sleep and dreams. The be used in place of crude opium preparations
nethyl ether codeine (2, Fig. 7.1) was subse- for medicinal purposes (23). Because of its
3ntly isolated from the poppy plant Papaver complex structure, it took more than a century

(-)-Morphine(1)
Cavity
H

Flat surface

Binding site
OH Figure 7.11. Beckett and Casy model
for opioid receptor binding (adapted
(+)-Morphine from Ref. 1).
Narcotic Analgesics

after its isolation before the correct structure


of morphine was proposed by Gulland and
Robinson in 1925 (272). It was not until the
early 1950s that the proposed structure was
confirmed by total synthesis by Gates and
Tschudi (273, 274). The relative stereochem-
istry of the five chiral centers was determined
by chemical synthesis (275) and X-ray
crystallography in the early to mid-1950s (55) Heroin
(276).The absolute configuration was subse-
quently proven by a combination of tech-
niques (277-279). Of the 16 possible iso-
mers, one isomer with the absolute
configuration 5R76S,9R,13S,14R,shown in
Fig. 7.11, is the isomer of morphine that is
found in opium.
The earliest model for how morphine and
other analgesics interact with opioid receptors R= H (56) Nalorphine
was proposed by Beckett and Casy (Fig. 7.11)
(1).Based on the SAR of analgesics available,
this model consisted of three sites: an anionic Figure 7.12. Early synthetic analogs of morphine.
binding site, which interacted with the pro-
tonated m i n e on the ligand; a flat surface that
5 STRUCTURE-ACTIVITY RELATIONSHIPS
interacted with the aromatic ring of the anal-
OF NONPEPTIDE OPlOlD LICANDS
gesic; and a cavity to accommodate the piper-
idine ring of the rigid opioid alkaloids. This
5.1 Introduction
model explained the stereospecificity of opioid
receptors; whereas the natural (-)-isomer of In a single chapter such as this it is impossible
morphine fits all three sites, in the unnatural to discuss the SAR of all of the com~ounds -
(+)-isomer the projecting ring would not fit with opioid activity in detail. Two comprehen:
properly into the cavity (Fig. 7.11). sive books on opiates published in 1986 (12,
Synthetic efforts to modifjr the structure of 13) cover much of the early literature, and
morphine began with the synthesis of 3,6-di- there have been more recent reviews of gen-
acetylmorphine (heroin, 55, Fig. 7.12) in the eral opioid SAR [see Refs. 282-285, and the
late 1800s (280). The first narcotic antagonist previous edition of this chapter (286)l. De-
N-allylnorcodeine (57) was prepared in 1915 tailed reviews on ligands targeting specific re-
(281). The subsequent demonstration of the ceptors, namely, reviews on &receptor ligands
antagonist activity of N-allylnormorphine (219, 220), K-receptor ligands (287, 288), and
(nalorphine, 56) in the 1940s stimulated the on selective antagonists for each receptor type
examination of other N-substituted morphine (289), have also recently been published. This
analogs for antagonist activity. The explora- chapter highlights key structure-activity rela-
tion of the SAR of morphine and its antagonist tionships from the earlier literature related to
derivatives was actively pursued during the important compounds used as clinical agents
1950s and 1960s, along with related synthetic or pharmacological tools, and concentrates on
morphinan and benzomorphan analogs. It was more detailed discussion of recent develov-
the differences observed in the patterns of ments in the field. Readers are referred to the
pharmacological activity for different com- above-mentioned reviews for a more detailed
pounds that resulted in the proposal of multi- discussion of opioid SAR and for additional
ple opioid receptors in the 1960s and their references to the journal and patent litera-
subsequent classification by Martin and co- ture.
workers in the mid-1970s (5, 6) (see Section Compounds with opioid activity are struc-
3.2.1). turally diverse, ranging from rigid multicyclic
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

-
Rigid opiates

H3C
I

OH OH OH

TTH3'\
Morphine Morphinans Benzomorphans

H~C/
N
%
Flexible opiates

N /- ~C'
H H3c\N$

H3C /
'\
0
CH3

\ \
Axial Equatorial
phenylpiperidines phenylpiperidines Methadone

Figure 7.13. Systematic dismantling of morphine (adapted from Ref. 290).

compounds such as morphine to flexible acy- Opium contains over 50 alkaloids that fall into
clic analgesics such as methadone and the opi- one of two chemical classes: the phenanthrene
oid peptides. The majority of the classical non- class, including morphine and related deriva-
peptide opioids fall into one of five chemical tives; and the benzylisoquinoline alkaloids,
classes: the 4,5a-epoxymorphinans, the mor- such as papaverine (58,Fig. 7.14; see Ref. 291
phinans, the benzomorphans, phenylpiperi- for a complete listing of alkaloids present in
dine derivatives, and acyclic analgesics. Al- opium). In addition to morphine, which on av-
though not related in many cases to how the erage accounts for 10-20% of opium, other re-
opioid activity of these different chemical
classes was originally identified nor to how
these compounds are prepared, these different
chemical classes can be related conceptually
by a systematic dismantling of morphine (Fig.
7.13). As rings present in morphine are elimi-
nated, conformational flexibility increases and
changes in SAR occur. The effects on confor-
mation and SAR are discussed for each of -0CH3
these chemical classes in turn below, followed (58) Papaverine
by descriptions of agonists selective for K and S
receptors and of affinity labels, which interact
with opioid receptors in a nonequilibrium
manner.

5.2 4,5cu-Epoxymorphinans: Morphine


and Derivatives
(59) Thebaine
5.2.1 Morphine and Alkaloids from Opium.
Morphine (1) is the principal alkaloid in Figure 7.14. Alkaloids found in opium. The struc-
opium, which is derived from the seed capsules tures of morphine(1)and codeine (2)are shown in
of the poppy plant Papaver somniferum. Fig. 7.1.
Narcotic Analgesics

Figure 7.15. Structure of morphine.

lated alkaloids to morphine found in opium 5.2.2 Morphine Derivatives. The synthesis
include codeine (2) (0.5%) and thebaine (59) of 3,6-diacetylmorphine (heroin, 55) in the
(0.3%).Whereas the latter is inactive as an late 1800s (280) marked the beginning of syn-
analgesic, it is a key synthetic intermediate for thetic efforts to modify the structure of mor-
the preparation of several potent analgesics phine, and since then numerous structural
(see Section 5.4 below); although present in modifications have been made to morphine
low amounts in P. sornniferum, it is the prin- (see Refs. 299, 300 for detailed reviews). Al-
cipal alkaloid found in another species of though modifications have been made to all
poppy, Papaver bracteaturn (292). portions of the molecule, the focus has been in
One interesting finding has been the detec- three regions: the phenol at position 3, the C
tion of morphine and related opiate alkaloids ring, and the basic nitrogen. The phenol, al-
in vertebrates, including in a variety of mam- though not critical for activity, enhances opi-
malian tissues (see Refs. 58, 293-295 for re- oid receptor affinity (301).Masking of the phe-
views; see also Ref. 296 for a review of isolation nolic hydroxyl group generally decreases
techniaues). The conversion of codeine and opioid activity. Methylation of the 3-phenol of
thebaine, which are known intermediates in morphine gives codeine (2, Fig. 7.1), which has
the biosynthetic pathway in P. somniferum, to approximately 10-20% the potency of mor-
morphine in several tissues from rat supports phine. As noted in Section 2.3.2, a small but
-
the conclusion that the momhine found in an- significant percentage (-10%)of codeine is 0-.
imals is of endogenous origin. Endogenous demethylated to morphine, accounting for its
morphine has been postulated to be involved analgesic activity. Heroin, on the other hand,
in neural and immune regulation (see Ref. is approximately twice as potent as morphine.
295), but the levels detected in mammalian Heroin penetrates the blood-brain barrier
tissues are low [low pmol/g (295)l compared to very rapidly [68% uptake of heroin versus un-
those of the endogenous opioid peptide levels measurable uptake of morphine 15 s after ca-
(2971, so what physiological roles such endog- rotid injection into rats (302)], and this may
enous opiate alkaloids play are still unclear. partially account for its greater potency. Her-
The conformation of morphine was deter- oin is rapidly deacetylated to give 6-acetylmor-
mined from X-ray studies (see Ref. 298 for a phine, which has potency similar to that of
review). The overall shape of the molecule is a morphine. As discussed in Section 2.3.2, the
three-dimensional "T," with rings A, B, and E 6-glucuronide metabolite of morphine (12) is
forming the vertical portion of the "T" and about twice as potent as morphine (58) and
rings C and D forming the top of the "T"(Fig. may account for a significant portion of mor-
7.15). The piperdine (D) ring is in the energet- phine's analgesic activity, especially with
ically favored chair conformation, but the C chronic use (59).
ring of morphine is in a boat conformation, Much of the early synthetic efforts focused
which places the 6a-hydroxylin the equatorial on modifications of the C ring. Changing the
position (see Ref. 298). (+)-Morphine, the en- B-C ring juncture in morphine or codeine from
antiomer of the naturally occurring (-)-mor- cis to trans decreases potency 2- to 10-fold
phine, has been synthesized (see Refs. 283, (303). This is understandable because such a
299) and is devoid of analgesic activity. change causes severe distortion in the C ring
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

R= H (60) Dihydromorphine (5) Hydromorphone (63) Oxymorphone


R = CH3 (61) Dihydrocodeine (62) Hydrocodone (6) Oxycodone

(64) Nalmefene (65) TRK-820

OyFOH
OH
(66) Nalbuphine

Figure 7.16. C-ring derivatives of morphine. Structures of hydromorphone (5) and oxycodone (6)
from Fig. 7.1 are included for comparison. Nalmefene (64) is an antagonist, TRK-820 (65) is a
K-selectiveagonist, and nalbuphine (66) is a mixed agonist/antagonist.

of trans-morphine. Reduction of the C,-C, ring is in the chair conformation (see Fig. 7.16
double bond of morphine and codeine yields and Ref. 298). Numerous additional modifica-
dihydromorphine (60, Fig. 7.16) and dihydro- tions have been made to the 6 position of 4,5a-
codeine (61), respectively, which have similar epoxymorphinans (see Refs. 299, 300). These
to slightly increased (15-20%) potencies com- include analogs that can bind irreversibly to
pared to those of their parent compounds. Ox- opioid receptors and selective antagonists in
idation of the C, hydroxyl in morphine de- which additional rings are attached at the 6
creases analgesic potency, but when this same and 7 positions; these types of opiates are dis-
modification is made to dihydromorphine or cussed in Sections 5.11 and 5.3, respectively,
dihydrocodeine to give hydromorphone ( 5 ) later in the chapter. Zwitterionic groups have
and hydrocodone (62), respectively, opioid po- also been attached at the 6 position to produce
tency is enhanced. This modification also al- peripherally selective derivatives with de-
ters the conformation of the C ring of the opi- creased ability to penetrate the CNS (304). A
ate (see Fig. 7.16). Although the C ring of 14p-hydroxylgroup can be introduced into the
morphine and other derivatives containing a opiate skeleton by oxidation of thebaine (see
6a-alcohol (60 and 61) is in a boat conforma- Refs. 299, 300) and this modification can en-
tion, in oxymorphone (63)and the antagonist hance potency. The 14P-hydroxylatedderiva-
derivative naloxone (16) (see below), the C tives oxyrnorphone (63)and oxycodone (6) are
Narcotic Analgesics

potent analgesics, with oxymorphone exhibit- The N-ally1 derivative of oxymorphone, nalox-
ing approximately 5-10 times the potency of one (16, Fig. 7.4), was the first example of a
morphine. The analgesic activities of these pure opioid antagonist essentially devoid of
morphine derivatives, along with a variety of agonist activity, and is 7-10 times as potent an
other opioids, are compared in Table 7.1 in antagonist as nalorphine (see Ref. 305). Nal-
Section 2.1 above. oxone has a short duration of action and is
used for the treatment of narcotic overdoses
5.3 N-Substituted 4,5a-Epoxymorphinans: (see Section 2.1). Although naloxone exhibits
Opioid Antagonists some preference for p receptors, it also antag-
onizes Sand K receptors as well (see Table 7.8),
5.3.1 introduction. A critical determinant and sensitivity to antagonism by naloxone is
of the type of activity observed for morphine routinely used as a criterion for opioid recep-
derivatives is the identity of the nitrogen sub- tor involvement in an observed response. The
stituent, and variation in this group yields N-CPM derivative naltrexone (17) is a pure
compounds ranging in activity from pure ago- antagonist that is more potent than naloxone,
nists to pure antagonists. Removal of the N- has a longer duration of action, and is orally
methyl of morphine to give normorphine de- active, making it more useful for the treat-
creases potency (the relative potency of ment of former opiate addicts. The two antag-
normorphine, however, is dependent on both onists have different metabolic routes, which
the route of administration and the species accounts for the differences in duration of ac-
examined; see Ref. 305). Although some nitro- tion and doses required (see Section 2.3.2 and
gen substituents such as phenethyl enhance Ref. 305). The 6-methylene analog of naltrex-
agonist activity, other nitrogen substituents, one, nalmefene (64), is also used clinically as
notably propyl, allyl, cyclopropylmethyl (CPM), an antagonist (see Table 7.4) to reverse the
and cyclobutylmethyl (CBM), impart antago- effect of opioids and has a longer duration of
nist activity to the compounds. The replace- action than naltrexone (24). Interestingly, at
ment of the N-methyl group of morphine and cloned p opioid receptors nalmefene is an in-
codeine by an allyl group yields N-allylnor- verse agonist, whereas naloxone and naltrex-
morphine (nalorphine, 56), and N-allylnorco- one are neutral antagonists
- (the latter two
deine (57, Fig. 7.12), respectively. Although compounds display inverse agonist activity4f
the first narcotic antagonist N-allylnorcodeine the cells were pretreated with morphine)
was prepared in 1915 (2811, it was the demon- (308). The 6p-fluoro analog of naltrexone, cyclo-
stration of the antagonist activity of nalor- foxy, has been prepared in tritiated form (309).
phine in the 1940s that stimulated the exam- Recently, the 6P-substituted naltrexamine
ination of other N-substituted morphine derivative TRK-820 (65) was reported to be a
analogs for antagonist activity (see Ref. 305). K-selective agonist [Ki = 3.5 nM, Ki(dp)ratio
Nalorphine is inactive as an analgesic in ani- = 15; see Table 7.10 below], which acts as a
mals, but it is an effective analgesic in humans full agonist at K receptors, partial agonist at p
(306). Although it was thought that mixed ag- receptors, and a weak antagonist at ORLl re-
onist/antagonists such as nalorphine were ceptors (see Section 7.2 below) (310,311). The
agonists at K receptors and antagonists at p N-CBM analog of naltrexone is a mixed ago-
receptors, these drugs may be more accurately nistlantagonist, and the 6a-alcohol derivative,
described as partial agonists at both K and p nalbuphine (661, is used clinically (see Table
receptors (see Ref. 307). Nalorphine produces 7.3). Examination of diastereomeric pairs of
intense psychotomimetic effects and dyspho- nalorphine and naloxone quaternary ammo-
ria, which precluded its clinical use as an an- nium salts (which have chiral nitrogens)
algesic. However, it was used as an antidote found that the diastereomers with the N-ally1
for opioid overdose until the introduction of group equatorial were the more potent antag-
naloxone in the late 1960s. onists (312, 313).
Modification of the N-substituent of the po- The quaternary derivatives of several nar-
tent morphine analog oxymorphone has led to cotic antagonists have been used to explore
several compounds with antagonist activity. the central versus peripheral actions of opi-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 365

oids. These compounds generally have much tained from triethylene glycol (322,323). Both
lower affinity for opioid receptors and antago- the monovalent analog with a single pharma-
nist potency (1-12%) relative to that of the cophore and an analog with a longer spacer
corresponding tertiary antagonists (314), and were much less potent K antagonists, suggest-
in some cases (e.g., N-methylnaloxone) the ing that TENA contained the appropriate
quaternary antagonist or an active metabolite spacer length for K-receptor affinity and selec-
appears to enter the CNS after peripheral ad- tivity. Subsequently, glycyl units were used in
ministration (see Ref. 314). The peripheral se- the spacer, making it possible to easily vary the
lectivity of the quaternary antagonist meth- chain length of the spacer; a central succinyl (X
ylnaltrexone (315) appears to be greater than = -Glyn-COCH,CH,CO-Glyn- in 67) (324)or fu-
that of N-methylnaloxone or N-methylnalor- maryl group (-Glyn- COCH4HCO-Glyn- in
phine (316), most likely because of the higher 67) (325) were used in the spacer. Although
resistance of methylnaltrexone to N-demeth- the optimum length of the spacer for interac-
ylation (317). The extent of this metabolic tion with p receptors was similar in the two
pathway varies among species; in humans no series (two glycyl units, i.e., n = 2, in each half
appreciable N-demethylation has been ob- of the spacer), the optimum length of the
served, which probably has a significant im- spacer for interaction with K receptors was dif-
pact on the peripheral selectivity of this drug. ferent in the two series (325). In the series
Methylnaltrexone is currently being exam- with the succinyl spacer, the shortest spacer
ined in clinical trials for the treatment of opi- (with no glycyl units, i.e., n = 0) yielded the
oid-induced constipation (see Section 2.2.2.1). most potent K antagonist, whereas in the se-
Although the above agents have been use- ries with the more rigid fumaryl spacer a
ful pharmacological tools as well as therapeu- much longer spacer (two glycyl units, n = 2, in
tic agents, these compounds preferentially an- each half) was required for maximal K-antag-
tagonize p opioid receptors. Antagonists onist activitv.
"
selective for all three opioid receptor types are Incorporation of a rigid pyrrole spacer led
valuable tools in understanding both the phar- to the synthesis of the K-selective antagonists
macological effects of opioid agonists and the norbinaltorphimine (norBNI, 39, Fig. 7.6) and
physiological effects of the endogonous opioid binaltorphimine (40) (119, 120). These com-
peptides. In the past decade Portoghese and pounds were much more selective for antago-
coworkers have synthesized numerous nal- nism of K receptors than TENA (1201, and
trexone derivatives with additional groups norBNI has been routinely used to determine
and ring systems attached to the C ring. De- whether K opioid receptors are involved in an
pending on the modifications made, analogs observed activity. A more detailed under-
selective for both K and S receptors have been standing of how these compounds interact with
prepared (see Refs. 289,318-321 for reviews). opioid receptors has come from examining their
structure-activity relationships and molecular
5.3.2 Kappa-Receptor Selective Antagonists. modeling. The monovalent ligand with only the
Portoghese and coworkers used the bivalent pyrrole ring attached (73) is not selective for K
ligand approach to design K-selective ligands. receptors, suggesting that the pyrrole ring func-
In this design strategy it was envisioned that
two pharmacophores could bridge two neigh-
boring opioid recognition sites if they were
connected by an appropriate spacer. This
should then lead to substantial increases in
potency because of the close proximity of the
second pharmacophore to the neighboring site
and hence a large increase in the local concen-
tration of the pharmacophore (see Ref. 319).
The first K-selective antagonist TENA (68,
Fig. 7.17) was prepared by connecting two nal-
trexamine pharmacophores with a spacer ob-
Narcotic Analgesics

N-X-N
H H
OH OH
(67)
(68) X = -(CH2CH20)2CH2CH2-
(TENA)

Figure 7.17. K-Receptor selective antagonists and related compounds. The structures of norBNI
(39), binaltorphimine (401, and GNTI (41) are shown in Fig. 7.6.

tions as a spacer and does not contribute to K one pharmacophore is required for interaction
selectivity (326).This conclusion is supported by with K receptors (328).This suggested that the
comparison of different spacers; whereas the second half of the bivalent ligand might be
thiophene analog of norBNI in which a sulfur mimicking the basic C-terminal "address" se-
replaces the indole nitrogen, which has a very quence of dynorphin, which imparts K-recep-
similar structure, retains K-receptor selectivity, tor affinity to the peptide, and that simpler
a pyran derivative with a very different spacer derivatives could be used in place of the second
loses K selectivity (327). pharmacophore. A simplified analog of norBNI
While the K antagonists described earlier that does not contain the second aromatic ring
were designed using the bivalent ligand ap- (70)is twice as selective as norBNI for K recep-
proach, subsequent studies revealed that tors (329).The basicity of the second nitrogen
these ligands do not appear to bridge two opi- is important for K-receptor selectivity in both
oid binding sites, but that a basic amino group norBNI analogs (330) and the simplified ana-
in the second pharmacophore interacts with a log (70) (329). Examination of the binding of
subsite on the K opioid receptor. Thus the norBNI to mutated K receptors (175)suggests
meso isomer of norBNI (69) . . was also found to that this nitrogen interacts with G ~ at the u ~ ~
be a potent K antagonist, indicating that only top of TM6 on the receptor; a significant (70-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 367

fold) increase in affinity for the preceptor mu- to the synthesis of naltrindole (NTI, 32, Fig.
tated at the corresponding position ([K303E]) 7.5) (113,338),the first nonpeptide 8-selective
(331) is consistent with this conclusion. A antagonist. In addition to being 8 selective,
computational model of norBNI bound to K this naltrexone analog is about 500 times as
receptors has been developed ( N O ) , and in this potent as the 8-selective peptide antagonist
model the second nitrogen forms an ion pair ICI 174,864 (29, Fig. 7.5) (338). In a computa-
with G ~ u ~With
' ~ . the recent proposal that opi- tional model of NTI bound to 8 opioid recep-
oid receptors may exist as dimers (see Section tors ( N O ) , the indole moiety is directed toward
7.1 below), however, Portoghese is revisiting a hydrophobic pocket formed by residues from
these bivalent ligands and how they may in- TM6 and TM7, which includes zg9
two residues
teract with dimeric receptors (321). (TrpZs4 in TM6 and Leu in TM7 of the
These results led to the preparation of an- mouse 6 receptor) unique to the 8opioid recep-
alogs of the 8-selective antagonist naltrindole tor. Site-directed mutagenesis studies of these
(see below) with basic alkylamidino groups positions in 8, p, and K receptors were consis-
(71) (122, 332, 333) and guanidinium groups tent with these positions contributing to the
(GNTI, 41) (121-123) attached to the indole &receptor affinity and selectivity of NTI (334).
ring as K-selective antagonists. Like norBNI, Substitution of Ala in the position correspond-
the decrease in binding affinity of GNTI to ing to Leu2" in p and K receptors increased
[E297K] mutated K receptors and increase in the affinity for NTI by 21- and 96-fold, respec-
afinity for the corresponding [K303El mu- tively (334). Substitution of Trp284in the 8
tated p receptors and the [W284E] mutated 8 receptor had a smaller effect, with mutation to
receptors suggests that the guanidinium Glu (334) and Lys (166) (the residues found in
group of GNTI interacts with G ~ on uK opi-~ ~the corresponding
~ position in K and p recep-
oid receptors (121, 334). Interestingly, shift- tors, respectively) decreasing the affinity of
ing the position of the guanidinium group NTI 9- and 1Bfold [mutation to Ala decreased
from the 5' position in GNTI to the 6' position NTI affinity fivefold (16611.
(72) results in a potent K agonist (335). Fluorescent derivatives of naltrindole have
been prepared. The fluorescent analog in
5.3.3 Delta-Receptor Selective Antagonists which fluorescein was attached through a tet-
and Related Compounds. Portoghese and co- raglycine spacer to 7'-amino-NTI has been
workers used the "message-address" concept prepared (339); its fluorescence is blocked by
to design naltrexone derivatives selective for 6 NTI, indicating specific binding to 8 receptors.
receptors (see Ref. 336). The "message-ad- Recently, a fluorogenic "reporter affinity la-
dress" concept, which was originally described bel" derivative of naltrindole, PNTI, was pre-
by Schwyzer for ACTH (337), was applied to pared from 7'-amino-NTI that, in contrast to
the opioid peptide dynorphin by Chavkin and its reversible counterpart, is an agonist in the
Goldstein (263). In this model the "message" MVD (340) (see Section 5.11 below).
consists of the amino acids in the peptide that Naltrindole analogs containing other het-
are responsible for activating the receptor and erocyclic spacers have also been examined.
producing a biological response, whereas the The benzofuran analog naltriben (NTB, 46,
"address" component is the portion of the mol- Fig. 7.8) is also a 8-selective antagonist (195);
ecule that enhances affinity for a given recep- as discussed earlier in Section 3.2.4.3, subse-
tor type. Portoghese postulated that in the en- quent studies indicated that this analog is a
dogenous enkephalins the Tyrl residue selective 8, antagonist (341, 342).
functions as the "message" and the phenyl The aromatic ring in the "address" portion
ring of Phe4 functions as part of both the of naltrindole and its analogs is important for
"message" and the "address"; the intervening antagonist activity at 8 receptors. The tetra-
Gly2-Gly3 then functions as a spacer. In nal- hydroindole derivate is much less potent, as
trexone analogs, the naltrexamine moiety of are several 6-aryl derivatives (195). The 7(E)-
these antagonists functioned as the <<mes- benzylidine analog of naltrexone, 7-benzyli-
sage" portion and a phenyl ring was attached denenaltrexone (BNTX, 44, Fig. 7.81, how-
to the pyrrole spacer as the "address." This led ever, is a potent 8 antagonist (193,342). It has
Narcotic Analgesics

100-fold greater affinity for [3H]DPDPEsites ceptor affinity, in several cases [e.g., the N-2-
(6,) than for DSLET (6,) sites, and therefore is methylallyl naltrindole analog (351)], the
a selective 6, antagonist (193); it is also a se- 3-methyl ether of naltrindole (352), and the
lective antagonist for 6, receptors in the corresponding ring-opened 4-hydroxy-3-me-
mouse spinal cord in antinociceptive assays thoxyindolemorphinan (353), the selectivity
(342). Substitution on the phenyl ring of for 6 receptors increased. Replacement of the
BNTX with either o-methoxy or o-chloro re- cyclopropylmethyl (CPM) group by the
sulted in analogs with increased antagonist 2-methylallyl in NTB and SoRI 9409 (see be-
potency and 6-receptor selectivity in smooth low), but not BNTX or SIOM (see below), re-
muscle assays, but in vivo in the tail flick assay sulted in compounds that retained reasonable
these analogs exhibited similar selectivity but 6-receptor affinity and selectivity (354). The
lower potency than BNTX (343). Both the E- 14-alkoxy derivatives, with or without a
and corresponding 2-isomers of a series of aryl 5-methyl group, also exhibited high 6-receptor
analogs of BNTX have been prepared (344), selectivity in the MVD assay (355,356). Inter-
and the 2-isomers were found to have higher estingly, the N-cyclohexylethyl derivative (76)
6-receptor selectivity; the (2)-1-naphthyl de- derivative is a p-selective agonist (357). Addi-
rivative exhibited the highest 6-receptor affin- tional analogs of naltrindole have been re-
ity (Ki = 0.7 versus 6.2 nit4 for BNTX) and ported in the patent literature (see Refs. 219,
selectivity for 6 over p receptors. 220 for reviews).
-
The relative ~osition of the "address" aro- Fragmentation of the indolomorphinan
matic ring in these analogs is important. structure of NTI by removal of the 4,5a-epoxy
Those analogs with the phenyl ring in the and 10-methylene groups resulted in a series
same region of space as the phenyl ring of the of octahydroisoquinolines (see Refs. 219,358).
indole in NTI are active as 6 antagonists (345); The compounds that are the analogs of NTI
a large decrease in activity was observed for with a five-membered ring spacer [SB
indole regioisomers of NTI that have the aro- 205588B (78) and SB 206848 (79, Fig. 7.18)
matic ring in a different relative position are 6-receptor antagonists, whereas com-
(346). Attachment of the phenyl ring directly pounds with a six-membered ring as the
to the 7 position of the morphinan system re- spacer are 6 agonists (see Section 5.10.2 be-
sulted in analogs with decreased 6 receptor low). Interestingly, the related compound (84)
potency and selectivity (347). peripherally se-
lective naltrindole analogs were prepared by
conjugating amino acids to 7'-carboxynaltrin-
dole (74, Fig. 7.18); these derivatives are S-se-
lective antagonists in smooth muscle assays
and 6,-selective antagonists in vivo (348).
Benzylation of the indole nitrogen of NTI, by
contrast, results in a selective and long-lasting
6, antagonist (75) (349). Attachment of fluo-
resceinearnine through a thiourea linkage to
the para position of the benzyl ring of N-ben-
zylnaltindole resulted in an analog with po-
tent antagonist activity in vitro. The inability
to block the fluorescence by several &selective
ligands, including NTI, however, suggested
that the fluorescent analog exhibits high non-
specific binding, possibly because of the high without the pyrrole ring spacer and the cis
lipophilicity of the fluorophore (350). configuration of the ring juncture is an antag-
A number of other naltrindole analogs have onist at p and K receptors (359).
been synthesized, including numerous ones by As discussed earlier in Section 3.3.1, 6-re-
Rice and coworkers. Although most of the ceptor antagonists can decrease the develop-
modifications examined decreased 6 opioid re- ment of tolerance and dependence to mor-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

(74) R = Gly, Asp, etc. R = CPM, R' = CH2Ph (75) N-Benzylnaltrindole


n
,q= -
R'=H CH~CH~Q (76)
R=CH3, R'=H (77) Oxymorphindole

R = CPM (79) SB 206848


-

''a
R = CH3 (81) SlOM
R = CPM (82) SlNTX

Figure 7.18. Delta receptor antagonists and agonists related to naltrindole (32).Other &selective
ligands, including naltrindole, are shown in Figs. 7.5 and 7.8.

phine, and therefore there is considerable tached to a pyridine rather than to an indole
interest in the development of compounds ex- ring (230), is a 8-receptor antagonist, but un-
hibiting both 8 antagonist activity and p ago- expectedly also exhibits p opioid agonist activ-
nist activity. Recently, Rice and coworkers ity in the GPI assay (230); interestingly, the
identified naltrindole analogs with p agonist corresponding derivative without the chlorine
activity as well as &receptor antagonist activ- is a preceptor antagonist. Further examina-
ity (230, 360). The 7'-phenoxy naltrindole de- tion of SoRI 9409 in nociceptive assays indi-
rivative exhibits weak (IC,, = 450 nM) ago- cated that the compound is a weak partial ag-
nist activity in the GPI, while retaining potent onist in the high intensity (55°C)tail flick test
6-receptor antagonist activity (K,= 0.25 nM) and weak full agonist in the acetic acid writh-
in the MVD (360). The naltrindole analog ing assay (230,361); studies in vivo were also
SoRI 9409 (SO), bearing a phenyl ring at- consistent with activity as a mixed partial p
Narcotic Analgesics

agonist16 antagonist. In contrast to morphine, zospiroindanyl derivative of SINTX exhibits


repeated doses of SoRI 9409 did not produce improved selectivity for 6 over p receptors, al-
tolerance (230, 3611, and SoRI 9409 sup- though lower potency in vitro compared to
pressed withdrawal signs when coadminis- SINTX and is a 6, antagonist in uivo (366).
tered with naloxone to morphine-dependent The 1Chydroxyl group contributes to both 6
animals. In [35S]GTPyS assays, however, agonist and antagonist activity, and its re-
SoRI 9409 exhibits no p-agonist activity and moval from SIOM and NTI decreases agonist
instead acts as an antagonist at p and K as well and antagonist potency, respectively (367).
as at 6 receptors; at this time the reason for The 7-spirobenzocyclohexyl derivatives of
this difference between the in vitro and in vivo SIOM are also potent 6 agonists, but the cor-
results is not clear. responding analogs of SINTX (83, both a and
Attempts have also been made to prepare p isomers) are p-selective antagonists (368).
agonist analogs of NTI by modification of the
5.4 Diels-Alder Adducts
basic nitrogen. The N-methyl analog oxyrnor-
phindole (OMI, 77, Fig. 7.18) is a partial ago- Thebaine (59), which is present in large
nist (IC,, = 100 nM) (338), whereas the un- amounts from the species of poppy Papaver
substituted and the N-phenethyl derivatives bracteaturn (292), serves as the precursor for
are full agonists (IC,, = 85-180 nM) in the the 6,14-endoetheno opiates. Although the
MVD (362). These derivatives either did not natural levorotatory isomer of thebaine is in-
exhibit any S antagonist activity or were only active as an analgesic, it was recently reported
weak 6 antagonists in this smooth muscle that the (+) isomer exhibits significant an-
preparation. In vivo, these analogs, along with tinociceptive activity (369); both isomers ex-
naltrindole, exhibit antinociceptive activity hibit some affinity for opioid receptors [the
(362, 363). On the basis of antagonism by se- (+) isomer for p receptors and the (-) isomer
lective antagonists, the antinociceptive activ- for 6 receptors], but the affinities were very
ity of all of the compounds except the unsub- low (piw.
stituted derivative appears to be mediated by K The Diels-Alder reaction of thebaine with
rather than 6 receptors (the unsubstituted de- various electrophiles yields compounds (Fig.
rivative was not antagonized by any of the se- 7.19) that have extremely high potencies,
lective antagonists). At lower doses these com- over 1000-fold higher than morphine in
pounds also exhibit antagonism at S receptors some cases (see Refs. 370, 371). X-ray (372)
in vivo. Modification of the indole structure of and NMR (373) analysis of 19-propylthevinol,
OM1 to change the orientation of the phenyl the 3-methyl ether of etorphine (42 above),
ring yields the 7-spiroindane derivative, 7-spi- indicates that the 6,lCetheno bridge is held
roindanyloxymorphone (SIOM, 81),which is a "inside" (endo) the tetrahydrothebaine ring
6, agonist (364). Portoghese et al. suggested system and below the plane (a) of the C,-C8
that the phenyl ring of the indane ring system bond (see Fig. 7.19 and Ref. 283); the C ring is
adopts a conformation similar to that of the held in a boat conformation by the 6,14-endo-
phenyl ring of Phe4 of the &selective enkepha- etheno bridge.
lin analog DPDPE (24). [Linking the C-termi- The C, substituent in these compounds is
nal sequence Phe-LeuOMe of leucine en- in the a configuration and in many cases con-
kephalin to oxymorphanone (but not to tains a chiral center. The stereochemistry at
naltrexone) Also significantly increases affin- C,, can have significant effect on potency of
ity for 6 receptors (365).1Like NTI, the results the derivatives (see Ref. 283); generally, the
of site-directed mutagenesis of positions zg9cor- diastereomer with the R configuration at C,,
responding to Trp284(in TM6) and Leu (in is the more potent isomer, with the differences
TM7) of the 6 receptor in 6, p and K receptors in potencies of the diastereomers sometimes
were consistent with these positions being in- exceeding 100-fold.
volved in the 6-receptor affinity and selectivity A variety of Clg alcohol derivatives have
of SIOM (334). Replacing the N-methyl group been prepared (see Refs. 370,3711, and three
of SIOM with a CPM group gives SINTX (82) of these compounds are frequently used in opi-
which is a potent 6 antagonist (345). The ben- oid research. Etorphine (42) is a potent anal-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

0CH3
(59) Thebaine endoetheno
derivatives

P
0'
. Figure 7.19. Diels-Alder reaction to
give 6,14-endoetheno derivatives of
thebaine (59)and the structures of bu-
R = CH3 (43) Diprenorphine (86) BU48 prenorphine (85) and BU48 (86). The
structure of diprenorphine (43) is in-
R = C(CH3)3 (85) Buprenorphine cluded for comparison.

gesic, over 1000-fold more potent than mor- unique pharmacological profile offers several
phine, which has been widely used to clinical advantages; it causes less severe respi-
immobilize animals, including large game an- ratory depression than full agonists and has
imals. It exhibits high affinity for all three opi- less abuse potential. It can suppress witli-
oid receptor types (see Table 7.8), and there- drawal symptoms in addicted individuals un-
fore f3H1etorphine has been used as a dergoing withdrawal from opiates and thus
universal tritiated ligand for opioid receptors has been used in the maintenance of these pa-
(see Section 3.2.3.2). The N-cyclopropyl- tients. Because of its partial agonist activity,
methyl 6,14-ethano derivatives diprenorphine however, it can also precipiate withdrawal
(43) and buprenorphine (85, Fig. 7.19), which symptoms in those addicted to opiates. The
differ only in the identity of one of the alkyl 18,19-dehydro derivative of buprenorphine
groups attached to C,, (see Refs. 374, 375 for HS-599 exhibits higher affinity, selectivity,
structural studies of these compounds), ex- and potency at p receptors than does the par-
hibit antagonist and partial agonist activities, ent compound (377). A series of buprenor-
respectively. Diprenorphine also has high af- phine analogs were prepared in which C,, was
finity for all three opioid receptor types and its constrained in a five-membered ring to assess
tritiated form has been used as a universal the influence of the orientation of the C,, hy-
tritiated ligand for opioid receptors (see Sec- droxyl on activity; although the configuration
tion 3.2.3.2); it antagonizes p, 6, and K ligands of this hydroxyl did not affect the binding af-
in the MVD (see Table 7.8). Buprenorphine, finity, it did influence K-receptorefficacy and
which is used clinically, is a potent partial ag- potency (378). One of these novel ring-con-
onist at preceptors with antagonist (or partial strained analogs BU48 (86) exhibits an un-
agonist) activity at K receptors (376).This very usual pattern of pharmacological activity, pro-
lipophilic agent dissociates slowly from opioid ducing 6 opioid receptor-mediated convulsions
receptors, and its complex pharmacology is but not S receptor-mediated antinociception
not completely understood (see Ref. 307). Its (238).
Narcotic Analgesics

R = CH3 (87) Levorphanol R= H (89) Dextrorphan


R = CPM (88) Cyclorphan R = CH3 (90) Dextromethorphan

Figure 7.20. Morphinan derivatives. (91) Butorphanol

5.5 Morphinans Substitution on the nitrogen of morphi-


Morphinans differ in structure from morphine nans has similar effects on activity as found in
and other 4,5a-epoxymorphinans in that they derivatives of morphine (see Ref. 383). Thus
lack the 4,5a-ether bridge. Although the 4,5a- replacement of the N-methyl with groups such
epoxymorphinans are typically prepared from as an ally1or CPM group to yield levallorphan
naturally occurring alkaloids, the morphinans and cyclorphan (88),respectively, imparts an-
are generally made from racemic materials tagonist activity at p receptors. As indicated
and therefore must be resolved to obtain indi- earlier for nalorphine, these compounds were
vidual isomers. Racemorphan (379) was one of thought to be mixed agonists/antagonists with
-
the first momhinans studied. After resolution agonist activity at K receptors, but may be
the analgesic activity was found exclusively in more accurately described as partial agonists
the levo isomer, levorphanol (87, Fig. 7.20) at both K and p receptors (see Ref. 307). Neu-
(3801, which has a configuration identical to meyer and coworkers recently described the
that of momhine and is about 4-5 times as
A
receptor binding affinities of a series of N-sub-
potent, whereas the dextro isomer, dextror- stituted morphinans as potential therapeutics
phan (89), has negligable opioid activity. for cocaine abuse (384,385). A comparison of
Levorphanol and dextrorphan were used in cyclorphan with its cyclobutylmethyl analog
one of the first attempts by Goldstein to dem- in vivo illustrates the effect small changes in
onstrate stereospecific binding to opioid recep- the N-substituent can have on the activity
tors (381). Dextrorphan, and particularly its in this class of compounds. Interestingly,
3-methyl ether dextromethorphan (go), has cyclorphan (88) produced antinociception
significant antitussive activity. In derivatives through ti as well as K receptors and was a
with an unsubstituted 6 position such as dex- preceptor antagonist; although the N-cy-
tromethorphan the C ring exists in the chair clobutylmethyl derivative was also a K ago-
conformation (382). In contrast to the mor- nist in antinociceptive assays, it was an ag-
phine derivatives, the morphinans with a onist at p receptors but was without effect,
trans B-C ring juncture are potent analgesics either agonist or antagonist, a t ti receptors
(see Ref. 283). (384).
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

R/
3 7 / 6 1,
N $
Q
,: R
/ /

#
\
2'
'0 \ 8
Figure 7.21. Numbering systems for benzo-
3' 9 morphans based on benzomorphan and benzazo-
cine nomenclature (used in Chemical Abstracts).
(92) Benzazocine numbering The more common benzomorphan numbering is
6,7-Benzomorphan numbering (Chemical Abstracts) used in this chapter.

As is the case for morphine derivatives, 14- carbons as that of morphine (i.e., 1R,5R; see
hydroxylation yields potent analogs. The N- Refs. 283, 388), although in some cases the
cyclobutylmethyl derivative with a 14P-hy- dextro isomers retain weak activity.
droxyl group, butorphanol (91) is one of the The majority of the benzomorphan deriva-
mixed agonists/antagonists used clinically in tives were prepared before the classification of
the United States (Table 7.3); in addition to a multiple opioid receptors and were character-
parental formulation, a nasal spray formula- ized by the use of in vivo assays. In the classi-
tion of this drug was introduced in 1992. Be- fication of multiple opioid receptors Martin
cause 4,14-dimethoxy-N-methylmorphinan-6- and coworkers (5, 6) used the benzomorphan
one proved to be a very potent agonist, ketocyclazocine (13,Fig. 7.3) as the prototyp-
Schmidhammer et al. prepared the corre- ical ligand to define K receptors (see Section
sponding N-CPM derivative cyprodime (18, 3.2.1 above), and subsequent characterization
Fig. 7.4) (104). Cyprodime is a pure preceptor indicated that a variety of benzomorphans had
antagonist without any agonist activity (1041, high affinity for K receptors. Several of these
which has enhanced preceptor selectivity benzomorphans, both agonists and antago-
compared to that of naloxone and naltrexone nists, were important ligands in early studies
(see Table 7.8). of K receptors. The selectivity of these benzo-
morphans for K receptors is generally low,
5.6 Benzomorphans
however (see Table 7.10). and much more se-
Further structural simplification by elimina- lective agonists and antagonists [i.e., the aryl-
tion of the C ring of the morphinan structure acetamide agonists (Section 5.9) and antago-
yields the benzomorphans (see Fig. 7.211, nists norBNI and GNTI (Section 5.3.2)l are
which are also known as benzazocines. now available for studying K receptors.
Although the benzomorphan ring system A variety of benzomorphans have been pre-
was first synthesized in 1947 by Barltrop pared with various combinations of alkyl sub-
(386),it was the synthesis of 2,5-dimethylben- stituents (methyl, ethyl, propyl) at the 5 and 9
zomorphan (92, R = R' = CH,) by May and positions (see Refs. 283,388). The alkyl group
Murphy (387) that began the investigation at the 9 positioncan be oriented either a, in
into the synthesis and pharmacology of this which the substituents in the 5 and 9 positions
structural family. As is the case for the mor- are cis, or p, in which these substituents are
phinans, the benzomorphans are prepared trans (see 92, Fig. 7.21). The synthetically mi-
synthetically and therefore are obtained as ra- nor p isomers, which have the opposite stere-
cemic mixtures. A number of these racemates ochemistry from that of the corresponding po-
have been resolved and the activities of the sition in morphine (C,), are more potent than
individual isomers examined (see Refs. 283, the a isomers as antinociceptive agents (see
388: for reviews. also see Ref. 389). The active Refs. 283, 388). Attachment of a 3-alkanone
isomers are the'levo isomers, which have the side chain at the 9/3 position of metazocine
same absolute configuration at the bridgehead (94) yielded a series of potent compounds
374 Narcotic Analgesics

Table 7.10 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of
Benzomorphan Derivatives and TRK-820"
-

a. Agonist Ki (nM) KiRatio GO


b-~im
Agonists K F 6 KId8 GPI MVD
(-1-EKC (33) 0.52 1.0 5.5 1/1.9/10.6 0.18' 4.4b
(-)-Bremazocine (34) 0.075 0.62 0.78 1/8.3/10.4 0.13' 1.98'
Mr2034 (97) 0.45 0.66 5.8 111.4113 0.77' 20'
TRK-820 (65)' 3.5 53 1,200 1/151340 0.0048 0.036
b. Antagonists Ki (nM) Ki ratio K, (nM)
Antagonist K P 6 dp/8 P (GPI) K (GPI) 8 (MVD)
(-)-Win 44,441 (93) 0.69 0.67 6.4 1/1/9.6 0.67 2.8 15
Mr2266 (98) 0.28 1.3 2.7 114.619.6 1.5 1.3 14
"Data for EKC and bremazocine from Table 7.8 are included for comparison. Data from Ref. 130 except where otherwise
indicated.
*Antagonistat p and 6 receptors in the rat and hamster vas deferens, respectively.
"From Refs. 310,311.

which range from pure agonists to pure antag- fluences the relative agonist versus antagonist
onists, depending on the length of the side activities of these compounds, with the orien-
chain (390). One of these derivatives, Win tation of this group affecting antagonist po-
44,441 (93, Fig. 7.22) is a potent K-receptor tency less than agonist potency (see Ref. 283).
antagonist that has been used to characterize A number of these derivatives exhibit dys-
K receptors; the active isomer is the levo iso- phoric and psychotomimetic effects, limiting
mer, Win 44,441-3 (391). It is also a potent their clinical usefulness. Thus the N-ally1 de-
antagonist at p receptors, however, and does rivative N-allylnormetazocine (SKF 10,047,
not exhibit selectivity for K over p receptors 14, Fig. 7.3) was the prototypical ligand used
(see Table 7.10). In the benzomorphan deriv- by Martin and coworkers (5,6)to characterize
atives introduction of a 9p-hydroxyl in the 9a- u receptors and exhibits psychotomimetic arid
methylbenzomorphans, which corresponds to dysophoric effects in humans (see Ref. 393);
the 14-hydroxyl in oxymorphone and nalox- based on animal studies, these adverse effects
one, does not enhance the agonist activity in appear to reside in the dextro isomer (394).
the N-methyl derivatives (see Ref. 283), but in The N-dimethylallyl derivative pentazocine
benzomorphans with other substituents on (95), however, produces considerably less dys-
the nitrogen [e.g., cyclopropylmethyl or di- phoria than does cyclazocine (96) (307) and is
methylallyl (see below)], a 9P-hydroxyl en- the only benzomorphan used clinically (see
hances antagonist potency 3- to 10-fold (392). Table 7.3). The N-CPM analog cyclazocine
As in the morphinan series, a variety of (96) is a potent mixed opioid agonistlantago-
substituents on the nitrogen have been exam- nist, but its considerable psychotomimetic ef-
ined (see Refs. 283,388,389). Metazocine (941, fects prevent its clinical use (see Ref. 393). As
with an N-methyl substituent analogous to indicated earlier, the 8-keto derivative keto-
morphine, exhibits agonist activity, and the cyclazocine (13)was used in the initial char-
N-phenethyl analog phenazocine shows in- acterization of K receptors by Martin and
creased analgesic potency. Replacing the N- coworkers; the 5-ethyl, 8-keto derivative eth-
methyl with groups such as ally1 or cyclopro- ylketocyclazocine (EKC, 33, Fig. 7.6) has also
pylmethyl (CPM) led to compounds with been used in a variety of studies of K receptors.
antagonist or mixed agonist/antagonist activ- The closely related benzomorphan (-1-brema-
ity (generally agonist activity at K receptors zocine (34, Fig. 7.6) (395) exhibits some pref-
and antagonist activity at other opioid recep- erence for binding to K receptors [Ki (AK)ratio
tors, similar to nalorphine; see Ref. 130). The = 8.2; see Table 7.101 and thus has been used
orientation of the alkyl group at position 9 in- in its tritiated form in radioligand-binding
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

R = CH3 (94) Metazocine


(93) WIN 44,441 R = CH2CH=CH2 (14) SKF 10,047
R = CH2CH=CH2(CH3)2 (95) Pentazocine
R = CPM (96) Cyclazocine

Figure 7.22. Benzomorphan derivatives.

assays for K receptors (see Section 3.2.3.2); in (see Ref. 130). Although this levo isomer is in-
smooth muscle assays these compounds ex- active at u-PCP receptors, it also produces
hibit mixed agonist/antagonist activity, with dysphoric and psychotomimetic effects in hu-
agonist activity at K receptors and antagonist mans that are antagonized by naloxone, sug-
activity at p and 6 receptors (see Ref. 130). gesting that in this case these adverse effects
A series of analogs with tetrahydrofurfuryl are mediated by K receptors (393). In the case
(396, 397) and furfuryl (398) groups on the of the furyl-substituted analogs the chain
nitrogen have been used as K-receptor ago- length affects the type of activity observed;
nists and antagonists. The tetrahydrofurfuryl thus the N-2-furfuryl derivative exhibits an-
derivative Mr2034 [97, absolute configuration tagonist activity, whereas the longer N-[2-(2-
lR,5R,9R,YS (39711 exhibits high affinity for fury1)ethyll derivative is a potent analgesic
K receptors and has been used as a K agonist, (398). Mr2266 (98),the levo isomer of the 5,9-
but it binds equally well to p opioid receptors diethyl N-2-furfuryl analog, has been used as a
(see Table 7.10); like other benzomorphan K-receptorantagonist in a variety of studies,
mixed agonistlantagonists, it exhibits agonist particularly in early studies when more K-se-
activity at K receptors, but antagonist activity lective antagonists were not available. Similar
at p and 6 receptors in smooth muscle assays to other benzomorphans, its selectivity for K
Narcotic Analgesics

R, R~ (105) Ketobemidone
Figure 7.23. Examples of piper-
idine analgesics with different CH3
substituents on C,. The struc- H
tures of meperidine (7)and fenta- CH2CH=CH2
nyl(8) are shown in Fig. 7.1. H

receptors is low [Ki ( p / ~ratio


) = 4.6; see Table B ring the phenyl ring can be either axial or
7.101 and in smooth muscle assays it antago- equatorial, depending on the substitution pat-
nizes both p and K receptors at similar concen- tern on the piperidine ring (see Fig. 7.13).
trations (see Table 7.10). Thus the structure-activity relationships for
The requirement for a phenol for opioid re- the phenylpiperidines can be complex, with
ceptor interaction was recently revisited in a differences in SAR observed for different
series of cyclazocine analogs in which the hy- groups within this structural family; these dif-
droxyl was replaced by a primary, secondary ferences can partly be explained by conforma-
or tertiary amino group (399) and several of tional differences and the orientation of the
these analogs retained high affinity for opioid phenyl ring.
receptors; the same modifications to morphine
The prototype of this class meperidine (7,
decreased p-receptor affinity by at least 35-
Fig. 7.1) was discovered serendipitously in
fold (400).
1939 during examination of compounds for
A series of analogs of the benzomorphans antispasmodic activity (402).During the phar-
were prepared in which the amino group is
macological testing in mice it was noticed that
exocyclic (99 and 100) (401). In contrast to the
meperidine caused a Straub tail reaction, in
benzomorphans and other rigid opiates, the
which the animals carried their tail in an erect
receptor binding of (99) and its analogs exhib-
position and which is a characteristic effect of
its almost no stereoselectivity [Ki (p) = 2.0
narcotic analgesics in this species. Subsequent
and 2.2 n M for the (+) and (-) isomers]; in
examination of meperidine verified that it was
vivo, both isomers of (99) were inactive. Race-
an analgesic, with 10-20% the potency of mor-
mic (100) exhibits an almost 10-fold increase
phine. This discovery stimulated research into
in K-receptor affinity (Ki = 6.6 nM) compared
this class of analgesics. Later it was found that
to that of the isomers of (99) while retaining
meperidine's affinity for opioid receptors is
nanomolar affinity for p receptors (Ki = 2.0
very low (0.2% that of morphine); however
nM); this compound is a full K agonist in vivo.
meperidine penetrates into the brain more
readily and reaches much higher (600-fold)
5.7 Piperidine Derivatives
concentrations in the brain than does mor-
Further structural simplification by elimina- phine (403).
tion of the B ring of the benzomorphans yields The piperidine analgesics can be classified
the phenylpiperidines (Fig. 7.13). This dis- into groups based on the substitution on C ,
rupts the fused three-ring system found in the (Fig. 7.23). In the case of the 4-arylpiperidines
morphinans and benzomorphans, resulting in the second substituent can be attached to the
much more flexible compounds. Thus, al- piperidine ring either through a carbon (e.g.,
though the B ring in the rigid opioid alkaloids meperidine, 7) or an oxygen atom (e.g., a- and
fixes the phenyl ring in an axial orientation P-prodine,101 and 102). Another group of pi-
relative to the piperidine (D) ring, without the peridine analgesics are the extremely potent
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 377

4-anilidopiperidines (e.g., fentanyl, 8, Fig. ents have been examined (see Ref. 405). Sev-
7.1). Meperidine, a-prodine, and fentanyl are eral phenylalkyl groups [e.g., phenethyl (in
all p opioid agonists (404). All portions of the pheneridine) andp-aminophenethyl (in anile-
piperidine analgesics-the N-substituent, the ridine)] increase potency; N-ally1 or cyclopro-
phenyl ring, the piperidine ring, and the C, pylmethyl groups, however, do not generate
substituent-have been modified. Modifica- antagonists in the meperidine series. Intro-
tions made to the piperidine ring include sub- duction of a 3-methyl group into the piperi- '

stitutions, particularly 3-alkyl substitutions, dine ring yields two isomers, with the 3P-
that affect the preferred conformation of these methyl isomer (with the methyl and phenyl
compounds, introduction of conformational cis) 8-10 times more potent than the a isomer
constraints to fix the conformation of this ring (411); the 3P-methyl group should increase
and the orientation of the 4-aryl ring, and ex- the population of the the axial 4-phenyl con-
pansion or contraction of the piperidine ring. former (283). In conformationally constrained
It is not possible to cover all of the details of tropane derivatives of meperidine (412, 413)
the structure-activity relationships of the pip- the small difference in potency between the a-
eridine analgesics in this chapter, and thus and p-phenyl isomers (the a-phenyl derivative
selected modifications are discussed here. 106 has only 3-4 times the potency of the
More detailed discussions of the SAR are given
in the comprehensive books on opiates (see
Refs. 12, 405) and extensive reviews by Casy
(283, 284, 406); the reviews by Casy discuss
conformational studies in considerable detail.

5.7.1 4-Arylpiperidines with a Carbon Sub-


stituent at C,. The carbon substituents at C,
of the 4-arylpiperidines can be a carbalkoxy
(e.g., meperidine, 7, Fig. 7.1), a ketoxy (keto-
bemidone, 105, Fig. 7.23) or alkyl substituent.
In the case of meperidine (also called pethi-
dine) examination by X-ray crystallographic P-phenyl isomer) suggested that the analgesic.
(407, 408) and NMR (409) techniques indi- activity of meperidine analogs is not very sen-
cates that the phenyl ring is equatorial in the sitive to the conformation of the phenyl ring.
major conformer, although in computational In the a-phenyl analog (1061, in which the
studies the calculated energy differences be- phenyl ring adopts a pseudoaxial orientation
tween the equatorial and axial phenyl confor- (413), introduction of a m-hydroxyl group de-
mations of meperidine is small (0.6-0.7 kcall creases potency (4141, suggesting that, even
mol) (410). though the phenyl ring in these meperidine
A large number of analogs of meperidine derivatives adopts a similar conformation to
have been prepared (see Ref. 405). The 4-sub- that found in morphine, the interactions of the
stituent in meperidine is optimal for analgesic phenyl ring with the receptor are different for
activity; lengthening or shortening of the es- these two types of compounds.
ter chain decreases activity, and except for ke- A variety of 4-arylpiperidines without an
tobemidone, substitution of the ester by an oxygen functionality on the second substitu-
amide or a ketone or hydrolysis to the acid ent at C, (107, Fig. 7.24) have been prepared.
reduces activity. Introduction of an m-hy- All of the active derivatives contain a m-hy-
droxyl on the phenyl ring of meperidine to give droxyl group on the phenyl ring (406). The
bemidone enhances activity. This substitu- 4-alkyl derivatives favor an axial aryl confor-
tion, however, can have complex effects on bi- mation (107) (409,415,416). Introduction of a
ological activity, and depending on the nitro- 3-methyl group, however, can alter the pre-
gen substitution, both potent agonists and ferred conformation, with the 3p-methyl iso-
antagonists have been produced in this series mer favoring the equatorial aryl conformation
(see Ref. 405). A wide variety of N-substitu- (108) (415, 416). The structure-activity rela-
Narcotic Analgesics

Figure 7.24. 4-Alkyl-4-arylpiperidines.


5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 379

tionships found in the more rigid opiates, antagonist activity (427).Introduction of a 9P-
particularly with regard to the nitrogen sub- methyl group, which is comparable to the
stituent and its effects on agonist versus an- 3-methyl substituent of the trans-3,4-dimeth-~
tagonist activity, do not hold in the 4-alkyl- ylphenylpiperidines, resulted in compounds
4-arylpiperidine series. In the case of with antagonist activity; the N-phenethyl de-
4-alkylpiperidines, where the axial aryl con- rivative (117) was much more potent than the
formation is preferred; for example, the N-al- N-methyl analog (428). These derivatives stiii
lyl derivative of 4-propyl-4-(m-hydroxyphe- retain rotational freedom around the phenyl-
ny1)piperidine (107, R = allyl), are agonists piperidine bond. Further constraint of the
with only weak antagonist activity (415,416). 5-arylmorphans, with an ether bridge be-
In contrast the 1,3P,4-trimethyl derivative tween the aryl ring and the morphan ring sys-
(109) is an antagonist rather than an agonist tem, yielded compounds with low affinity for
(417).In this series the &methyl group is crit- opioid receptors (see Ref. 2831, but the con-
ical for antagonist activity and an N-ally1 or strained benzofuro[2,3-clpyridin-6-01s(118),
cyclopropylmethyl group did not increase an- in which the phenyl ring is constrained to a
tagonist potency (417). Further variation of dihedral angle of 92" (426), retain p opioid re-
the nitrogen substituent of the trans-3,4-di- ceptor affinity and are potent analgesics (429).
methylphenylpiperidines (108) has resulted In the trans-4a-aryldecahydroisoquinolines
in the synthesis of several potent analogs with (119), in which the aryl ring is constrained to
antagonist activity at both p and K receptors the axial conformation, the N-methyl deriva-
(418-&I), including compounds such as tive has twice the potency of morphine; inter-
LY255582 (110), which has potent anorectant estingly, although the N-methyl derivative is
activity, and the peripherally selective antag- selective for p receptors, the N-CPM deriva-
onist LY246736 (111, now designated AD tive exhibits a slight preference for K receptors
8-2698 or alvimopan) (420), which is under- (430).
going clinical trials for the treatment of gas- Active analogs were also prepared by shift-
trointestinal motility disorders (see Ref. 38 ing the alkyl and aryl substituents to the 3
and Section 2.2.2.1). Potent antagonists that position. All active derivatives of the &methyl-
exhibit some selectivity for K receptors 3-arylpiperines contain the m-hydroxyl on the
[LY227053 (112), LY253886 (113)(4211, and phenyl ring (283). Although the N-methyl de-
(115) (422)], along with p-selective antago- rivatives are weak analgesics, derivatives with
nists (114) (423), have also been identified. an N-arylalkyl substituent are significantly
Conformationally constrained derivatives more potent (12). Some derivatives with N-
of the 4-alkyl-4-arylpiperidines, in which the allyl or N-CPM groups behave as antagonists,
aryl ring is constrained into both axial and similar to the morphinan series. Ring con-
equatorial conformations, have been pre- tracted and expanded analogs have also been
pared. Arylmorphans (116) are constrained prepared, including the mixed agonistlantag-
analogs in which the aryl ring is $quatorial onist meptazinol (120). The pharmacological
(see Ref. 283,406). The N-methyl derivative is effects of this compound are somewhat un-
equipotent with morphine after subcutaneous usual (see Ref. 431) and may involve both opi-
administration to mice (424); the configura- oid and cholinergic mechanisms (432). It has
tion of the more potent dextro enantiomer of
this analgesic [the 1S,5R isomer (42511 is re-
lated stereochemically to the more potent en-
antiomer of 4-arylpiperidines such as a- and
p-prodine (101 and 102, respectively) rather
than to the rigid benzomorphan (-)-metazo-
cine (283). The receptor affinities of both iso-
mers for different receptor types have also
been examined (426). Consistent with the ste- C H ~
reochemical relationships, the N-ally1 and N-
CPM derivatives are agonists with little if any (120) Meptazinol
Narcotic Analgesics

/N
H3C
- -
MA0

0
(121) MPPP (122) MPTP (123) MPP+

Figure 7.25. Formation of MPTP and MPP+ from MPPP.

been proposed that the opioid actions of ethyl derivative, (CH,),NHC,H, (436)], the
meptazinol are mediated by p1 receptors resulting compound can be more than 1000-fold
(431). more potent than meperidine.
A variety of C, alkylated derivatives of the
5.7.2 4-Arylpiperidines with an Oxygen reversed esters of meperidine were examined
Substituent at C,. Reversal of the ester in me- (see Ref. 405). Incorporation of a methyl group
peridine gives MPPP (N-methyl-4-phenyl-4- at C, yields a- and p-prodine (101 and 102,
propionoxypiperidine, 121) and increases an- Fig. 7.23) (437). The P isomer (102) has five
algesic activity 5- to 10-fold (see Ref. 405). times the potency of the a isomer. X-ray crys-
First described in 1943 (433), this compound tallography and NMR indicate that the pre-
took on new significance in the late 1970s ferred conformation of the prodines is the
when the drug began appearing as a "designer chair form, with the phenyl ring equatorial
drug (a compound with a minor structural
JJ

(see Refs. 283, 438). Computational studies


change that was prepared in attempts to evade also indicate a preference for this conformer;
laws regulating controlled substances) and in the case of the reversed esters the energy
sold on the streets as a heroin substitute. Dur- differences between the equatorial and axial
ing the synthesis of MPPP in clandestine drug conformers (1.9-3.4 kcallmol) are much
laboratories, however, dehydration occurred greater than the differences between the two
during the acylation of the 4-phenyl-4-piperi- conformers of meperidine (7) and ketobemi-
dol, resulting in the formation of MPTP (N- done (105)(410).
methyl-4-phenyl-l,2,3,6-tetrahydropyridine, Larger alkyl groups (ethyl, propyl, allyl) are
122; see Fig. 7.25). People who took the con- also tolerated at the 3 position, but for these
taminated drug exhibited symptoms of par- derivatives the a isomer is more potent than
kinsonism, even in subjects in their twenties the p isomer. For the a isomers the more po-
(434). The neurotoxic effects of MPTP are tent enantiomer has the 3R,4S stereochemis-
thought to be attributable to its metabolism to try (439); This led to the suggestion that the
MPP+ (123, N-methyl-4-phenylpyridinium) prodine derivatives present the pro-4R face of
by monoamine oxidase and destruction of do- the molecule to the receptor (see Fig. 7.26; also
paminergic neurons, resulting in the parkin-
sonism-like symptoms (see Ref. 435).
A wide variety of modifications have been
made to MPPP, including modification of the
ester functionality, variation in the nitrogen
substituent, substitution on the piperidine ring,
etc. (see Ref. 405). The propionyl chain is the
optimum length, and hydrolysis of the ester to
the corresponding alcohol usually results in
compounds with little if any activity. Several N- Figure 7.26. Pro-4R and pro-4s face of prodine de-
phenylalkyl substitutions such as phenethyl in- rivatives. Positions that tolerate methyl substitu-
crease potency; in some cases [i.e., the anilino- tion are indicated by an asterisk.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 381

see Ref. 283); thus substitution on the 4R side propose an alternative mode of interaction to
interferes with drug-receptor interactions, explain how a-allylprodine (103) and other
whereas substituents on the 4 s side are not phenylpiperidines in which the phenyl ring is
involved in interaction with the receptor and equatorial can interact with the same recep-
are well tolerated. A variety of other methyl- tors as morphine and other rigid opiates
and dimethyl-substituted derivatives of the where the phenyl ring is axial. In the initial
reversed esters have been prepared, resulting bimodal binding model proposed by Portogh- '
in compounds with a wide range of potencies ese (82), the m i n e of different opiates was
and with different orientations of the phenyl postulated to interact with a common anionic
ring, depending on the substitution pattern site and the rest of the molecule then would
(see Refs. 283, 405, 440); positions that toler- pivot around the nitrogen to bind in one of two
ate methyl substitution are indicated in struc- possible orientations. The bimodal binding
ture (124) (Fig. 7.26) by an asterisk. Very po- model was subsequently modified to include a
tent analogs have been prepared by bridging second lipophilic site (443), where the equato-
the 3 and 5 positions with a trimethylene rial phenyl ring of phenylpiperidines such as
chain (125, 126) (441). Both the a isomer a-allylprodine (103)was proposed to interact.
A substantial reduction in analgesic po-
tency was also observed for the rn-hydroxyl
derivative of the 2a-methyl reversed ester in
which the preferred conformation of the phe-
nyl ring is axial (444), suggesting that there
can also be differences in receptor interactions
for the axial aryl moiety in this derivative and
in morphine. This in turn may be attributable
to differences in the relative orientation of the
aryl rings in the rigid morphine versus the
phenylpiperidine derivatives in which the aryl
ring is free to rotate.

5.7.3 4-Anilidopiperidines. 4-Anilidopip?


eridines, in which an amido nitrogen function-
ality is positioned between C , of the piperidine
ring and the phenyl ring, are extremely potent
analgesics. Fentanyl (8, Fig. 7.1), the proto-
type of this class, has almost 500 times the
potency of meperidine and 200-500 times the
potency of morphine (see Ref. 445). Like me-
(125, in which the aryl ring is axial) and the P peridine, fentanyl is a p agonist (404). Because
isomer (126, in which the aryl ring is equato- of their rapid onset and short duration of ac-
rial) have similar potencies; introduction of a tion fentanyl and other 6anilidopiperidines
m-hydroxyl group on the phenyl ring results have been used extensively in anesthesia. In
in a dramatic (400- to 1000-fold) increase in 1991 fentanyl became available as a transder-
the potency of both isomers. The correspond- mal patch for the treatment of chronic pain,
ing m-hydroxyphenyl-3,7-diazabicyclanes also and lozenge formulations have recently be-
exhibited significant antinociceptive activity come available (see Table 7.1).
(442). The preferred conformation of fentanyl
In contrast to meperidine and other phe- and other 4-anilidopiperidines has been exam-
nylpiperidines with a C, carbon substituent ined by X-ray crystallography, NMR, and com-
discussed earlier, introduction of a m-hy- putational methods (see Refs. 187, 284, 446).
droxyl group on the phenyl ring of the allylpro- In the crystal structure the anilido moiety
dines (103 and 104, Fig. 7.23) results in inac- adopts an equatorial conformation (see 8, Fig.
tive compounds (443). This led Portoghese to 7.1) (447). Several conformationally con-
Narcotic Analgesics

(131) Carfentanil

Figure 7.27. Fentanyl analogs.

strained analogs of fentanyl have been pre- tional conformationally constrained 1,5-ben-
pared [see the previous edition of this chapter zoxazepine derivatives constrained through
(286) for a detailed review]. Generally, confor- cyclization between the ortho position of the
mationally constrained derivatives in which phenyl ring and the 3 position (130) are also
the phenyl is constrained in the P orientation potent analgesics (450).
are inactive (see Ref. 448), but in conforma- A large number of modifications have been
tionally constrained tropane analogs of fenta- made to fentanyl (see Refs. 284,406,445,448).
nyl the p analog (128, Fig. 7.27), in which the Unlike the phenylpiperidines a second sub-
anilido group is equatorial, is more potent stituent at C, is not required, but the addition
than the a isomer (127), in which the propa- of a polar carbon substituent (C0,CH3 or
nanilido moiety is pseudoequatorial (449). CH,0CH3) at this position to give, for exam-
The high potency of the conformationally con- ple, carfentanil (131),enhances potency 27-
strained spirane derivative (129) provides ev- fold over that of fentanyl and results in com-
idence that the phenyl ring may be oriented a pounds 7800 times the potency of morphine
when fentanyl binds to opioid receptors. Addi- (451). In the case of the anilido side chain, the
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

(134) a-Methylfentanyl
R= (135) Sufentanil

N-N
If \.
\\

R= / N,~H2CH3
(136) Alfentanil

R = C02CH3
R' = C02CH3 (137) Remifentanil

(138) Ohrnfentanyl

Figure 7.27. (Continued.)

propionamide is the optimum length (448); branched-chain derivative a-methylfentanyl


the methoxyacetamides are also potent anal- (134) has achieved notoriety as the street drug
gesics (see Ref. 406). Replacement of the pro- "China White" (454). The phenethyl substitu-
pionamide with 2- or 3-fumaramide resulted ent is the optimum length, but potency can be
in compounds with antagonist activity against enhanced by replacement of the phenyl ring
both morphine-induced analgesia and respira- with a heterocycle such as the 2-thienyl ring
tory depression (132) or against respiratory (451). Combination of a heterocycle substitu-
depression alone (133)(452);the flat aromatic tion on the piperidino chain and a polar carbon
furan ring appears to be important for antag- substituent attached to position 4 have yielded
onist activity. Previous attempts to produce the clinically used agents sufentanil(135) and
antagonist derivatives of fentanyl by replace- alfentanil (136) (Table 7.1), which like fenta-
ment of the piperidino phenethyl group with nyl are used as adjuncts in anesthesia. Al-
ally1or CPM were unsuccessful (449,453),and though less potent than fentanyl and sufen-
thus it appears that changes should be made tanil, alfentanil has a faster onset and shorter
around the amide nitrogen rather than to the duration of action than these other 4-anili-
basic piperidino substituent to impart antago- dopiperidines. The rapid onset of action of al-
nist activity to fentanyl analogs (450). fentanil may be attributed to its physiochemi-
A variety of changes to the nitrogen sub- cal properties; alfentanil is a much weaker
stituent on the piperidine ring have been base (pK, = 6.5) than fentanyl (pK, = 8.4) and
made that produce potent analgesics. The sufent.mil (pK, = 8.0),so that a higher propor-
Narcotic Analgesics

Figure 7.28. Comparison of


the 3R,4S isomer of cis-3-meth-
ylfentanyl (139) and the 3S,4S
isomer of P-prodine (102).

tion of the unprotonated amine would be supporting this conclusion. A series of cis/
available to penetrate the blood-brain barrier trans pairs of 3-methylfentanyl analogs was
(406). Other heterocyclic substitutions have reported (460),and in some cases in which the
been made on the piperidino chain (450), re- anilido ring had an ortho substituent, the
sulting in some compounds with less respira- trans isomers were more potent than the cis
tory depression. Incorporation of an ester isomers. This may be due to steric hindrance
functionality into the piperidino substituent between the ortho substituent and the
to give remifentanil (137) (Table 7.1) results 3-methyl group in the cis isomers interfering
in a compound that is 30-fold more potent with the phenyl ring adopting an a orientation
than alfentanil, and that has very rapid onset (see above) (284). As discussed earlier, the
(1.6 min) and offset (5.4 min), which is inde-
conformationally constrained 1,5-benzoxaz-
pendent of the duration of administration
epine derivatives linked through the ortho po-
(455, 456). This is due to the rapid hydrolysis
sition on the phenyl ring and the 3-methyl
by esterases to the acid derivative, which has
very low analgesic activity and is rapidly substituent (130)are active in antinociceptive
excreted. assays (450).
Introduction of a methyl substituent in the Recently, two models of cis-(+)-3-methyl-
3 position of the piperidine ring results in fentanyl (139) and other 4-anilidopiperidines
chiral comvounds. The racemic cis derivative docked to p opioid receptors were described
of fentanyl is more potent than the trans de- (182, 187). The binding mode for cis-3-meth-'
rivative (457). For the cis racemate the dextro ylfentanyl in the two models is different,
isomer has 120 times the potency of the (-)- which has been attributed to different con-
isomer; the absolute stereochemistry of the formations of this compound used for dock-
(+)-cis isomer is 3R,4S (458). The analog of ing to the receptor (187). Comparison of cis-
cis-3-methylfentanyl with a hydroxyl group on 3-methylfentanyl to N-phenethylnormor-
the N-phenethyl chain ohmfentanyl (138) is phine suggested that there was considerable
extremely potent (7000 times morphine) in overlap in the region of the receptor occu-
antinociceptive assays and exhibits remark- pied by the N-phenethyl groups, but that
able selectivity for p receptors [27,000-fold there was no overlap in the region in the
selectivity for p versus 6 receptors (45911. receptor binding pocket occupied by the N-
Comparisons of the 3R,4S isomer of cis-3- phenyl ring of cis-3-methylfentanyl and the
methylfentanyl(139) and the 3S,4S isomer of phenol ring of the morphine analog (see Fig.
p-prodine (102, Fig. 7.28) suggest that al- 7.5 in Ref. 187).
though these compounds are both p agonists, Affinity label derivatives of fentanyl and
they represent different classes of ligands that (+)-cis-3-methylfentanylFIT (198, 461) and
have different modes of interaction with opi- SUPERFIT (4581, which have an isothiocya-
oid receptors (284) (there is an error in the nate group on the phenyl ring of the piperidino
stereochemistry at position 3 of p-prodine in substituent, have been prepared. Unlike the
Ref. 284, p. 504). Fentanyl derivatives con- reversible parent compounds, which are p
taining propyl and ally1 substituents at C3 ex- agonists, these affinity labels irreversibly bind
hibit significant differences in SAR from the to 6 receptors. These compounds are discussed
corresponding prodine analogs (see Ref. 284), further in Section 5.11 on affinity labels.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

(140) lsomethadone (141) eryfhre5-Methylmethadone

(145) Diampromide (146) Phenampromide

Figure 7.29. Methadone analogs.

5.8 Acyclic Analgesics permitting once-daily dosing, and is reported


to produce less euphoria than does morphine.
Methadone (9, Fig. 7.1) and its analogs can be
viewed as ring-opened derivatives of the phe- The major metabolic pathway for methadone
nylpiperidines. As was the case for meperi- involves N-demethylation, although these de-
dine, methadone was not discovered by this rivatives are not stable and undergo cycliza-
systematic structural approach, but was in- tion to inactive metabolites through intramo-
stead identified in Germany during World War lecular Schiff base formation (see Ref. 463).
I1 while investigators were looking for com- Methadone is also metabolized to an active
pounds with antispasmodic activity (462). metabolite methadol (see below).
These acycylic analgesics are highly flexible Methadone and its isomer isomethadone
molecules capable of adopting a multitude of (140, Fig. 7.29), which was also obtained from
conformations (see Ref. 284). Methadone is a early syntheses of methadone (see Ref. 463),
potent analgesic, and the racemate has ap- each contain an asymmetric center. The more
proximately twice the potency of morphine active isomers for both compounds are the (-)
and 5-10 times the potency of meperidine (see isomers (see Refs. 284,463). The (-) enantio-
Ref. 463). The principal use of methadone, mer of methadone, which has the R configura-
however, has been in the maintenance of indi- tion, has 7-50 times higher potency in antino-
viduals addicted to narcotics. It has relatively ciceptive assays and greater than 10-fold
good oral activity and long duration of action, higher affinity for opioid receptors than that of
Narcotic Analgesics

the (+) isomer. In the case of isomethadone, but activity can be restored by acetylation
which is slightly less potent than methadone, (470); the resulting acetates are more potent
the more active (-) enantiomer has the S con- than the parent ketones. The more active
figuration and has 40 times the potency of the methadol isomers, (-)-a- and (-)+methado1
(+) isomer (see Refs. 284,463). NMR, circular [with absolute configurations 3S,6S and
dichroism (464), and molecular modeling 3S,6R, respectively (47111, both have the same
studies (465) suggest that isomethadone may 3 s configuration, suggesting that the stereo-'
be less flexible than methadone because of the chemistry around the alcohol is more impor-
proximity of the methyl group to the phenyl tant in these derivatives. The more active
rings in isomethadone. 3S,6R isomers of p-methadol and P-acetyl-
These flexible analgesics exhibit their own methadol are derived from the more active
distinct SAR (see Refs. 284, 463, 466). A vari- R-(-) enantiomer of methadone. An interest-
ety of nitrogen substituents have been exam- ing reversal in enantioselectivity occurs in the
ined, and whereas larger acyclic groups mark- a series; although the more potent 3S,6S iso-
edly decrease or abolish activity, compounds mer of a-methadol is derived from the less ac-
containing a cyclic substituent, such as pyrro- tive S-(+) isomer of methadone, acetylation
lidine, piperidine, or morpholine, on the nitro- reverses the enantioselectivity, so that the
gen retain activity. The two-carbon chain more potent isomer is the 3R,6R-(+) isomer
length between the quaternary carbon and the (471). leuo-a-Acetylmethadol (LAAM, 143)
nitrogen is the optimal length, and lengthen- has a longer duration than methadone, requir-
ing the chain abolishes activity. Removal of ing dosing only once every 3 days, and is being
the methyl group from the alkyl chain to give used in the United States for maintenance of
the achiral compound normethadone de- individuals addicted to narcotics. Like metha-
creases potency 6- to 10-fold relative to that of done, the major route of metabolism of this
methadone and isomethadone, respectively. compound is N-demethylation. In the case of
Introduction of a second methyl group at posi- the methadols and acetylmethadols, these sec-
tion 5 yields erythro- and threo-5-methyl- ondary amines-derivatives are active, with po-
methadone (467). The erythro form (141) has tencies similar to those of the parent tertiary
five times the potency of methadone, whereas mines, and probably contribute to the activ-
the threo form is inactive. The more active leuo ity and longer duration of action of LAAM (see
isomer of erythro-5-methylmethadone has the Ref. 463). The ketone of methadone has also
5S,6S configuration (468). Interestingly, one been replaced with a variety of other func-
of the isomers of the inactive threo racemate, tional groups, including esters, ethers, and
with the 5S,6R configuration, combines the amides (see Ref. 463). In the acyloxy series
configurations found in the more active enan- propionyloxyisomethadone shows significant
tiomers of methadone and isomethadone activity (472); further modification of this
(467). NMR analysis suggests that the erythro compound yields propoxyphene (see below).
form exhibits greater conformational flexibil- Most modifications of the phenyls in the
ity than that of the threo form. The authors diphenyl fragment of methadone result in sub-
suggested that the marked difference in anal- stantial loss of analgesic activity (see Ref.
gesic activity may be attributable to different 463). In normethadone analogs replacement
conformational preferences of the threo and of one of the phenyl rings by a benzyl group
erythro forms (467), and that the conforma- abolishes activity (473), but in the isometha-
tion observed for erythro-5-methylmethadone done analog with a propionoxy group in place
in the solid state (469) is the active conforma- of the ketone this modification results in
tion of erythro-5-methylmethadone, as well as propoxyphene (10, Fig. 7.1), which has modest
for (-)-methadone and (-)-isornethadone. analgesic activity (approximately 1/10 the po-
The ketone side chain is also important for tency of methadone 472; see Table 7.1). The
activity (see Ref. 463) and changing the length replacement of one of the phenyl rings by
of this chain decreases activity. Reduction of a benzyl group introduces a second chiral cen-
the ketone to the two possible alcohols, a- and ter into this molecule. The active (+) isomer
P-methadol (142 and 144) decreases activity, has the 2S,3R stereochemistry, which is the
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 387

same absolute configuration at C, as in the Acting Agonists. Benzo-


5.9.1 Centrally
active (-)-isornethadone (see Refs. 284, 463). morphan ligands such as EKC (33) and
N-Arylpropionamide analgesics such as the bremazocine (34, Fig. 7.6) have been used to
methadone analog diarnpromide (145) and the study K opioid receptors, but these compounds
isornethadone analog phenampromide (146) exhibit low selectivity for these receptors [Ki
contain a single aromatic ring attached to a ratio ( p / ~=) 1.9 for EKC and 8.3 for bremazo-
nitrogen, analogous to the 4-anilidopiperi- cine; see Table 7.101. As discussed earlier "
dines, and are exceptions to the requirement (Section 5.3.1), the 4,5a-epoxymorphinan
for a second phenyl ring. Diampromide is TRK-820 (65, Fig. 7.16) is also a potent ago-
somewhat more potent than phenampromide, nist at K opioid receptors, exhibiting modest
with a potency between meperidine and mor- selectivity for these receptors [K, ratio (CL/K) =
phine. The more active isomer of phenam- 15; see Table 7.101. The benzodiazepine tiflua-
prornide is the R-(-) isomer (which has the dom (147) reported by Romer (476) is also a K
same configuration as the more active (-)-
isornethadone), whereas the more active iso-
mer of diampromide has the S configuration,
which is opposite that of (-)-methadone (see
Refs. 284,463). This led Portoghese to suggest
that methadone and diampromide probably
differ in their modes of interaction with opioid
receptors (82).

5.9 Kappa-Selective Agonists


There has been considerable interest in devel-
oping K agonists as analgesics that would not
have the side effects characteristic of mor-
phine and other p opiates (e.g., respiratory de-
pression and addiction), and therefore numer-
ous K-selective compounds have been reported
over the last two decades (see Refs. 287, 288, opioid receptor agonist, but it too exhibits low
474 for reviews). As noted earlier (Section selectivity for K receptors [Kiratio ( p / ~=) 5.4;
3.3.21, although K receptors can mediate anal- see Table 7.111. Racemic tifluadom exhibits
gesia, there are differences between the effects only very weak affinity for benzodiazepine re-
mediated by p and K receptors (see Ref. 146 for ceptors (IC,, = 4.1 @) (477); the (- ) isomer
a review). There has also been interest in w e - has greater affinity for opioid receptors and is
lective compounds as potential neuroprotec- more selective for opioid over benzodiazepine
tive and anticonvulsant agents (see Refs. 256, receptors than the (+) isomer (477). Tiflua-
475 for reviews). dom also exhibits high affinity for peripheral
Although some compounds with K agonist CCK receptors [IC,, = 29 nM for the (-) iso-
activity are used clinically as analgesics (e.g., mer] and is an antagonist at these receptors
pentazocine, nalbuphine, and butorphanol, (478). Additional analogs of tifluadom with
Table 7.3 above), the use of many K agonists comparable affinity and somewhat greater se-
has been severely limited by centrally medi- lectivity have been reported that are devoid of
ated side effects, mainly dysphoria and seda- affinity for CCK receptors (179). A computa-
tion, associated with most of these compounds tional model of tifluadom bound to K opioid
(146).The ability of K agonists to produce an- receptors has also been described (179).
algesia in inflammatory pain through interac- The first K-selective nonpeptide derivative
tion with peripheral K opioid receptors has identified was the benzacetamide U50,488
stirred interest in the development of periph- (35, Fig. 7.6), which was found while investi-
erally selective kappa agonists (see Section gators examined cycloalkane-1,2-diaminesas
5.9.2). antidepressants (115). This compound exhib-
388 Narcotic Analgesics

Table 7.11 Opioid Receptor Affinities, K Selectivity, and Analgesic Activity of K Opioid
Ligandsa
Receptor Affinity Analgesic Activity MPE,,
(Ki, nM) Ki (mglkg?
Ratio
Compound K" cL" P ~ K i.v. p.0. References(s)
Tifluadom (147)
U50,488 (35)
(- ) isomer
( +) isomer
U69,593 (36)
Spiradoline
(U62,066, 148)
(- ) isomer
(+) isomer
PD 117302 (149)
(- ) isomer
(-1 CI-977 (37)
DuP 747 (150)
S,S isomer
Niravoline
(RU 51599,151)
BRL 5253711 (155)
BRL 52656A (156)
GR 89696 (158)
R-84760 (159)
Apadoline
(RP 60180,160)
ICI 197067 (161)
ICI 199441 (162)
HZ2 (163)
"Data from Ref. 118 except where otherwise indicated.
*Rat paw pressure test, MPE,,, is the dose required to produce 50% of the maximum possible analgesic effect, except
where otherwise indicated.
'Inhibition of [3H]U69,593binding in guinea pig forebrain, except where otherwise noted.
dInhibition of [3HlDAMG0 binding in guinea pig forebrain, except where otherwise noted.
'U50,488 Ki = 6 and 825 nMin K and p assays, respectively (494).
fMouse phenylquinonewrithingassay ED,, S.C.andp.~.,respectively. ED,, for U50,488 = 1.2 mgkg S.C.and 13 mglkgp.0.
(494);0.47 mgkg S.C.and 27 mgkg p.0. (506).
SED,, mouse tail flick assay. U50,488 ED,, = 1.9 mgkg s.c.
'Binding determined in monkey cortical membranes.
'Mouse acetylcholine writhing assays ED,, s.c. ED,, for U50,488 = 0.41 mgkg s.c.
JIC5, values for U50,488 = 7.59 and 571 nM for K and p binding, respectively.
kInhibition of l3H1EKC binding in guinea pig cerebellum.
'Ki (6) = 1.6 nM (l3H1EKC binding in NG 108-15 cells), Ki ratio (61~)= 2.9.
"IC,, values for inhibition of [3Hlbremazocinebinding in guinea pig brain minus cerebellum and [3Hlnaloxonebinding
in rat brain for K and preceptors, respectively. U50,488 IC5, = 95.5 and 14,200 nM, respectively.
"ED,, in mouse acetic acid abdominal constriction assay. U50,488 ED,, = 1.1 mglkg s.c.
"Inhibition of [3HlCI-977 and [3Hlnaloxonebinding in rat brain membranes for K and preceptors, respectively.

its high K selectivity in binding assays (see Ta- finity for K receptors (482) (see Table 7.11).
ble 7.11) and produces analgesia through K re- The absolute stereochemistry of the levo iso-
ceptors in vivo (479,480). mer was determined by X-ray crystallography
U50,488, which was initially characterized of an intermediate to be 1S,2S (481). The pro-
as the racemic mixture, was resolved (481), tective effects of U50,488 against the tempo-
and the levo isomer found to have greater af- rary bilateral carotid occlusion model of cere-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

(148) Spiradoline
((+I U62,066)

(151) Niravoline
(RU 51 599)

Figure 7.30. K-Receptor selective agonists. The structures of U50,488 (361, U69,593 (36),and
CI-977 (37) are given in Fig. 7.6.

bra1 ischemia also reside predominantly in the displays preceptor selectivity (see Table 7.11)
levo isomer (483), consistent with the hypoth- (486). Like U50,488 spiradoline exhibits neu-
esis that K receptors may be involved in these roprotective effects and is even more effective
protective effects. than U50,488 in reducing postischemic necro-
Introduction of a spiro ether group on the sis of the vulnerable hippocampal CAI neu-
cyclohexane ring was one of the earliest rons (487). Further examination of C, andlor.
modifications to U50,488 reported, giving (-)- C, methyl ether and spiro tetrahydrofuran
U69,593 (36, Fig. 7.6) (116) and spiradoline substituents indicated that optimal K-receptor
(U62,066, 148, Fig. 7.30) (484). U69,593 ex- selectivity was obtained when the oxygen was
hibits improved K-receptor selectivity over in the equatorial (PI orientation at C, of the
U50,488 (116) (see Table 7.11). The tritiated ring (117).
form of U69,593 was prepared by catalytic tri- From the initial compounds it was clear
tiation of the aromatic chlorines of U62,066 that the spacing between the amide and the
(116), and this highly selective tritiated K li- aromatic ring system in the N-methylamide
gand has been used extensively in radioligand- side chain is critical for K-receptor activity.
binding assays (see Section 3.2.3.2). The X-ray Whereas phenylacetamide derivatives (i.e.,
structure of U69,593 has been reported [see -NCH,COCH&) such as U50,488 and its an-
Ref. 485; however, as noted by Rees (474), alogs exhibit K activity, benzamide derivatives
there is a discrepancy between the X-ray (i.e., -NHCOAr and -NCH,COAr) exhibit mor-
structure as drawn in this paper (5R,7S,8S) phine-like effects (115,488). In both series N-
and that indicated in the title (5S,7S,8S), methyl substitution increases potency over
which has led to some confusion concerning the unsubstituted secondary amides (115,
the absolute stereochemistry of U69,5931. As 489).
is the case with U50,488, the (-) isomer of Numerous variations have been examined
spiradoline is much more potent (>30-fold) in all portions of the U50,488 and spiradoline
than the (+) isomer in analgesic assays (484) structures [see Refs. 287,288,474 and the pre-
and possesses much greater affinity for K re- vious edition of this chapter (286) for detailed
ceptors (see Table 7.11) (486); the (+) isomer reviews]. Figure 7.31 shows the general struc-
Narcotic Analgesics

(a) (b) Enhance K


. activity

oral / Block
metabolism
activity
Enhance agonist activity

Figure 7.31. (a)General structure (154) common to most of the analogs of U50,488;(b) summary of
SAR for analgesic activity of U50,488(35) (from Ref. 287).

ture (154) common to most of the analogs and


a summary of the SAR of U50,488 (287). In
addition to varying the spacing between the
amide and aromatic ring, other modifications
in the N-methvlamide
" side chain of U50.488
and spiradoline examined include replace-
ment of the amide linkage, substitution on the
methylene between the amide and the aro-
matic ring, and varying the identity of the ar-
omatic ring system. The amide linkage ap-
pears to be important because substitution of
this linkage with a variety of replacements (re-
versed amide, reduced N-methyl amide, or es-
ter) all caused significant decreases in K-recep-
tor affinity (489);only the N-methylthioamide
derivative retained significant affmity, and
even this minor substitution of sulfur for ow- -
gen resulted in approximately a 15-fold de-
crease in affinity. Whereas substitution of a
methyl group a to the carbonyl results in a
large (200-fold)decrease in K-receptor affmity,
conformational constraint involving linking
the CK carbon to either the aromatic group
(152) (490) or the amide nitrogen (153)(491) exhibits much greater affinity for K receptors
resulted in analogs with high affinity for K than the R,R isomer (see Table 7.11) and is the
receptors. one exhibiting analgesic activity. Similar re-
Variations in the aromatic ring system of placement of the phenyl ring of U69,593 with
the N-methvlamide
" side chain led to two well- the Cbenzofuran ring system yields (-1 CI-
characterized agents. Replacement of the di- 977 (enadoline, 37, Fig. 7.6) (117, 118), which
chlorophenyl ring with either 4-benzo[b]thio- is also one of the most potent and highly selec-
phene to give (k)PD 117302 (149, Fig. 7.30) tive K ligands (see Table 7.11) (117, 118). Tri-
or 6benzofuran (492) yields potent com- tiated CI-977 is commercially available (see
pounds with high K-receptor selectivity (see Table 7.7) and is frequently used in radioli-
Table 7.11). Again, the (-)-S,Senantiomer gand-binding assays.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 391

Numerous variations and substitutions on proposed pharmacophore (503). In both the


the cyclohexane ring have also been reported. piperidine and the related tetrahydroiso-
The configuration of the 1,2-diarninoamide on quinoline series (e.g., 157) the (-)-S isomer
the cyclohexane ring is critical for K-receptor was the active enantiomer (503-505). A com-
affmity and activity. Kappa ligands such as pound with the related thiazine ring system
U50,488 and its analogs all have the trans con- (R-84760, 159) (506) has also been reported
figuration; isomers with the cis configuration to have K opioid receptor activity. R-84760 is ,
have weak affmity for K receptors and instead an extremely potent K agonist, with a po-
have much higher affinity for the (+)-3-PPP tency of 2.5-20 times that of CI-977 in sev-
[(+)-3-(3-hydroxypheny1)-N-(1-propy1)piperi- eral different assays; the stereochemistry of
dine] or u binding site (482). For the amine R-84760, the most active isomer, is 3R,lrS.
side chain the pyrrolidine ring is the optimal Because of the "relative inaccessibility" of
substituent; changing the ring size decreased the 2,ksubstituted piperidine ring system,
K-receptor affinity and selectivity and "open- the Glaxo group evaluated piperazine ana-
ing" the ring to give the N,N-diethyl analog logs where N, substituents could be more
resulted in almost a 500-fold decrease in K-re- easily introduced (507). This led to the de-
ceptor affinity (492). Attachment of aromatic velopment of racemic GR 89696 and its R
rings to the cyclohexane ring has been exam- isomer GR 103545 (158)(507, 508). Neuro-
ined by several groups (493-495). By combin- protective effects have been demonstrated
ing the structures of U50,488 and 2-amino- for GR 89696 (509). GR 89696 has been ex-
tetralin, researchers a t DuPont Merck amined in the guinea pig hippocampus and
developed tetrahydronaphthyl analogs as K reported to be an agonist at the K,-receptor
agonists (494,495);a 5-methyl ether substitu- subtype but an antagonist at K, receptors
ent gave optimal activity and led to the identi- (510). Recent studies in rhesus monkeys
fication of DuP 747 (150)as a new K analgesic. (511) found that GR 89696 exhibited consid-
Analysis of the two enantiomers of racemic erable affinity for preceptors (Table 7.11) in
DuP 747 indicated that again the (+)-S,Siso- binding assays, but low efficacy and potency
mer was the one with high K-receptor affinity (100-fold lower t h a n a t K receptors) in
and analgesic activity (495). The related com- [35S]GTPySassays. In vivo, the effects of GR
pound niravoline (RU 51599,151), in which a 89696 were less sensitive than those o f ,
cyclopentane ring replaces the cyclohexane U50,488 or U69,593 to antagonism by nal-
ring (496, 497), has been studied for its di- trexone and insensitive to norBNI, consis-
uretic effect in rats with cirrhosis (498-500) tent with action through the postulated K,
and in brain edema in animal models of isch- receptors. Interestingly, substitution of a
emia and stroke, traumatic brain injury, and methyl group a to the pyrrolidine nitrogen
brain tumors (see Refs. 501,502). had a marked effect on the affinity of the
Alternative ring systems to the 1,2-dia- derivatives for p opioid receptors, with the
mine substituted cyclohexane skeleton have S,S isomer exhibiting subnamolar affinity
also been examined (Fig. 7.32). Researchers for p as well as K receptors, whereas the S,R
from Glaxo and SmithKline examined both and R,S exhibited very low (>1phf) affinity
piperidine and piperazine analogs as K ago- for p receptors (512). Addition of a 3-hy-
nists (see Refs. 286-288 for detailed re- droxyl to the pyrrolidine ring led to com-
views). Researchers a t SmithKline in Italy pounds with significant peripheral selectiv-
identified a common pharmacophore (-N-C- ity (see below) (513). The phenothioazine
C-N-COCH,Ar) in K-selective ligands, with a derivative apadoline (RP 60180, 160) (514)
torsion angle of 60" around the C-C bond exhibits 100-fold selectivity for K over p re-
(503), which led them to develop piperidine ceptors, but it possesses only a small (three-
derivatives such as BRL 52537A (155) and fold) selectivity for K over 6 receptors.
BRL 52656A (156). The torsion angle found Compounds with K receptor activity that do
for the N,-C,-C,-N,, pharmacophore by X- not contain the cyclohexane ring have also
ray and NMR analysis of these compounds been identified (Fig. 7.32). Although replace-
was approximately 60°, similar to that in the ment of the cyclohexane ring with an unsub-
Narcotic Analgesics

X = 3,4-diCI (155) (S) BRL 52537A


X = 4-CF3 (156) (S) BRL 52656A

C")
(158) (R,S) GR 89696
C")
(R) GR 103545

R = CH(CH3)2 (161) (S) ICI 197067


(160) Apadoline
(RP 60180) = (162) (S) ICI 199441

Figure 7.32. K-Receptor selective agonists with alternative ring systems and open chain analogs of
the 1,2-diaminesubstituted cyclohexane ring.

stituted ethyl chain results in compounds with that only those compounds capable of adopt-
weak K-receptor affinity, a substituent a to the ing a conformation similar to that of U50,488
amide functionality yields compounds with were K agonists. The most potent analogs were
high affinity for K receptors (515,516). Exam- the isopropyl (ICI 197067, 161) and phenyl
ination of both isomers indicated that a derivatives (ICI 199441, 162, Fig. 7.32). Fluo-
methyl group at the 1 position with the S con- rescent derivatives of ICI 199441 have been
figuration was active and had reasonable af- prepared by attachment of fluorescein isothio-
finity for K receptors, whereas the isomer with cyanate by a spacer to the meta or para posi-
the R configuration at this position was inac- tion of the central phenyl ring (517). Attach-
tive (516). Conformational analysis suggested ment of an acidic functionality to the meta
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 393

position of the central phenyl ring of ICI ported to have potent antinociceptive activity
199441 gave ICI 204448, which has limited and, like other K agonists, to be active against
ability to penetrate the CNS (518) (see below). inflammatory pain (522). The quaternary
U50,488 and its analogs are structurally methiodide derivative retains high K-receptor
distinct from the benzomorphan K opiates and affinity, and thus may be useful as a periph-
are considerably more flexible than are the eral K agonist (523).
rigid alkaloids. This raises questions concern- Several of the K-selective ligands have un-
ing their bioactive conformation and how they dergone testing in humans (524-531; see Ref.
bind to opioid receptors compared to the more 475 for areview). Side effects associated with K
rigid alkaloid opiates. Early studies (519-521) receptors include sedation and dysphoric ef- .
attempted to identify possible bioactive con- fects (146). The dysphoric effects are of partic-
formations of U50,488 and its congeners by ular concern and have severely limited the
conformational analysis of the ligands and su- usefulness of the majority of centrally acting K
perimposition of the arylacetamides with ben- agents. Many of the older nonselective com-
zomorphans. With the cloning of opioid recep- pounds possessed high affinity for u and PCP
tors and development of computational sites, raising the possibility that these sites
models of these receptors (see Section 3.2.4.2 might contribute to the dysphoric effects. The
above), several groups (179, 182, 183, 186) benzomorphan Mr2034 (971, which is inactive
have proposed possible binding modes for the at these sites (3931, and the K-selective agonist
arylacetamides docked to the K opioid recep- spiradoline (148) also produce naloxone-
tor. Although all of the models of the arylacet- sensitive dysphoric effects (5321, however, in-
amides docked to K opioid receptors assumed dicating that K receptors mediate psychotomi-
an interaction of the protonated m i n e of the metic effects. Clinical trials of spiradoline for
ligand with Asp13', there are significant differ- the treatment of pain have been discontinued
ences in other proposed receptor-ligand inter- (475). Initial evaluation in humans of enado-
actions in these models (see Ref. 186 for a de- line (CI-977,37, Fig. 7.6) for its diuretic effect
tailed comparison of the models). These found that the dysphoric effects attributable
results illustrate the complexity of modeling to the drug were minimal and not considered
these more flexible ligands and determining clinically significant (5251, although in a sub-
how they interact with their receptors. sequent study of its use in postsurgical pain
HZ2 (163), which is structurally unrelated adverse neuropsychiatric events led to early
to the arylacetamide K-selective agonists, ex- termination of the study (527). Enadoline has,
however, been granted orphan drug status for
the treatment of severe head injuries (475).
Apadoline (RP 60180,160) has been evaluated
in an experimental human pain model and re-
ported to cause fewer side effects than the clin-
ically used agent pentazocine (529). Nirav-
oline (151) was examined for its aquaretic
effect in patients with cirrhosis; the highest
doses examined induced personality disorders,
but moderate doses produced the desired
aquaretic effect and were well tolerated (531).
However, clinical development of this agent
has been discontinued (see Ref. 475). Clinical
investigation of several centrally acting K-se-
hibits reasonable K-receptor affinity (Ki = 15 lective agents (apadoline, DuP 747, enadoline,
nM) with low affinity for p receptors (Ki > and the 4,5a-epoxyrnorphinan TRK-820) has
1000 nM) (521). NMR and molecular modeling continued (288).
studies were performed to compare this novel
bicyclononanone to the arylacetamides and 5.9.2 Peripherally Acting Agonists. Concern
ketocyclazocine (521). The compound is re- over centrally mediated side effects has
Narcotic Analgesics

R = 0CH2C02H (164) (R,S) ICI 204448 (166) R = 0CH2C02H,etc.

V- OH
(167) EMD 60400 (168) Asimadoline
(EMD 61753)

(169) BRL 52974 (170) Fedotozine

Figure 7.33. Peripheral K-receptor selective agonists.

prompted attempts to develop peripherally se- amide side chain phenyl ring and found that
lective K opioid agonists. Peripheral opioid re- the 4-trifluoromethyl group resulted in an an-
ceptors can mediate analgesia, particularly in alog with high K-receptor aMinity and less cen-
cases of inflammation (see Refs. 72-74 for re- tral activity compared to that of the parent ICI
views). To limit penetration of the blood-brain 199441 (536); incorporation of additional
barrier (BBB), generally polar andlor charged functionalities into the central phenyl ring
functionalities have been introduced into the (e.g., 166) were examined to further restrict
compounds (see Ref. 534 for a review). Several the compounds to the periphery (537). Re-
modifications to the K-selective agonist ICI searchers at Merck prepared EMD 60400
199441 (162, Fig. 7.32) have been reported to (167) (538) by introducing an amino substitu-
restrict the compounds, access to the CNS. In ent on the phenyl ring of the phenylacetamide
ICI 204448 (164, Fig. 7.33) an acid functional- side chain and a 3-hydroxyl group on the pyr-
ity was introduced on the central phenyl ring rolidine ring; researchers at Glaxo prepared
(518), and Portoghese and coworkers pre- analogs of GR 103545 with reduced penetra-
pared aspartic acid conjugates of ICI 199441 tion of the BBB by the use of a similar ap-
(165) (535) to decrease penetration into the proach (513). In the case of BRL 52974 (169)
CNS. Investigators at the Adolor Corporation (539), an imidazole ring was attached to the
tested various substituents on the phenylacet- piperidine ring to increase hydrophilicity.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 395

In asimadoline (EMD 61753,168) (540) an been investigated clinically for the treatment
additional phenyl ring was attached a to the of digestive disorders characterized by abdom-
amide on the phenylacetamide side chain, inal pain, namely, dyspepsia and irritable
which increases lipophilicity. This compound bowel syndrome (see Ref. 548 for a review). In
is also a peripherally selective K agonist (541); Phase 111111 studies for both disease states
studies in knockout mice lacking P-glycopro- (549-551) significant improvement of symp-
tein indicate that asmidaloline is transported toms in the patients treated with fedotozide
by P-glycoprotein, and that transport by this compared to placebo was reported. Fedotozine
protein limits the compound's penetration of also relieves visceral hypersensitivity to gas-
the BBB (542). As noted by Barber et al. (541), tric and colonic distention, which are often ob-
served in dyspepsia and irritable bowel syn-
amphiphilic structures such as asimadoline
drome, respectively (552, 553). Although
generally have greater oral activity than hy-
clinical trials of fedotozine have been discon-
drophilic compounds; consistent with this
tinued (see Ref. 475), peripherally selective K
they found that asimadoline exhibits much agonists remain potentially important thera-
greater potency by the oral route than did ICI peutic agents for treatment of these digestive
204448 (in pressure nociception in inflamma- disorders.
tory hyperalgesia: ID,, for asimadoline = 0.2
mgkg S.C.and 3.1 mg/kg p.0. versus ID,, for
5.1 0 Delta-Selective Agonists
ICI 204448 = 0.8 mgkg s.c. and 30 mgkg p.0.).
Oral absorption of asimadoline was not signif-
icantly altered in the P-glycoprotein knockout 5.10.1 BW373U86, SNC 80, and Ana-
mice, indicating that the intestinal P-glyco- logs. Initially, all of the &selective agonists
protein did not impede absorption after oral were peptide derivatives. The first nonpeptide
administration (542). Unexpectedly, increases agonist selective for 6 receptors, BW373U86
in pain were reported in clinical trials of this (26, Fig. 7.5), was discovered by screening
compound in patients after knee surgery (554). The pharmacology of this compound
(543). Subsequent investigation of this com- has been examined in considerable detail (see
pound in inflammation in the rat found that, Refs. 219, 221 for reviews). This compound
although the analgesic effects of asimadoline has only modest selectivity for 6 receptors in
were K opioid receptor mediated, the adverse binding assays (see Table 7.12). In antindci-
hyperalgesic and proinflammatory effects ob- ceptive assays in mice it appears to function as
served were not mediated by opioid receptors a partial agonist at both 6 and preceptors. The
(543). activity of BW373U86 is highly dependent on
Fedotozine (Jo-1196, 170), which is struc- the route of administration, with effects at the
turally related to the acyclic K agonists, has in spinal level mediated by 6 receptors and su-
vivo antinociceptive effects on duodenal pain praspinal effects involving interactions with p
that appear to be mediated by peripheral K receptors (555). In monkeys BW373U86 did
opioid receptors, but the compound is inactive not produce antinociceptive effects in the
after central administration (544). In binding warm-water tail-withdrawal assay after sub-
assays (in dog myenteric plexus), however, cutaneous administration (556). This com-
this compound exhibits similar affinity (Ki = pound also produces convulsant effects in both
0.3-0.8 f l )for all three types of opioid recep- mice and monkeys (556-558), which appeared
tors (545). Unlike other K agonists, fedotozine to be mediated by 6 receptors.
does not induce diuresis after either S.C. or in- BW373U86 is a racemic mixture and this
tracerebroventricular i c v administration could complicate its pharmacological profile.
(546). Fedotozine also fails to substitute for Therefore Rice and coworkers undertook the
either U50,488 or morphine in animals synthesis and characterization of isomers of
trained to discriminate these drugs (547). The BW373U86 (107).The isomers with the R con-
main effects demonstrated for fedotozine have figuration at the benzylic carbon exhibited
been in the gastrointestinal tract (see Ref. 548 greater affinity for S receptors than did the
for a detailed review of the pharmacology of isomers with the S configuration. One com-
fedotozine), and therefore this compound has pound, SNC 80 (27, Fig. 7 . Q the methyl ether
396 Narcotic Analgesics

Table 7.12 Opioid Receptor Affinities, 6 Selectivity, and Opioid Activity in the MVD
of 6 Opioid Agonistsa
*IC,, or Ki (nM) Ic50 Ic50
Ratio (nM)
Agonist 6 P K CL/6 MVD Reference
BW373U86 (26)
SNC 80 (27)

172
(-) SL-3111(174)
(-) 175
176
177
(?) TAN 67 (28)
(SB205607)
(-1 TAN 67
(SB213698)
(+) TAN 67
(SB213697)
(-) 178

"Data for BW373U86, SNC 80, and TAN 67 fiwm Table 7.8 are included for comparison.
'IC,, in the GPI are 143 and 5500 nMfor BW373U86 and SNC 80, respectively.
'IC,, in the GPI is 26,500 n M

of (+)-BW373U86,exhibited marked selectiv- substituted with other groups with retention


ity for 6 over p receptors in binding and of &receptor affinity and selectivity; the deriv-
smooth muscle assays (see Table 7.12) (107, ative without a substituent at this position has
559), making it the most &selective nonpep- higher 6 affinity and selectivity [IC,, = 0.94
tide agonist reported. SNC 80 is a systemically nM, IC,, (p/S) ratio > 26601 than that of SNC
active 6 receptor selective agonist, with its an- 80 (561). The amide functionality is particu-
tinociceptive actions produced through inter- larly sensitive to modification, with the N,N-,
action with both 6, and S2, but not p, opioid dialkylbenzamide derivatives having higher
receptors (559). SNC 80 is more effective in 6-receptor aMinity than the monosubstituted
nociceptive assays than BW373U86, and con- or unsubstituted derivatives (562). This sug-
sistent with its higher selectivity for 6 recep- gests that the amide group is an important
tors, the antinociceptive effects of SNC 80 ap- structural feature for interaction with S
pear to be mediated only by 6 receptors (see receptors.
Ref. 221). Brief, nonlethal seizures were ob- Modifications can be made to the pipera-
served in mice only at very high doses of SNC zine ring, including removal of the methyl
80 (100 mg/kg) (559);this may be attributable groups and replacement of N1 by carbon, with
to metabolism of SNC 80 to a BW373U86-like retention of reasonable 6-receptor affinity and
compound (560). In monkeys SNC 80 does not selectivity (563, 565, 566). A series of simpli-
cause convulsions at doses up to 32 mg/kg, fied piperazine derivatives were prepared, in-
suggesting it may be safer than BW373U86 cluding (171) (Fig. 7.34), with improved 6-re-
(221). ceptor selectivity (IC,, ratio = 1240 versus
Several groups have explored the SAR of 245 for SNC 80) and increased metabolic sta-
SNC 80. Rice and coworkers examined substi- bility over that of SNC 80 (567).A piperidinyli-
tutions for the methoxy group on the phenyl dene derivative of SNC 80 with a double bond
ring (561), modifications of the amide func- to the benzylic carbon exhibits higher Srecep-
tionality (562),modifications to the piperazine tor affinity than that of the corresponding pi-
ring (563),and different substitutions on N4 of peridine derivative (563). Researchers at
the piperazine ring (564). The methoxy group AstraZeneca examined an extensive series of
on the one phenyl ring of SNC 80 could be these piperidinylidene analogs (568) and iden-
?

i
1;i 5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 397
i

Figure 7.34. SNC 80 analogs.


Narcotic Analgesics

tified derivatives (e.g., 172) that exhibited ex- diarylaminotropane derivatives (176) were
tremely high selectivity for 6 receptors (see reported by two groups (574, 575), with the
Table 7.12) and were considerably more stable unsubstituted derivative exhibiting high S-re-
to degradation by rat liver microsomes than ceptor affinity and exceptional 6 selectivity
was SNC 80 (568). Interestingly, the analog (see Table 7.12) (575); the N-ally1 and related
DPI 2505 (173) in which the 2-methyl group is derivatives exhibit decreased efficacy and an-
shifted to the 3 position has been reported to tagonist activity in the [35SlGTPyS assay
be an antagonist (228). The basic N4 nitrogen (574). In an alternative approach chosen to
is critical for 6 receptor binding, and opening yield achiral 6 agonists without the compli-
the piperizine ring also results in large de- cated stereochemistry of SNC 80, researchers
creases (>60-fold) in &receptor affinity (563). at R. W. Johnson also prepared a series of
A variety of alkyl substituents on N4 of the piperazinyl benzamidines (576); the highest
piperazine ring are tolerated by the 6 receptor affinity ligand (177) exhibited affinity and se-
(564, 566), but SNC 80 analogs containing a lectivity similar to SNC 80 (see Table 7.12). A
saturated alkyl group exhibit decreased effi- number of other SNC 80 analogs described in
cacy compared to SNC 80 in the [35S]GTPyS the patent literature were reviewed by Dondio
assay; the N-cyclopropylmethyl analog is also (219, 220).
a partial agonist (564). Thus the SAR of the One question is how SNC 80 interacts with
nitrogen substituent of SNC 80 for S-receptor 6 opioid receptors compared to the more clas-
affinity is distinctly different from the SAR of sical morphinan ligands. Dondio et al. (577)
this group in the morphinans for interaction compared SNC 80 to the S antagonist SB
with p receptors. 205588 (78, Section 5.3.3). In this model the
Hruby and coworkers designed a series of basic N4 nitrogen and the oxygenated phenyl
piperazine derivatives as peptidomimetic ana- ring of SNC 80 were superimposed on the cor-
logs of the 6 selective peptide [(2S,3R)- responding groups in SB 205588, with the cen-
TmtllDPDPE (Tmt = 3,2',6'-trimethylty- troid of the second phenyl ring of SNC 80 over-
rosine) (569, 5701, with SL-3111 (174) (see lapped with the pyrrole ring of SB 205588.
Table 7.12) as the lead compound. Although Based on this model, it was hypothesized that
SL-3111 is structurally similar to SNC 80, the the amide group of SNC 80 might function as a
large decrease in S-receptor affinity upon nonaromatic 6 "address" and thus be resp9n-
methylation of the phenol and the high afin- sible for the 6 selectivity of SNC 80. Loew and
ity of SL-3111 for the W284Ll mutated hu- coworkers in their pharmacophoric model for
man 6 receptor is in contrast to the results for a wide range of 6 receptor ligands also overlaid
SNC 80 and more closely parallel those for the the basic N4 nitrogen and oxygenated phenyl
peptide p-C1-DPDPE, suggesting that the ring of SNC 80 with the corresponding groups
binding profile of SL-3111 is more similar to in the epoxymorphinans, with the amide occu-
that of the peptide than to SNC 80 (569). pying the third site in the three-point model
A series of 4-aminopiperidine derivatives for &selective opioid recognition (578). Coop
was designed by researchers at the Research and Jacobson, however, developed a four-
Triangle Institute by transposition of the N4 point pharmacophoric model based on a series
of the piperazine ring and the benzylic carbon of 4,5a-epoxymorphinans with high affinity
(571-573), with the cis (3S,4R) isomer (175) for 6 receptors and found that SNC 80 did not
exhibiting the highest affinity. This transposi- fit the model, suggesting that SNC 80 does not
tion decreased 6-receptor affinity while in- bind to the 6 receptor in the same orientation
creasing preceptor affinity, such that the pi- as oxymorphindole (579).
peridines exhibited somewhat lower 6 Mutational analysis of S opioid receptors
selectivity than the piperazine derivatives (see has found that three residues, Trp284at the
z
Table 7.12). A large series of these 4-aminopi- top of TM6 and Val g6 and in the third
peridine analogs was also prepared by re- extracellular loop, are crucial for the S-recep-
searchers at R. W. Johnson Pharmaceutical tor affinity of SNC 80 as well as other 6-recep-
Institute and subjected to CoMFA analysis tor agonists (166). Computational models of
(188). Recently, a series of constrained 4- BW373U86 (182) and Caminopiperidine ana-
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 399

logs of SNC 80 (188) docked to the 6 receptor was active in the tail flick assay in diabetic
have been described. In the models the basic mice (58211;antagonism by BNTX but not nal-
nitrogen and oxygenated phenyl ring of these triben suggested that TAN 67 produced its an-
compounds occupy similar regions in the re- tinociceptive effects through 6, receptors
ceptors as the corresponding groups in the ep- (583).
oxymorphinans, although there are some dif- The pharmacological effects of the two en-
ferences in the exact location of the two types antiomers of TAN 67 are distinctly different
of compounds and orientation of their phenyl (see Ref. 584 for a review). (-) TAN 67 (also
rings (see Ref. 182). In both models the benz- named SB 213698 by the Italian group), which
amide ring occupies a region at the TMIextra- has the same absolute configuration as that of
cellular interface, and interacts with one or morphine, shows high affinity and selectivity
more of the residues identified as critical from for 6 receptors (Table 7.121, and is a full ago-
mutagenesis studies. Comparison of the dock- nist in the MVD (5801, whereas the (+) isomer
ing of SIOM with the 4-aminopiperidine com- is inactive in vitro. I n vivo (-1 TAN 67 exhibits
pounds suggested that the benzamide ring oc- antinociceptive activity in the tail flick assay
cupies a similar region to the spiroindane of after both i.c.v. (585) and intrathecal (i.t.1
SIOM, consistent with the pharmacophoric (586) administration, which appears to be me-
models, and thus functions as an "address" to diated by 6, receptors. Whereas (+) TAN 67
target the compounds to the 6 receptor (188). was inactive after i.c.v. administration (585),
after i.t. administration (+) TAN 67 produced
5.1 0.2 Other &Receptor Agonists. Attempts nociceptive behavior (586); interestingly, the
to identify Sselective agonists related to the effects of (+) TAN 67 were blocked by both
epoxymorphinans have concentrated in two naltrindole and ( -) TAN 67 (584). ( -) TAN 67
areas. Modification of the nitrogen substitu- exhibits decreased affinity for the [W284L]
ent of NTI resulted in the identification of mutated 6 receptor compared to the wild-type
SIOM as a 6, agonist (see Section 5.3.3 above). receptor, but the magnitude of the decrease is
Other 6-selective agonists identified have been less than that for SNC 80 (587). In contrast
octahydroisoquinolines. As discussed earlier this mutation increases the intrinsic activity
(Section 5.3.31, octahydroisoquinolines are ei- of SNC 80 (indicated by an increase in the
ther antagonists or agonists, depending on the maximum [35SIGTPyS binding), but it de-
ring size of the spacer. Although compounds creases the intrinsic activity of (-1 TAN 67,
with five-membered ring spacers are brecep- suggesting that these compounds may inter-
tor antagonists, introduction of a six-mem- act with different active receptor conforma-
bered ring spacer, explored by both Japanese tions (587). In a recent report of a pharma-
and Italian researchers, resulted in a new cophoric model for the 6 opioid receptor, low
class of Breceptor agonists (108,358,580; see energy conformations of TAN 67 were identi-
Refs. 109,219 for reviews), with TAN 67 (28, fied in which the phenol, the basic m i n e , and
Fig. 7.5) (108, 109) being the most extensively the second aromatic m i n e could be superim-
studied. The rationale for the design of TAN posed on the corresponding groups in OM1
67 by the Japanese group involved making the and SIOM (588).
phenol ring freely rotatable by removing the Based on their comparison of the antago-
4,5-epoxy and 10-methylene functionalities of nist SB 205588 and SNC 80 and the resulting
the epoxyrnorphinans and using a heteroatom hypothesis that the amide of SNC 80 might
capable of forming a hydrogen bond with the function as a nonaromatic "address", Dondio
receptor as an additional pharmacophoric and coworkers prepared pyrrolooctohydroiso-
group (109). Racemic TAN 67 shows high af- quinolines (178) (Fig. 7.35) lacking the second
finity and selectivity for 6 receptors (Table aromatic ring, which exhibit high 6-receptor
7.12) (log), and is a potent agonist in cloned 6 aMinity and selectivity (see Table 7.12) (577).
human cells (581), and in the MVD (109). I n The analog in which the pyrrole ring was in
vivo racemic TAN 67 exhibits antinociceptive the opposite orientation (179) also retained
activity in the acetic acid writhing assay, but high &receptor affinity (Ki = 3 nM), suggest-
not the tail flick test, in normal mice [TAN 67 ing that this ring functions as a spacer (589).
Narcotic Analgesics

Figure 7.35. Other nonpeptide &receptorselective agonists.

An attempt has also been made to con- exhibited somewhat higher Breceptor affinity
vert 5-(3-hydroxypheny1)-2-methylmorphan, and potency, but the selectivity for 6 receptors
which has negligable &receptor affinity, to was still low [IC,, ratio ( ~ 1 6values
) of 18 and
6-selective agonists by use of the "message- 7, respectively] (591).
address" concept (590). Addition of an indole Recently, a new type of nonpeptidic 6 ago-
ring system to the morphan skeleton, to give nist (182), which lacks a basic nitrogen, was
(180), increased 6-receptor affinity more than identified by high throughput screening (592).
140-fold (IC,, = 7 nM); this structural change Further structural modification of this lead
had little effect on preceptor affinity, how- compound to improve its water solubility led
ever, so that the selectivity of this compound to a series of amide derivatives (e.g., 183) with
for 6 receptors was low [IC,, ratio ( ~ 1 6=) 4.21. modest 8-receptor affinity (IC,, = 37-256 nM)
Based on differences between the SAR of SNC and in vivo potency comparable to TAN 67
80 and the indole phenylmorphan derivatives, (593).
Rice and coworkers postulated that the indole
5.1 1 Nonpeptide Affinity Labels Used to
phenyl ring, not the phenol, of the indole phe-
Study Opioid Receptors
nylmorphans might be structurally analogous
to the methoxyphenyl group on SNC 80. Affinity labels, ligands that interact with re-
Therefore, they prepared a series of methoxy- ceptors in a nonequilibrium manner, are use-
substituted derivatives of (180); the C9' and ful pharmacological tools to study opioid re-
C10' substituted derivatives (181, Fig. 7.35) ceptors and receptor-ligand interactions.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

Receptor type A
X

Receptor type B

G'

-
1 " Recognition
N O reaction

Receptor type C
Figure 7.36. Two-step mechanism for covalent binding of an affinity label containing a selective
electrophilic group X with receptor type A. Although receptor types A-C have similar topographical
features that lead to reversible binding (lorecognition), they differ with respect to the reactivity of
the receptor-based nucleophiles (G1and G2)and their locations. Only with receptor type A is the
nucleo~hileG1reactive with resvect to X and within covalent binding distance (2" recognition) (from
Ref. 3i9).

Tritiated affinity labels have been useful in highly reactive intermediates, most often a ni-
rece~torisolation and for determination of the
A
trene or carbene, upon exposure to light of the
molecular weights of solubilized receptors (see appropriate wavelength and these reactive
Refs. 86, 99 for reviews). These compounds species then can react covalently with the re-
can be used to irreversibly block one or more ceptors. Reaction of affinity labels with recep-
receptor type in tissues containing multiple tors involves a two-step mechanism (Fig. 7.36)
receptor types, so that the remaining receptors (319, 594). Initially the ligand binds to the re-
can be studied in isolation. The covalent binding ceptor reversibly, followed in the second step
of a n i t y labels can be used to study receptor- by covalent bond formation between the reac-
l i-m d interactions. Thus Liu-Chen and cowork- tive functionality on the ligand and a group on
ers have characterized the binding of the a n i t y the receptor. Depending on the nature of the
labels p-funaltrexamine (P-FNA)and SUPER- reactive functionality on the affinity label, the
FIT to p and S receptors, respectively, by use second step can enhance receptor selectivity.
of a combination of molecular biology ap- Whereas an electrophilic affinity label may
proaches and protein isolation (see below). bind reversibly to more than one receptor
There are two types of affinity labels based type, covalent bond formation requires the
on the type of reactive functionality. Electro- proper juxtaposition of an appropriate nucleo-
philic affinity labels contain an electrophilic phile on the receptor with the electrophilic
group that can react with nucleophiles on the group on the ligand (see Fig. 7.361, so that
receptor. Photoaffinity labels are converted to covalent binding can occur to only one type of
Narcotic Analgesics

(188) PNTl
0
OH

R = allyl, CPM, or CH3

Figure 7.37. Affinity label derivatives of naloxone, morphine, and naltrindole.

receptor; examples of electrophilic affinity la- reactivity of the photolyzed intermediate is so


bels that exhibit such enhanced selectivity are high that they can react with almost any resi-
P-FNA (186, Fig. 7.37) and naltrindole iso- dues on the receptor, and therefore the selec-
thiocyanate (NTII, 47, Fig. 7.8) (see below). In tivity is determined only by the first reversible
the case of photoaffinity labels, however, the step in the mechanism.
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands 403

A variety of affinity labels, mostly nonpep- receptors. [There are conflicting reports on
tide ligands, have been prepared for opioid re- whether the effects of P-FNA on 6 receptors
ceptors. Detailed reviews of the structure-ac- are irreversible (605, 606).] The orientation
tivity relationships for affinity labels have and configuration of the fumaramide func-
been published [see the previous edition of tionality are important for irreversible bind-
this chapter (286) and Refs. 319, 594-5961. ing to p opioid receptors; neither the 6P-male-
Therefore the discussion below focuses on imide with a cis double bond nor a-FNA with'
those ligands that have been most useful in the electrophile in the 6a position is an irre-
the characterization of opioid receptors, and versible p antagonist (605). Examination of
on recent reports of new affinity label deriva- the conformations of a- and P-FNA by X-ray
tives. diffraction (607) offers insight into the differ-
ences in reactivity of these two isomers. The
5.1 1 .I Morphine and Naltrexone Deriva- conformations of the ring system in the two
tives. A variety of morphine and naltrexone compounds are almost identical except for the
derivatives have been prepared that incorpo- C ring, which is in a twist-boat conformation
rate a reactive functionality, often at the 6 po- for the a isomer and a chair conformation for
sition (Fig. 7.37). Incorporation of a nitrogen P-FNA (see 186). The fumarate group is then
mustard at the 6P position of naltrexamine by equatorial in both compounds, which when
Portoghese and coworkers yielded p-chlornal- the morphinan skeletons are superimposed
trexamine (p-CNA, 184) (597, 598), the first places the fumarate double bond in a-FNA
successful opioid antagonist affinity label. more than 2 A away from the double bond in
This compound is a potent affinity label that P-FNA and in the wrong orientation for reac-
because of the reactivity of the nitrogen mus- tion with a nucleophile on the receptor.
tard blocks all opioid receptor types (see Ref. The binding of P-FNA to p opioid receptors
594). It has been a useful tool in studying opi- was examined by Liu-Chen and coworkers by
oid receptors and has been used to single out a use of a combination of molecular biology ap-
specific receptor type in tissues containing proaches and protein isolation. These studies
multiple receptor types. The desired receptor illustrate the utility of using affinity labels to
type for study can be protected by incubation study receptor-ligand interactions. The bind-
with a ligand selective for that receptor and ing of [3H]P-FNA to p / ~receptor chimeras
the tissue subsequently treated with P-CNA to suggested the region of the receptor from the
irreversibly block the remaining opioid recep- middle of the third extracellulular loop (EL31
tors (133, 134, 599). Only one of the chloro- to the C-terminus was necessary for irrevers-
ethyl groups of p-CNA is required for irrevers- ible binding to p receptors (608). Subsequent
ible antagonist activity (600). The nitrogen isolation and partial purification of the labeled
mustard analog of oxymorphone, p-chloroxy- receptor and digestion with CNBr, however,
morphamine (P-COA, 185)(601,6021, has also
-
located the point of attachment of P-FNA to
been prepared. It is a potent irreversible ago- the EL2-TM5 region of the receptor; subse-
nist in the GPI and appears to bind irrevers- quent site-directed mutagenesis of residues in
ibly to opioid receptors in vivo; in vivo, it ini- this region indicated that the point of attach-
tially produces analgesia followed by a long- ment was Lys233at the EL2-TM5 interface,
lasting antagonism of morphine analgesia which is a conserved residue among the opioid
(602,603). receptors (177). Thus the selectivity of P-FNA
To obtain affinity labels selective for a sin- irreversible binding for p opioid receptors ap-
gle receptor type, Portoghese incorporated pears to be due to differences in the tertiary
less reactive electrophiles at the 6P position structure of the receptor, not the primary se-
leading to the preparation of P-FNA (186) quence. This illustrates the subtleties of re-
(604). This compound illustrates how the sec- ceptor-ligand interactions and the importance
ond step in the mechanism of affinity labels of examining receptor-ligand interactions
can enhance selectivity; whereas P-FNA inter- directly.
acts reversibly with K receptors, where it is an Recently, Portoghese and coworkers re-
agonist, it is an irreversible antagonist at p ported the phthalaldehyde derivatives of 6P-
Narcotic Analgesics

naltrexamine (187) and naltrindole (188) as been incorporated into the indole N-benzyl ar-
"reporter affinity labels" (340, 609). Reaction omatic ring of the 6,-selective antagonist N-
of the phthalaldehyde group with an amine benzylnaltrindole (BNTI, 75) to give (190)
and thiol (from Lys and Cys side chains, re- (617). Interestingly, the meta-substituted iso-
spectively, in the receptor) results in a fluores- thiocyanate derivative was an irreversible 6
cent isoindole; detection of fluorescence indi- agonist in the MVD; the ortho- and para-
cates that covalent reaction has occurred. In substituted isothiocyanates and the haloaceti
contrast to naltrindole, the phthalaldehyde amides were 6-receptor antagonists that
derivative PNTI (188) is an agonist in the exhibited time-dependent increases in antag-
mouse vas deferens, leading to the proposal onism consistent with covalent interaction
that the covalent binding of PNTI to 6 opioid with 6 receptors. In uiuo, these compounds
receptors results in a conformational change were less selective for 6, over 6, receptors than
in the receptor and agonist activity (340). BNTI.
Pasternak and coworkers have prepared a A number of 14P-amino substituted deriv-
series of hydrazone derivatives of the 6-ketone atives containing electrophilic groups (Fig.
of naloxone, naltrexone and oxymorphone 7.38) were prepared by Archer and coworkers
(189, Fig. 7.37) (209,210, 610). Prolonged ac- [see the previous edition of this chapter (286)
tions in uiuo and nonequilibrium binding in for a detailed review]. Reactive functionalities
uitro have been reported for several of these that have been attached to the 14P-amino
compounds. The hydrazone naloxazone (48, group include bromoacetamide, thioglycol-
Fig. 7.8) (209) and the corresponding azine amide, and cinnamoyl groups. The naltrexam-
naloxonazine (49) (210) have been used to ine derivative clocinnamox or C-CAM (191)
characterize the postulated pl-receptor sub- (618) has been the most extensively studied
type (see Ref. 208); the azines are 20- to 40- and is a potent long-lasting p antagonist (619-
fold more potent than the corresponding hy- 621). Binding studies indicated that clocin-
drazones (210). Studies with [3H]naloxazone namox selectively decreases the density of p
suggested that a portion of the binding may receptors (621), but not of S or K receptors
involve covalent interaction with pl-receptors (622), without affecting receptor affinity, as
(611); other researchers, however, have not would be expected for an irreversible ligand. A
found evidence for irreversible binding to opi- subsequent examination of [3H]clocinnamox
oid receptors (612, 613). The acylhydrazone binding to mouse brain membranes, however,
naloxone benzoylhydrazone [Nal(Bzo)H, 50, (623) found that the binding was fully revers-
Fig. 7.81 exhibits extremely slow dissociation ible, although half of the binding dissociated
from p receptors ("pseudoirreversible" bind- very slowly (t,,, = 11 h). The p-nitro-substi-
ing), which may be related to interactions with tuted derivative with a 5P-methyl group MET-
a G-protein (614); it also binds reversibly to K CAM0 (194) was the first N-methyl derivative
receptors and the tritiated form has been used reported with long-lasting p-receptor selective
to characterize the proposed K,-receptor sub- antagonist activity with no agonist activity
type (see Section 3.2.4.3) (217,615). (624); it appears to bind irreversibly to p re-
Portoghese and coworkers prepared deriv- ceptors (625,626). Like MET-CAMO, the cor-
atives of the 6-selective antagonist naltrindole responding p-chloro-substituted, 5p-methyl
containing reactive functionalities as affinity derivative MET-C1-CAM0 (195) is also along-
labels for 6 receptors. An isothiocyanate group lasting p-receptor antagonist with no agonist
was incorporated at the 5' position of naltrin- activity, which appears to bind irreversibly to
dole to give NTII (47, Fig. 7.8) (196), which is p receptors (627). The p-methyl derivative of
a potent and selective nonequilibrium S-recep- clocinamox, methocinnamox or M-CAM (193),
tor antagonist. NTII antagonizes the antino- has been reported to be a more p receptor se-
ciceptive activities of [D-Ala2]deltorphin11and lective, long-lasting antagonist in uiuo than
DSLET, but not that of DPDPE, and therefore clocinnamox or P-FNA (628), although in
was proposed to be a selective 6,-receptor an- standard binding assays, like clocinnamox, its
tagonist (616). Electrophilic moieties, either selectivity for p receptors is very low (Kiratio
an isothiocyanate or haloacetamide, have also = 3-8). Recently, the relative importance of
5 Structure-Activity Relationships of Nonpeptide Opioid Ligands

R = H, X = CI (191) Clocinnamox (C-CAM) X = NO2 (194) MET-CAM0

R = CH3, X = CI (192) MC-CAM X = Cl (195) MET-CI-CAM0

R = H, X = CH3 (193) M-CAM

Figure 7.38. Affinity label derivatives of naloxone and morphine containing a reactive functionality
at the 14P position.

the 3-hydroxyl group to the opioid receptor illustrates how much the alkylation step can
affinity of clocinnamox was examined by pre- influence the receptor selectivity of affinity la-
paring both a series of 3-alkyl ether deriva- bels. Both BIT and FIT have been prepared in
tives (629) and the 3-deoxy analog (630). In- tritiated form (631) and r3H]FIT used to
terestingly, in the 3-alkyl ether derivatives the specifically label a 58-kDa protein from
identity of the alkyl group affects efficacy. In NG108-15 cells (632). The enantiomeric pair
vivo, the 0-methyl derivative MC-CAM (192) of the cis-&methyl derivatives of FIT were
is a p-partial agonist, the propargyl ether is a synthesized and one of these isomers, the (+)-
potent agonist, and the cyclopropylmethyl an- 3R,4S enantiomer, SUPERFIT (198) was
alog is a long-lasting antagonist with little ag- found to be a very potent (5-10 times the po-
onist activity; both the methyl and propargyl tency of FIT) and selective irreversible ligand
ethers exhibit delayed long-lasting antagonist for 6 receptors (458). SUPERFIT was used to
activity. The 3-deoxy analog exhibits high p purify 6 receptors from NG108-15 cells to ap-
opioid receptor affinity comparable to that of parent homogeneity (633). Liu-Chen and co-
clocinnamox, indicating that the C,-hydroxyl workers used similar approaches to those de-
does not play a significant role in the binding scribed above for P-FNA to study the binding
of these 14P-cinnamoyl epoxymorphinans to of SUPERFIT to 6 opioid receptors. The re-
opioid receptors; the deoxy derivative exhibits sults for wash-resistant inhibition of binding
greater selectivity for p over 6 receptors than to A6 chimeric receptors suggested that the
clocinnamox. segment from the start of the first intracellu-
lar loop to the middle of TM3 of 6 receptors is
5.1 1.2 Other Nonpeptide Affinity Labels. important for the selective irreversible bind-
Rice and coworkers prepared a variety of affin- ing of SUPERFIT (634). The enantiomeric
ity labels on the basis of the structures of eto- pair of the trans-3-methylfentanyl isothiocya-
nitazine, fentanyl, and oripavine (Fig. 7.39) nates have also been prepared (199). The (+)-
(198, 461). The etonitazene derivative BIT 3S,4S isomer was a Bselective acylating agent
(196) selectively inactivates p receptors, in vitro, with potency similar to that of SU-
whereas the fentanyl derivative FIT (fentanyl PERFIT, and has been used to selectively de-
isothiocyanate,197) and the oripavine deriva- plete S, binding sites (see Section 3.2.4.3
tive FA0 (fumaramido oripavine, 200) selec- above) (200).
tively inactivate 6 receptors. The selective al- Several derivatives of K-selective com-
kylation of 6 receptors by FIT, which is a pounds containing an isothiocyanate have
derivative of the p-selective ligand fentanyl, been prepared as potential irreversible ligands
Narcotic Analgesics

S=C=N

iN(cH2cH
Q- dNLC
abQ I

0CH2CH3
N

R1 0 .>

(196) BIT R1 = R2 = H (197) FIT

(202) UPHIT (203) DIPPA (S)

Figure 7.39. Other nonpeptide affinity labels.

for K receptors (Fig. 7.39). de Costa et al. pre- pig brain. This led de Costa and coworkers to
pared analogs of U50,488 (201) and (202) prepare UPHIT (202), the chlorine-contain-
(635-637). In the series of enantiomerically ing analog of (201), to improve affinity and
pure analogs of (201) the (-1-1S,2S isomers selectivity (636). In contrast to (201), this
generally exhibited wash-resistant inhibition compound inhibited binding to K receptors af-
of binding of [3H]U69,593 to guinea pig brain ter i.c.v. administration (636). In vivo, in mice
membranes, but none of the compounds irre- UPHIT antagonizes antinociception produced
versibly inhibited the binding of [3H]bremazo- by U69,593, but not by bremazocine, provid-
cine to either guinea pig or rat brain mem- ing additional supporting evidence for K-re-
branes (635, 637), supporting the conclusion ceptor subtypes (638).
of heterogeneity of K receptors. The (-)-o-iso- Isothiocyanate derivatives of the K-selec-
thiocyanate isomer of (201) exhibited selec- tive agonist ICI 199441 have also been de-
tive wash-resistant inhibition of [3HlU69,593 scribed. Chang et al. prepared the m-isothio-
binding, and was the most potent in vitro, but cyanate derivative DIPPA (203) (639, 6401,
it failed to produce any irreversible inhibition which exhibits wash-resistant inhibition of
of K receptors after i.c.v. injection into guinea L3H1U69,593 binding and long-lasting K re-
6 Opioid Peptide Analogs 407

ceptor antagonism in vivo. Liu-Chen and co- tive. This clinically used analgesic is a mixed
workers examined the binding of the corre- agonistlantagonist (645) (see Table 7.3) with
sponding p-isothiocyanate derivatve to p / ~ partial p agonist activity; it may also have ac-
chimeric receptors and determined that the tivity at K receptors (see Ref. 307). The cyclo-
region from TM3 to the C-terminus of the K hexane derivative tramadol (Ultram, 206) is
receptor is important for the binding of this an atypical analgesic (see Refs. 307, 646, 647
compound (641). Nelson and coworkers in- for reviews), which appears to produce analge-
corporated the isothiocyanate in the phenyl- sia through both opioid and nonopioid mecha-
acetamide phenyl ring of ICI 199441 (642). nisms (648). Tramadol antinociception ap-
These isothiocyanate analogs all exhibited pears to be mediated through both activation
wash-resistant inhibition of binding, whereas of p opioid receptors, where it exhibits low af-
the parent compound with an unsubstituted finity (Ki = 2 @ I)
and by ,
inhibition of mono-
phenylacetamidephenyl ring was completely re- amine uptake. Examination of the isomers of
moved by washing; the lead compound ICI tramadol (649) found that although the (+)
199441, with chlorines on this ring but without enantiomer had higher affinity for p receptors
the isothiocyanate group, however, was not (Ki = 1.3 piW, the activities of the isomers
completely removed by the washing procedure. were complementary and synergistic. Other
A number of photoaffinity label derivatives recently reported compounds with opioid
of opiates have also been prepared [see the receptor affinity and activity include pyrroli-
previous edition of this chapter (286) and Ref. dinylnaphthalenes, which are structurally
594 for more detailed reviews]. Azide deriva- related to heterosteroids (650). Highly con-
tives of a number of different opiates, includ- strained tricyclic piperazine derivatives (207)
ing etonitazene, carfentanil, and 6a- and 6P- and (208) were prepared, which are structur-
substituted naltrexamine derivatives, have ally related to the 4-anilidopiperidines and
been prepared (see Ref. 286). A significant which exhibit reasonable affinity (Ki values of
problem with using opioid photoaffinity labels 10 and 7 nM,respectively) and selectivity [Ki
is the sensitivity of opioid receptors to destruc- ratio (p/6/~)= 1/230/300 and 1/71/110] for p
tion by short-wavelength UV irradiation receptors; in vivo, (208) is a sixfold more po-
(643). Incorporation of a nitro group into the tent analgesic than morphine (651). 3-Amino-
aromatic ring bearing the azide functionality 3-phenylpropionamide derivatives were pre.-
shifts the absorption maximum so that photo- pared as small molecule mimics of the peptide
lysis can be conducted at longer wavelengths, antagonists CTOP and CTAP and analogs
where little if any photodestruction of opioid identified with high affinity for p and K opioid
receptors occurs. receptors (e.g., 209) (652).
5.1 2 Miscellaneous Nonpeptide Opiates
6 OPlOlD PEPTIDE ANALOGS
A variety of compounds in other chemical
classes have also been identified that have an-
6.1 Introduction
algesic activity (see Ref. 466). In addition to
the K-receptor selective arylacetamides, such The identification of the opioid peptides in the
as U50,488 and related compounds, the ben- mid-1970s opened up a whole new area for the
zodiazepine tifluadom (147) is a K agonist (see development of opioid receptor ligands. The
Section 5.9). The benzimidazole etonitazene endogenous opioid peptides, both mammalian
(204, Fig. 7.40) is a potent analgesic, having and amphibian (see below), have served as
approximately 1500 times the potency of mor- lead compounds that have been extensively
phine in mice (6441, and is a preceptor ago- modified to enhance potency, receptor type se-
nist. The aminotetralin dezocine (205) bears lectivity, stability, and/or decrease conforma-
some resemblance to the benzomorphans and tional flexibility. Peptide ligands selective for
contains a phenol and basic amino group; in both p and S opioid receptors are found in
contrast to other opiates, however, the m i n e more than one type of peptide sequence. Thus
group is a primary amine. Dezocine is the levo some enkephalin analogs, as well as the re-
isomer of the p epimer; the (+) isomer is inac- cently discovered endomorphins, analogs of
Narcotic Analgesics

Etonitazene

-
(205) Dezocine (206) Tramadol

Figure 7.40. Miscellaneous nonpeptide opiates.

the peptide P-casomorphin (derived from ca- tagonists, have been prepared, and novel pep-
sein) and the amphibian peptide dermorphin, tides with opioid receptor affmity have been
preferentially interact with p opioid receptors identified through the use of combinatorial ap-
(see Sections 6.2.1, 6.4.1, and 6.5.1 below). proaches (see Section 6.6). Affinity label deriv-
Other enkephalin analogs, as well as analogs atives of opioid peptides that bind irreversibly
of the amphibian peptides the deltorphins, to opioid receptors have also been identified
preferentially interact with 6 opioid receptors (see Section 6.7). In addition to preparing an-
(see Sections 6.2.2 and 6.5.2 below). For K re- alogs of opioid peptides, inhibitors of opioid
ceptors the endogenous opioid peptides identi- peptide metabolism have been developed as an
fied to date have been limited to one class of indirect approach to using opioid peptides as
peptides, the dynorphins (see Section 6.3 be- potential therapeutic agents (see Section 6.8).
low). Peptides with aMinity for opioid recep- Much of the early SAR of the enkephalins
tors, which have sequences completely differ- has been discussed in a classic review by Mor-
ent from those of the endogenous opioid ley (653) and in The Peptides, Volume 6 (654).
peptides, have also been identified. Analogs of Subsequent reviews of opioid peptides include
somatostatin, which are p opioid receptor an- those by Hruby (655, 656) and Schiller (657,
6 Opioid Peptide Analogs

Derrnorphin (212) Tyr-D-Ala-Phe-Gly-Tyr-Pro-SerNH2

Deltorphin (dermenkephalin,deltorphin A, 213) Tyr-D-Met-Phe-His-Leu-Met-AspNH2

[D-~la~ldeltorphin
I (deltorphin C, 214) Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2

[D-~la~ldeltorphin
I I (deltorphin B, 25) Tyr-D-Ala-Phe-GIu-Val-Val-GlyNH,

Figure 7.41. Opioid peptides from frog skin.

658),which contain extensive tabular data. An 6.1 .I Opioid Peptides from Amphibian Skin.
issue of Biopolymers (Peptide Science) (Vol.
Based on their finding amphibian skin pep-
51, Number 6, 1999) is devoted solely to re-
tides, which were counterparts to other mam-
views of peptide and peptidomimetic ligandsmalian bioactive peptides, Erspamer and co-
for opioid receptors. The reader is referred to
workers examined amphibian skin for opioid
these reviews for additional references to the
peptides (see Ref. 663 for a review). This led
literature. first to the isolation and characterization of
In addition to the four classes of opioid pep-
dermorphin (212, Fig. 7.41), which is a p-se-
tides discussed earlier (Section 3.4), other pep-
lective peptide (see Table 7.13), from the skin
tides of mammalian origin with opioid activity
of South American Phyllemedusinae hylid
have also been identified. p-Casomorphin frogs in the early 1980s (664). Inspection of
(210),obtained by enzymatic digestion of the
the sequence of one of the cloned cDNAs for
milk protein casein (659, 6601, exhibits some
the precursor of dermorphin suggested the ex-
selectivity for p receptors. Human p-casomor-
istence of another heptapeptide with a similar
phin (211) differs from the bovine sequence in
N-terminal sequence (665). This then led to
two positions; the human p-casomorphin pen-the isolation of deltorphin (also called dermen-
tapeptide and tetrapeptide fragments are less
kephalin or deltorphin A, 213, Fig. 7.41), the
potent than the corresponding bovine pep- first &selective amphibian opioid peptide,
tides (661). Other peptides with affinity for
from these frogs (666, 667). Synthesis con-
opioid receptors include peptides derived from
firmed that the amino acid in position 2 of
hemoglobin (see Ref. 662). deltorphin was D-methionine rather than
L-methionine (666, 668, 669). Two additional
Bovine p-casomorphin (2 10) peptides [D-Ala2]deltorphinI (also referred
to as deltorphin C, 214, Fig. 7.41) and
Tyr-Pro-Phe-Pro-Gly-Pro-Ile [D-Ala2]deltorphin I1 (also referred to as del-
Human p-casomorphin (211) torphin B, 25, Fig. 7.5) were subsequently dis-
covered (106) which exhibited even greater
Tyr-Pro-Phe-Val-Glu-Pro-Ile &receptor affinity and exceptional selectivity

Table 7.13 Opioid Receptor Affinities and Opioid Activity in the GPI and lVND of Peptides
from Amphibian Skina
Ki (nMIb K,Ratio I(& (nM)
Peptide P 6 p/8/K GPI MVD
Dermorphin (212) 0.70 62 1/89/> 14,000 1.4 2.4
Deltorphin (213) 1,630 2.4 680/1/>4,000 5,000 1.4
[D-Ala2]Deltorphin1 (214) 3,150 0.15 21,000/1/>66,000 >1,500 0.21
[D-Ala2]Deltorphin11(25) 2,450 0.71 3,400/1/> 14,000 >3,000 0.32
"Data from Ref. 106.
bK,> 10,000 nM for K receptors for all of the amphibian skin peptides.
Narcotic Analgesics

(see Table 7.131, making them the most selec- decreases in potency when this residue was
tive of the naturally occurring opioid peptides. substantially modified. A D-amino acid in posi-
[D-Ala2]deltorphinI1 has been used to study tion 2 was one of the early modifications exam-
the proposed 8,-receptor subtype (see Section ined to decrease the cleavage of the Tyr-Gly
3.2.4.3 above). The pharmacology of these am- bond by aminopeptidases (671). Incorporation
phibian opioid peptides has been discussed in of a D-amino acid at this position increases po-
a recent review (670). tency at both p and 6 receptors and is found &
The unique feature of these amphibian the vast majority of enkephalin derivatives; an
skin opioid peptides is the sequence between L-amino acid at position 2 significantly de-
the important aromatic residues. In contrast creases potency at both receptors. In the eri-
to the enkephalins and other mammalian opi- kephalins the 3 position is very intolerant of
oid peptides that contain the Gly-Gly dipep- substitution, and therefore enkephalin deriv-
tide sequence between Tyr and Phe, the am- atives generally retain a glycine at this posi-
phibian opioid peptides contain a single tion. There are significant differences between
D-amino acid (see Fig. 7.41), which apparently p and 6 receptors, however, in the structural
arises from a post-translational conversion of requirements for residues in positions 4 and 5,
the L-amino acid to its D isomer (665). The and frequently modifications in these posi-
identification of these unusual opioid peptides tions have been used to impart selectivity for
expanded our understanding of the structural one of these opioid receptor types (see below).
requirements for interaction with opioid re-
ceptors and provided new lead compounds for 6.2.1 Mu-Selective Enkephalin Analogs
further modification (see Sections 6.5.1 and 6.2.1.1 Linear Analogs. Enkephalin ana-
6.5.2 below). logs with substantial structural changes from
the endogenous peptides, particularly in the
6.2 Enkephalin Analogs
C-terminus, retain affinity for p opioid recep-
The enkephalins have been the most exten- tors and can exhibit improved preceptor se-
sively modified of the opioid peptides, and lectivity. Thus the aromatic moiety of Phe4 is
thousands of analogs of these pentapeptides not an absolute requirement for interaction
have been prepared (see Refs. 653-658 for re- with p receptors, and a cyclohexane ring (672)
views). The naturally occurring enkephalins or leucine side chain (673, 674) is tolerated.in
exhibit some selectivity for 8 receptors (see this position. Significant variation is also tol-
Table 7.9), but these peptides are rapidly de- erated in residue 5 and the C-terminus by p
graded by a variety of peptidases (see Section receptors, and modifications in this region of
6.8 below). Therefore one major goal of struc- the peptides have been very useful in differen-
tural modification of these small peptides has tiating p versus 8 receptors. Thus, the C-ter-
been to increase metabolic stability. Depend- minus can be amidated, reduced, or elimi-
ing on the nature of the modifications made, nated completely with retention of p-receptor
both p- and &selectiveenkephalin derivatives affinity and often with a substantial increase
have been prepared (enkephalin derivatives in preceptor selectivity.
generally have very low affinity for K opioid One of the most commonly used p-selective
receptors). These derivatives have included ligands DAMGO (15,Fig. 7.4) (675) contains a
both linear peptides and conformationally reduced C-terminus and is available in triti-
constrained derivatives. Conformational con- ated form. Substitution of the glyol function-
straints have included cyclizations between ality of DAMGO with Met(0)ol (to give FK
residues in the peptide chain and local con- 33824) increases 6-receptor affinity 10-fold,
straints by incorporation of an amino acid decreasing p-receptor selectivity (130). Other
whose side-chain conformation is restricted. related tetrapeptide analogs with a modified
Early SAR studies (see Ref. 653 for a re- C-terminus syndyphalin-25 (Tyr-D-Met-Gly-
view) identified important structural features NMePheol) (676) and LY 164929 (NMeTyr-
of the enkephalins and which positions could D-Ala-Gly-NEtPhe[9(CH2NMe2)],2 15, Fig.
be readily modified. The importance of Tyrl 7.42) with a reduced C-terminal amide (677)
for opioid activity was apparent from the large exhibit significantly higher selectivity for p re-
6 Opioid Peptide Analogs

"I, 0

Figure 7.42. p-Receptor selective enkephalin analogs. The structure of DAMGO (15) is shown in
Fig. 7.4.

ceptors than DAMGO (Table 7.14). Shorter Fig. 7.43) in position 1 of [Leu51enkephalin
tripeptide amide analogs with a branched al- results in large increases in both I*. and 6 affin-
kyl chain in place of the second phenyl ring ity and an analog with some selectivity for F
also exhibit preceptor selectivity, although receptors (682), whereas incorporation of
their potency in the GPI is significantly lower 2',6'-dimethylphenylalanine(Dmp, Fig. 7.43)
(IC,, = 240-320 nM) (678). in position 4 results in increased preceptor
6.2.1.2 Conformationally Constrained Ana- selectivity as a result of decreased breceptor
logs. Local restriction of conformational free- affinity (683). Interestingly, combining the
dom can be accomplished by incorporating two modifications results in a weak antagonist
conformationally constrained amino acids (see (PA, = 6.90) with some selectivity (20-fold)for
Refs. 679,680 for reviews). In the case of the p receptors (683).
enkephalins, incorporation of 2-amino-6-hy- Enkephalin derivatives selective for p re-
droxy-2-tetralincarboxylic acid (Hat, Fig. ceptors have also been prepared by cyclization
7.43) in place of Tyrl in [Leu5]enkephalin between a D-amino acid and the C-terminus.
methyl ester results in a p-selective compound Tyr-cyclo[NY-D-Dab-Gly-Phe-Leu1 (216, Fig.
[ICE, ratio (MVDIGPI) = 5.11, whereas the ana- 7.42; Dab = a,y-diaminobutyric acid) (684) ex-
log containing 2-hydroxy-5-hydroxy-2-indane- hibits both high potency and preceptor selec-
carboxylic acid (Hai) is virtually inactive (681). tivity (Table 7.14), whereas the corresponding
Incorporation of 2',6'-dimethyltyrosine (Dmt, linear peptide [D-Dab2,Leu5]enkephalinamide
412 Narcotic Analgesics

Table 7.14 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of p-Selective
Enkephalin Analogsa
Ki
Ki (nM) Ratio Ic50(nM)
Peptide P 6 alp GPI MVD Reference

"Data for DAMGO from Table 7.8 are included for comparison.
bIC,, values.

is not preceptor selective (685). This was the accommodate an aliphatic residue in position
first demonstration that receptor selectivity 4 of enkephalins, S receptors generally require
could be imparted by conformational restric- an aromatic moiety in this position. At the C-
tion. Related analogs with D-Omor D-Lysin terminus 6 receptors prefer a free carboxylic
position 2 also exhibit high potency for p re- acid, and lengthening of the peptide with a
ceptors but decreased selectivity in radioli- residue such as Thr can result in increased 6
gand-binding assays (see Table 7.14) (686). selectivity.
The conformations of these peptides have Several linear enkephalin analogs have en-
been examined by both computational meth- hanced selectivity for 6 opioid receptors (Ta-
ods (687-690) and NMR spectroscopy (689, bles 7.8 and 7.15). DADLE (21; see Fig. 7.5 and
691). As expected, the ring structure reduces Table 7.8) (695) was an early analog prepared
conformational flexibility, but some flexibility that shows a slight preference for 6 opioid re-
in the ring remains, particularly for the larger ceptors. Roques and coworkers prepared sev-
ring sizes, and different intramolecular hydro- eral [Leu5,Thr61enkephalin analogs contain-
gen bond patterns have been proposed for the ing D-Ser, D-Thr, or a derivative in position 2,
cyclic structures. Modifications to the peptide which have greater selectivity for these recep-
bonds in these cyclic peptides, e.g., thioamide tors. Thus incorporation of D-Ser in position 2,
replacement of the Gly3-Phe4 peptide bond which yields DSLET (22) (6961, and substitu-
(692) or partial retro-inverso analogs of (216) tion of D-Thr in this position to give DTLET
e.g., Tyr-cyclo[~-Glu-Gly-gPhe-D-Leu1 (218, (23) (697) enhances breceptor selectivity. X-
Fig. 7.42) (6931, can further enhance p-recep- ray structures for both DADLE (698) and
tor selectivity (see Table 7.14). DTLET (699) have been reported; in both
cases a single bend conformation is found in
6.2.2 Delta-Selective Enkephalin Analogs the crystals (see Ref. 700 for a review). The
6.2.2.1 Linear Analogs. Differences in the steric bulk of the residues in positions 2 andor
SAR of enkephalin analogs for interaction 6 was increased by incorporating the t-butyl
with 6 versus p opioid receptors have been ex- ether derivatives of D-Ser andor Thr. The re-
ploited to develop Bselective derivatives. Thus sulting derivatives DSTBULET ([D-Ser
more hydrophilic D-amino acids, such as D-Ser (OtBu)', Leu5,Thr61enkephalin) and BUBU
or D-Thr, can be incorporated into position 2 to ([D-Ser(OtB~)~,Leu~,Thr(OtBu)~]enkephalin)
impart breceptor selectivity, whereas p opioid (696) exhibited decreased affinity for p recep-
receptors prefer a more hydrophobic residue tors and thus enhanced selectivity for 6 recep-
in this position (674).Whereas receptors can tors. Replacement of the ether in the side
6 Opioid Peptide Analogs

X=H,R=H Tic X = H Aic X = H Atc Aba-Gly


X = H, R = CH3 MeTic X = OH Hai X = O H Hat
X = OH, R = H Tic(0H)

X = H Dmp X = H Tmp R=H Dhp


X = O H Dmt X = OH Tmt R = CH3 Mdp

Figure 7.43. Conformationally constrained phenylalanine and tyrosine analogs.

chain at position 2 by a sulfur to give BUBUC temic administration is relatively weak (702).
([D-Cy~(StBu)~,Leu~,Thr(OtBu)~]enkephalin) Therefore modifications have been made to
(701) further decreases affinity for p recep- enkephalin analogs in an attempt to enhance
tors, resulting in an analog with a 1000-fold BBB penetration. Attachment of D-glucose
selectivity for 8 over p receptors (Table 7.15). through an 0-linkage to Ser6 in the DTLET
The penetration of the blood-brain barrier analog Tyr-D-Thr-Gly-Phe-Leu-SerNH, re-
(BBB) by enkephalin analogs is relatively low sulted in a peptide that retains similar opioid
and therefore their analgesic activity after sys- receptor affinity and potency in smooth mus-
41 4 Narcotic Analgesics

Table 7.15 Opioid Receptor Affinities and Opioid Activity in the GPI and lVIVD of &Selective
Enkephalin Analogsa
Ki
Ki (nM) Ratio IC50 (nM)
Peptide ti P 1 MVD GPI Reference(s)
m

Agonists
DSLET (22) 1.8
DTLET (23) 2.7
DSTBULET 2.8
BUBU 1.7
BUBUC 2.9
[D-Thr2,Leu5]enkephalin-Ser(OR)6
R=H 2.4
R = D-glucose 3.4
DPDPE (24) 2.7
DPLPE 2.8
[Phe@-C1)41DPDPE 1.6
cyclo[~-Pen2,Cys5]enkephalin-Phe61.4'
cyclo[~-Pen~,Phe@-X)~,Pen~]-
enkephalin-Phe6
X=F 0.43'
X = Br 0.20'
[2'-MeTyrl]DPDPE 0.8gb
[(2S,3R)-TmtllDPDPE 5.0
[(2S,3S)-TmtllDPDPE 210
[Hatl]DPDPE 2.36'
[(2S,3S)-p-MePhe41DPDPE 10
Antagonists
ICI 174,864 (29) 190
NJV-Dibenzyl Leu-enkephalin 78
[(2S)-Mdpl,~-Ala2,Leu5]enkephalin
amide 12
"Data for DSLET, DTLET, DPDPE, and ICI 174,864 from Table 7.8 are included for comparison. Data from Ref. 130
except where otherwise indicated.
bICSOvalues.
=1c,, = 5 f l .
dAntagonist, K, values (nM).
"Not active.

cle assays to the parent peptide (see Table its 150-260 times higher affinity for 6 and p
7.15) (702). Glycosylation led to significant in- receptors than the E isomer (705). For the
creases in both enzymatic stability and BBB peptides containing cyclopropylphenylalanine
permeability, resulting in significantly im- (VPhe), one of the Z isomers exhibits high af-
proved analgesia after i.v. administration finity for [3H]naloxone binding sites in rat
(703). brain (706), whereas the 2R,3S isomer of
6.2.2.2 Conformationally Constrained Ana- VEPhe exhibits high affinity (Ki = 13 nM) and
logs. Local restriction of conformation in the selectivity (Ki ratio = 250) for 8 opioid recep-
linear enkephalins has included incorporation tors (707); the latter compound, however, was
of dehydroamino acids [e.g., dehydrophen- essentially inactive in smooth muscle assays
ylalanine (APhe, Fig. 7.43)] and cyclopropyl- (IC5, = 2000-4000 nM).
methylphenylalanine (VPhe)into the peptides Delta-selective enkephalin analogs were
(see Ref. 704 for a review). In the case of the prepared by cyclization through disulfide bond
dehydrophenylalanine (APhe4) derivatives of formation. Cyclic enkephalin analogs contain-
[~-Ala~,Leu~]enke~halin, the Z isomer exhib- ing D- or L-Cys residues in positions 2 and 5
[
f
P
6 Opioid Peptide Analogs
E.
E
were first synthesized by Sarantakis (708) and Pen5]enkephalin (DPLPE) had only a modest
Schiller (709). These initial cyclic enkephalin effect on &receptor affinity or potency in the .
analogs exhibit only a slight preference for 6 MVD, but halogenationof the resulting DPLPE-
over p receptors, but introduction of methyl Phe resulted in increased Sreceptor affinity and
groups on the P carbons of the cysteine resi- exceptionally high Sreceptor selectivity and po-
dues by incorporation of penicillamine (Pen) tency (see Table 7.15) (721); the p-chloro and
in positions 2 and/or 5 markedly enhances p-bromo derivatives also exhibited enhanced
&receptor selectivity (710-713). The most penetration of the BBB (717).
&selective compounds in the series were the Glycopeptide derivatives of cyclo[n-
bis-penicillamine derivatives DPDPE (cyclo[n- Cys2,Cys5]enkephalin and DPDPE have
Pen2,n-Pen5]enkephalin, 24, Fig. 7.5) and been prepared by attachment of Ser(p-D-
DPLPE (cyclo[n-Pen2,~-Pen51enkephalin) (713). glucose)-GlyNH, to the C-terminus (722).
The individual contributions of the P-methyl After peripheral administration, the cyclo[n-
groups in residue 2 to &receptor affinity and Cys2,Cys5]enkephalin derivative exhibits
selectivity were examined by preparing significant analgesic activity that appears to
cyclo[(3S)Me-D-Cys2,n-Pen5]- and cyclo[(3R)- be centrally mediated, indicating that the
Me-D-Cys2,n-Pen5]enkephalin(714). The glycopeptide penetrates the blood-brain bar-
P-methyl groups in the 2 position had only rier. The penetration of the BBB was ini-
a minor affect on 6 opioid receptor affinity, tially postulated to be through interaction
and the similar affinity for p receptors of with the glucose transporter GLUT-1, but
cyclo[(3S)Me-D-Cys2,n-Pen5]- and cyclo[n- subsequent studies have proved this to be
Cys2,n-Pen5]enkephalin suggested that ad- incorrect (see Ref. 723 and references cited
verse steric interactions with t h e pro-R therein). I n a series of cyclo[n-Cys2,n-
methyl group are responsible for the low p-re- Cys5,Ser6,Gly7]enkephalinamide analogs in
ceptor affinity, and therefore &receptor selec- which the sugar attached to Ser6 was varied,
tivity, of DPDPE. the nature of the sugar affected analgesic
Additional modifications to DPDPE can fur- potency after i.v. administration; the a-glu-
ther enhance Sreceptor affinity andlor selectiv- cose derivative showed the highest analgesic
ity (see Ref. 656 for a review, including tables of potency and 6-receptor affinity of the glyco-
analogs). Halogen substitution on thepara posi- sylated analogs examined (723). Recently, a '
tion of the phenylalanine ring in position 4 en- prodrug derivative of DPDPE, in which PEG
hances both &receptor potency and selectivity (polyethylene glycol) is attached to the N -
(7151, and [Phe(p-C1)41DPDPEhas been used in terminus, has been reported to also exhibit
tritiated form in radioligand binding assays. Ha- enhanced analgesia compared to that of
logenation can also increase blood-brain barrier DPDPE after i.v. administration; this pro-
permeability (716, 717). [L-A~~~IDPDPE was drug has very weak affinity for 6 opioid re-
prepared and exhibits an unusual spectrum of ceptors, but is converted to DPDPE in vivo
activity (718). In the mouse vas deferens, (724).
[L-A~~~IDPDPE is a potent (IC,, = 12 nM) Sse- The conformation of DPDPE has been ex-
ledive agonist, whereas at central 6 receptors it amined by NMR and computational methods
is a moderately potent 6,-receptor antagonist (see Ref. 725 and references cited therein) and
and weak agonist with no apparent affects on an X-ray structure has been obtained (725).
central 6,-receptors. The conformation of There is generally good agreement between
[L-Ala31DPDPE has been compared to that of these studies on the conformation of the 14-
DPDPE (719),and the differences in conforma- membered ring, but there is still considerable
tion around residues 2 and 3 were proposed to conformational flexibility around Tyrl in
explain the differences in efficacy observed for DPDPE. This is evident in the crystal where
the two analogs. A C-terminal extension of cy- three distinct structures, with essentially
clo[n-Pen2,~-Cys5]enkephalin (DPLCE) with identical conformations for the 14-membered
phenylalanine resulted in an analog with ex- ring but with different conformations for
tremely high potency in the MVD (IC,, = 0.016 Tyrl, were found (725). The activity of the
nM)(720).A similar extension of cyclo[~-Pen2,~- Hat1, P-MeTyrl, and Tmt derivatives (see be-
Narcotic Analgesics

low) suggested that the preferred conforma- P-MePhe4 increases 6-receptor affinity and
tion of the side chain of residue l in DPDPE is potency 6- to 10-fold, so that [(2S,3S)-p-
trans (726-728). Based on the activity of the MePhe(p-N02)4]DPDPEexhibits potency at 6
P-MePhe4 derivatives (see below), the pro- receptors similar to that of DPDPE. Further
posed side-chain conformation for Phe4 is constraint of Phe4 by incorporation of 2',6',P-
gauche (-) (xl = -60") (729). trimethylphenylalanine (Tmp, Fig. 7.43),
Therefore, other modifications to DPDPE however, results in decreased 6 receptor bind-
have been made to incorporate additional con- ing and selectivity; in the case of the 2S,3S
formational constraint into the aromatic resi- isomer affinity for the p receptor increases,
dues in the peptide. Constrained Tyr analogs, resulting in a peptide with 10-fold selectivity
including 2'-methyltyrosine, Dmt, P-methyl- for p receptors (733).
tyrosine, 2',6',/3-trimethyltyrosine(Trnt, Fig. 6.2.2.3 Enkephalin Analogs with Antagonist
7.43), and Hat (726-728, 730), have been in- Activity at 6 Receptors. The first antagonists
corporated at position 1. Substitution of Dmt for 6 opioid receptors were prepared by N,N-
enhanced affinity at both 6 and p receptors dialkylation of the N-terminus of enkephalins.
and increased both in vitro and in vivo potency The first 6-selective antagonists reported were
(730). Peptides containing 2'-MeTyr and Hat N,N-diallyl Leu-enkephalin methyl ester and
were also potent analogs with high 6-receptor the derivative ICI 154,129 containing a
selectivity (726) (see Table 7.15). Of the four thioether in place of the peptide bond between
peptides containing P-MeTyr, the (2S,3R)-p- residues 3 and 4 (734),although the potency of
MeTyrl derivative has the highest affinity for these peptides was weak (K, against Leu-en-
6 receptors and the greatest potency in the kephalin in the MVD = 254 nM for ICI
MVD (726). In the Tmt derivatives, which 154,129). Substitution of Aib (a-aminoisobu-
combine methyl groups on the phenyl ring tyric acid) in positions 2 and 3 of NJV-diallyl
with the P-methyl substitution, only the pep- Leu-enkephalin to give ICI 174,864 (29, Fig.
tide containing the 2S,3R isomer of Tmt re- 7.5, Table 7.15) enhanced potency approxi-
tains high 6 receptor potency and selectivity mately 10-fold and 6-receptor selectivity at
(727,728), whereas the peptide containing the least fivefold compared to that of ICI 154,129
diastereomer 2S,3S exhibits much lower S-re- (110), and so ICI 174,864 has been frequently
ceptor affinity and selectivity (Table 7.15). In- used as a 6-selective antagonist in a number of
terestingly, in vivo [(2S,3S)-Tmtl]DPDPE is pharmacological studies. The structure-activ-
the more potent analog in the tail flick test ity relationships for the N,N-diallyl deriva-
after i.c.v. administration (731). The antinoci- tives as 6 antagonists are distinctly different
ceptive activity of both peptides is antagonized from those of the unsubstituted agonist series
by P-FNA as well as by DALCE (731),suggest- (735). Thus the N,N-diallyl derivatives of a va-
ing that in contrast to DPDPE the antinoci- riety of potent enkephalin agonists such as
ceptive activity of both these Tmt analogs is DADLE are weak nonselective antagonists.
partially mediated by p receptors as well as 6, Moreover, although ICI 154,129 is a selective 6
receptors; these results are surprising for antagonist, the corresponding [Gly3V(CH2S)-
[(2S,3R)-Tmtl]DPDPE, given its high selec- Phe4,Leu5]enkephalin is virtually inactive as
tivity for 6 receptors in binding assays. an agonist. Other modifications have been
Further conformational constraint in DPDPE made to the N,N-diallyl enkephalins, includ-
has also been examined by incorporation of ing replacement of Gly2-Gly3 with a rigid
constrained residues in position 4. All four 4-aminobenzoic acid spacer (736), whibh
isomers of P-methylphenylalanine have been yields a S antagonist with potency similar to
incorporated into DPDPE (732). [(2S,3S)- that of ICI 154,129. Substitution of benzyl
P-MePhe4]DPDPE (see Table 7.15) exhibits groups for the ally1 groups in N,N-diallyl Leu-
the highest 6-receptor affinity of the four pep- enkephalin enhances 6-antagonist potency,
tides, although it is 6- to 10-fold less potent whereas N,N-dialkylation with other alkyl
than DPDPE; it also exhibits the highest groups (e.g., phenethyl) result in derivatives
selectivity for 6 over EL receptors. Incorpo- with agonist activity (737). Interestingly, al-
ration of a p-nitro group into (2S,3S)- though ICI 174,864 is more potent than N,N-
6 Opioid Peptide Analogs

Tyr-D-Ala-Gly -NH Tyr-D-Ala-Gly-Phe-NH R2N-Tyr-D-Ala-Gly-Phe-Leu-NH


I I I
(CH2)n (W)n (CHdn
I I I
Tyr-D-AI~-GI~-NH Tyr-D-Ala-Gly-Phe-NH R2N-Tyr-D-Ala-Gly-Phe-Leu- NH
(219) n = 2 (DTRE)2 (220) n = 0 Biphalin (222) R = H, n = 2 (DPE);!
(221) n = 12 (DTE),* (223) R =-CH2CH= CH2, n = 2

Figure 7.44. Dimeric enkephalin analogs.

dibenzyl Leu-enkephalin in the MVD (737), In the tetrapeptide series biphalin [(Tyr-D-
the reverse was true in binding studies that Ala-Gly-Phe-NH),, 2201, with only a hydra-
used cloned 8 receptors (738), suggesting pos- zine spacer, is not selective for p or 8 receptors
sible differences in 8 receptors in the two prep- (Table 7.16) (742). This peptide exhibits po-
arations. NJV-DialkylLeu-enkephalin analogs tent analgesic activity in vivo (742, 743), even
bearing a reactive functionality recently have though its potency in smooth muscle assays is
been described (738) (see Section 6.7 below). modest (Table 7.16). Biphalin is equipotent
Recently, the Leu-enkephalin analog con- with morphine, but produces little if any phys-
taining a novel derivative of Dmt lacking a ical dependence after systemic 6.p.) adminis-
basic amine [(2S)-2-methyl-3-(2,6-dimethyl-4-tration. The truncated dimer Tyr-D-Ala-Gly-
hydroxypheny1)propanoicacid, (2s)-Mdp,Fig. Phe-NHNH(Phe)retains high binding affinity
7.431 was reported; this peptide is an antago- and potency in smooth muscle assays, indicat-
nist in both the MVD and GPI smooth muscle ing that the entire sequence of biphalin is not
preparations, with fivefold higher potency in required for activity (744). Modification of the
the MVD (739). residue in the 4 position can alter opioid recep-
tor affinities and impart some selectivity for
6.2.3 Dimeric Enkephalin Analogs. A num- either p or 8 receptors. Thus introduction of
ber of dimeric enkephalin analogs have been L-0-MePheor naphthylalanine in this position
prepared (Fig. 7.44). Their receptor selectivity results in analogs that preferentially interact .
depends on the peptide sequences and the with p receptors (see Table 7.16) (7451,
length of the spacer between the two peptides. whereas p-halogenation or nitration of the
The tripeptide dimer (DTRE), [(Tyr-D-Ala- phenyl rings enhances 8-receptor affinity
Gly-NH),(CH,),, 219, Table 7.161 is p selec- more than preceptor affinity (746);para chlo-
tive, whereas the corresponding monovalent rination also increases penetration across the
tripeptide T y r - D - A ~ ~ - G ~ ~(TRE)
N H , is much BBB (747,748).In situ brain perfusion studies
less potent and only moderately p selective of [1251-Tyr]biphalinsuggest that part of the
(740). Replacement of the Tyr residue in one transport of this compound may use the large
half of DTRE, with Phe or D-Tyr significantly neutral amino acid carrier (749).
decreased potency, which suggests that p opi- Other dimeric enkephalin derivatives have
oid receptors contain two similar sites that are been prepared that exhibit 8-receptor selectiv-
in close proximity to one another (741). ity. The dimer (DTE),, (221) with a long

Table 7.16 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Dimeric
Enkephalin Analogs

6 w 6 1 ~ MVD GPI Referenceb)


(DTRE), (219) 14,000 34 410 2300 410 740,741
Biphalin (220) 5.2 2.8 1.8 8.8 27 745
[(2S,3S)-P-MePhe4,4'lBiphalin 110 1.3 85 180 21 745
DTE,, (221) 10 38 0.26 38 1,000 750
Narcotic Analgesics

spacer (n = 12) between the two tetrapeptides posal. This helical structure of dynorphin A
is a &selective ligand (the monomer Tyr-D- has been docked to a computational model of K
Ala-Gly-PheNH, is p selective) (750). In the opioid receptors (181).
pentapeptide series (DPE), the dimer with n Studies of dynorphin A have been compli-
= 2 (222) exhibits the greatest S selectivity in cated by its metabolic lability (758). In addi-
this series (751),but the selectivity of this pep- tion to inactivation by peptidase cleavage jn
tide is low [IC,, ratio (d6) = 6.51. Dimeric the N-terminus, cleavage in the C-terminus
analogs with antagonist activity were also yields shorter active peptides, which may have
examined. The dimeric derivative of the an- different receptor selectivity profiles from that
tagonist N,N-diallyl Leu-enkephalin (223) of the parent peptide. Dynorphin A-(1-8),
is approximately ninefold more potent than which is the predominant form of dynorphin A
the monomeric N,N-diallyl-Tyr-Gly-Gly-Phe- present in rat brain (759,7601,is less selective
LeuNHEt (7521, but the antagonist activity of
for K receptors than the longer peptides (see
the truncated dimer N,N-diallyl-Tyr-Gly-Gly-
Ref. 761). C-Terminal amidation enhances the
Phe-Leu-NHCH,CH,NH(AcPhe-Leu) sug-
gests that the enhanced activity of the full metabolic stability of dynorphin A-(1-13)
dimer is not due to bridging two 6-receptor (758), and therefore this modification is typi-
binding sites. cally incorporated into dynorphin A analogs.
The peptide bonds in dynorphin A-(I-11)NH2
have been replaced by reduced amide bonds to
6.3 Dynorphin Analogs increase metabolic stability (762, 763); this
Dynorphin has not been nearly as well studied modification was well tolerated by K receptors
as other smaller opioid peptides. Although in the C-terminal "address" sequence, but led
several peptides with high affinity for K recep- to decreased opioid receptor affinity when
tors are obtained from prodynorphin (see Sec- incorporated in the 16message" sequence.
tion 3.4 above), SAR studies have focused on An analog of dynorphin A - 1 8 E2078
derivatives of dynorphin A (see Refs. 656, 753 ([NMeTyr1,NMeArg7,~-Leu8]dynorphin A-(1-
for reviews). Dynorphin A is a heptadecapep- 8)NHEt) (764, 765), containing modifications
tide, but dynorphin A-(1-13) accounts for es- to stabilize the peptide to metabolism has
sentially all of the activity of the larger peptide been studied extensively in vivo. It exhibits a
(754). Further truncation of dynorphin A-(1- slight preference for K receptors in binding as-
13) from the C-terminus identified the basic says (see Table 7.17) and produces analgesia
7 after both i.v. and S.C.administration (764-
residues Arg and Lysl1 as important for K
receptor potency and selectivity (263). Thus, 766), apparently by spinal K receptors (767).
typically, dynorphin A-(1-13) or A-(1-11) has
been used as the parent peptide for further
modification.
The possible conformations of dynorphin A
have been studied by a variety of spectral tech-
niques (see Ref. 753 for a review). Like other
linear peptides, a variety of conformations 6.3.1 Linear Analogs. Early structural modi-
have been observed for dynorphin A, which fications were made in the C-terminal "ad-
depend on the experimental conditions. dress" sequence of dynorphin A (263) and fo-
Schwyzer (755) proposed a "membrane-assist- cused on the nonbasic residues (see Refs. 656,
ed" model for dynorphin's interaction with K 753). D-Pro was incorporated in place of Prolo
receptors, in which the N-terminal "message" in both dynorphin A-(1-11) (768) and A-(1-13)
sequence adopts an a-helical structure from (769) and was reported to enhance K-receptor
residues 1-9 when it binds to the receptor. selectivity (see Table 7.17). Ala and D-Ala were
NMR studies of dynorphin A bound to dode- substituted for Iles with retention of K-recep-
cylphosphocholine micelles (756, 757) ob- tor affinity and selectivity (769, 770). Replace-
served a helical structure in the N-terminal ment of the basic residues individually by
portion of the peptide, supporting this pro- N'-acetylated lysine (771) indicated that
6 Opioid Peptide Analogs 419

Table 7.17 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Analogs of
Dynorphin A (Dyn A)
Ki (dfl KiRatio IC5, (nM)
Peptide K I*. 6 rdd6 GPI MVD Reference(s)
-

Agonist analogs
Dyn A-(1-13) 0.15 1.3 4.1 118.6127 1.7 78
Dyn Ia (225) 0.25 6.7 71 11261280 0.5 236
[~-Pro'~]Dyn A-(1-11) 0.032 2.0 7.5 1/621230 - -
E2078 (224) 1.9 4.5 27.2 112.4114 0.3 7.4
[N-Allyl,~-Pro'~]]Dyn
A-(1-11) 0.049 11 450 1/220/9,160 18 -
[N-CPM,D-P~O'O]D~~ A-(1-11) 0.020 9.6 560 1/480/28,000 2.2 -
[N-Benzy1,~-Prol0]Dyn
A-(1-11) 0.029 31 175 11107016,080 990 -
[Ala3]DynA-(1-11)NH2 1.1 210 730 1/190/660 1.7 -
[~-Ala~lDyn A-(1-11)NH2 0.76 260 1,000 1/350/1,300 8.1 -
[(R)-Atc4,~-Ala81Dyn
A-(1-ll)NH2 0.89 33 >10,000 1/37/>6,000 - -
[(s)-Atc4,D-Ala8]Dyn
A-(1-ll)NH2 9.5 88 >10,000 1/9/>1,000 - -
~~clo[C~s~,C~s'~]Dyn
A-(1-ll)NH2 0.28 0.27 1.6 llll6 1080 420
~~clo[Cys~,~-Pen'~]D~n
A-(1-ll)NHz 1.1 31 240 11281220 690 -
cyclo[~-Asp~,Da~~]Dyn
A-(1-13)NH2 0.22 0.49 10 112146 0.16 -
cyclo[~-hp~,Dap~]Dyn
A-(1-13)NH2 8.0 75 3,300 1191400 >5000 -
cyclo[~-hp6,DapglDyn
A-(1-13)NH2 2.6 4.4 48 1/2/19 46 -
cyclo[~-hp~,Lys~]Dyn
A-(1-ll)NH2 4.9 310 130 1/64/27 600 -
Antagonist analogs
[N&-Didlyl,~-ProlO]Dyn
A-(1-11) 21 135 350 1/6.5/17 190" -
[N&-D~CPM,D-P~O'~ID~~
A-(1-11) 0.19 3.9 166 1/21/880 -b -
Dynantin 0.82 213 163 112601200 3.9, -
0.63'
[Pro3]Dyn A-(1-11)NH2 2.7 5,700 8,800 112,10013,260 244, -
494'
Arodyn 10 1,700 5,800 1/170/580 -b -
JVA-901 (venorphin) 20 250 5,300 1/131270 -b -

"K,values against a dynorphin analog.


*Reversesthe agonist activity of Dyn A-(1-13)NH2 in an adenylyl cyclase assay using cloned K receptors.
CKevalues against U50,488 and a dynorphin analog, respectively.
g
substitution of Arg by a nonbasic residue is nal extended peptide dynorphin A-(1-13)-Tyr-
well tolerated, and that the basicity of Arg6 is Leu-Phe-Am-Gly-Pro (dynorphin Ia, 225),
not required for interaction with K receptors, based on the structure of a dynorphin-related
but contributes to K-receptor selectivity by de- peptide purified from bovine adrenal medulla,
creasing preceptor affinity. Analogs in which was synthesized (773) and found to be more
Arg6 or Arg7 was replaced by norleucine also selective than dynorphin A-(1-13) for K recep-
retained high K-receptor affinity, but exhib- tors; additional structural modifications (D-
ited decreased K selectivity (772). A C-termi- Leus andlor N-methylation of Tyrl) were
Narcotic Analgesics

made to reduce the motor effects observed 11)NH2(782). Interestingly, the peptide con-
with dynorphin Ia (774). Labeled derivatives taining (??)-Atc, which corresponds to a con-
of dynorphin A were prepared by attaching formationally constrained D-Phe analog,
functionalities to the C-terminus [DAKLI, possesses higher affinity for K and preceptors
[Arg1',13]dynorphin A-(1-13)- Gly-NH than the peptide containing the S isomer (Ta-
(CH2),NH-R, where R is fluorescein, lZ5I- ble 7.171, even though the ~ - P h eanalog ~
labeled Bolton Hunter reagent, or biotin exhibits relatively low affinity for these redp-
(775)l or to the side chain of Lys13 (biotin) in tors (Ki values of 8.9 and 146 nM, respec-
dynorphin A-(1-13) amide (776). tively). Both peptides exhibit negligible &n-
ity for 6 receptors. A novel conformational con-
Dynorphin Ia (225) straint, 4-aminocyclohexanecarboxylic acid,
has been incorporated into dynorphin A-(1-
13) amide in place of Gly2-Gly3 (783). Al-
Pro-Lys-Leu-Lys-Tyr-Leu-Phe-Am-Gly-Pro though the affinities of the two peptides for K
receptors is significantly reduced compared to
Several studies have focused on modifica- the parent peptide, it is interesting to note
tions in the N-terminal sequence of dynorphin that the peptides containing the cis and trans
A. Interestingly, the most K-selective deriva- isomers of 4-aminocyclohexanecarboxylicacid
tives of dynorphin A have been prepared by exhibit similar affinity for K receptors.
modifications in this 66message" sequence Cyclic derivatives of dynorphin A have
rather than in the C-terminal "address" se- been prepared by formation of both disulfide
quence. The N-terminal monoalkylation of and lactam linkages (see Ref. 656 for a review
[D-Prol0]dynorphinA-(1-11) with an allyl, cy- including extensive tables). The first cyclic
clopropylmethyl, or benzyl group results in dynorphin analog reported was cyclo[~-
marked enhancement in K-receptor affinity by Cys2,Cys5]dynorphin A-(1-13) (784), which is
a more potent agonist in smooth muscle assays
decreasing preceptor &nity (Table 7.17)
(777); NJ-dialkylation results in analogs than dynorphin A-(1-13). Subsequently, a va-
with antagonist activity (see below). An ala- riety of cyclic dynorphin analogs containing a
nine scan (770)verified the importance of Tyrl disulfide linkage in the C-terminus were de-
and Phe4 in dynorphin A-(1-13) for potency in scribed (785-787; see Ref. 656 for a tabular
smooth muscle assays and receptor affinity. summary of these analogs). Except for the an-
Although incorporation of D-amino acids in po- alogs cyclized through a D-amino acid in posi-
sition 2 can enhance metabolic stability and tion 5, these peptides with a constraint in the
yields analogs with high affinity for K recep- C-terminus retain high affinity for K receptors
tors, this modification significantly increases in radioligand binding assays. Three analogs
preceptor affinity and thus yields p-selective cyclized between positions 5 and 11 (cyclo-
analogs (263,778). In contrast, substitution of [Cys5,0-Pen1']-, cyclo[Pen5.11I-, and cyclo-
either Ala or D-Ala in position 3 of dynorphin [Pen5,~-Penl']dynorphin A-(1-11)NH2) show
A-(1-11)NH2 markedly enhances K-receptor increased K-receptor selectivity in the radioli-
selectivity (Table 7.17) (779); incorporation of gand-binding assays compared to that of the
other amino acids in this position, however, is linear parent peptide (Table 7.17). Interest-
ingly, a number of these cyclic disulfide-con-
generally less well tolerated (780). Recently,
[Pro3] dynorphin A-(1-11)NH2 was reported taining peptides, particularly those in which
to be a highly selective K-receptor antagonist position 5 is involved in the disulfide linkage,
show much lower potency in the GPI than ex-
(see below) (781).
pected from the binding assays; these discrep-
6.3.2 Conformationally Constrained Ana- ancies between the two assays were postulated
logs. Local constraints have been incorpo- to be due to different receptor subtypes
rated into dynorphin A. The conformationally present in the brain versus peripheral tis-
constrained phenylalanine derivative Atc (2- sues (785-787). A conformational search of
aminotetralin-2-carboxylicacid, Fig. 7.43) has s ~ ~cyclo[Cys5,~-Alas,Cys"l-
c y c l o [ C y ~ ~ , C ~and ]-
been incorporated in [D-Ala8]dynorphinA-(1- dynorphin A-(1-11)NH2 found a low energy
6 Opioid Peptide Analogs

Dynantin (2S)-Mdp-Gly-Gly-Phe-Leu-Arg-Arg-lle-Arg-Pro-LysNH2
TIPP-Dyn A Tyr-Tic-Phe-Phe-Leu-Arg-Arg-lle-Arg-Pro-LysNH2
Extacet AcArg-Phe-Met-Trp-Met-Arg-Arg-D-Ala-Arg-Pro-Ly~NH~
Arodyn AcPhe-Phe-Phe-Arg-Leu-Arg-Arg-D-Ala-Arg-Pro-Ly~NH~
JVA-901 1 AcTyr-Lys-Trp-Trp-Leu-Arg-Arg-D-Ala-Arg-Pro-Ly~NH~
venorphin +

Figure 7.45. Novel antagonist analogs of dynorphin A.

a-helical conformation for the disulfide- agonist in the GPI, while retaining reasonable
bridged ring in these peptides, suggesting that affinity for K receptors in the radioligand-
this conformation may be important for the binding assays (792, 793). For the i to i + 4
potency of these peptides at central K recep- derivatives (794) cyclo[o-Asp3,Lys7]dynorphin
tors (788). When ~yclo[C~s~,Cys~~ldynorphin A-(1-11)NH2 exhibited the highest K-receptor
A-(1-11)NH2 bound to micelles was examined affinity and selectivity (Table 7.17); the cyclic
by NMR and molecular dynamics, conforma- peptide cyclo[Lys5,~-Asp9]dynorphinA-(1-
tions resulting from cis-trans isomerism 11)NH2also exhibited nanomolar affinity for
around the Arg9-Prolo amide bond were ob- both K and p receptors. The synthesis of novel
served (789),with the trans isoform exhibiting N-terminal to side-chain cyclic dynorphin A
5 8
a p turn from residues Cys to Ile , whereas analogs was recently reported (795,796).
the cis isoform contained a type I11 P turn
from residues Arg7 to Pro1'. 6.3.3 Dynorphin A Analogs with Antagonist
Conformational constraint through lactam Activity. Early attempts to prepare K-selective
formation has been examined in both the N- antagonists by modification of dynorphin A
terminus and C-terminus of dynorphin A met with limited success, and the analogs re-
(790-794). The initially reported derivatives ported generally exhibited weak antagonist
exhibited low Ke values for antagonism by nal- activity, residual agonist activity, and/or low
oxone (K, = 1.5-4.5 nM) in the GPI, suggest- selectivity for K receptors (797,798). In recent
ing that these peptides preferentially inter- years antagonist analogs with improved p h d -
acted with p receptors (affinities for K macological profiles have been identified.
receptors were not reported) (790). More re- Modifications of Tyrl have resulted in dynor-
cently, two series of dynorphin A-(1-13) amide phin A analogs with antagonist activity.
analogs constrained through a lactam linkage Incorporation of Phe in place of Tyrl in
between residues in either the i and i + 3 po- [D-Ala8]dynorphinA-(1-11)NH, resulted in a
sitions (791-793) or i and i + 4 positions (794) peptide that antagonized dynorphin A (Ke =
have been reported (Table 7.17). These con- 30-65 nM) in the GPI, but still exhibited weak
straints were chosen to be compatible with the agonist activity (772). The NJV-terminal dial-
helical conformation proposed by Schwyzer as kylation of dynorphin A fragments with either
the bioactive conformation for the N-terminal ally1 or cyclopropylmethyl (CPM) groups re-
sequence of dynorphin A (755). For deriva- sulted in analogs with antagonist activity
tives constrained between a D-Aspin position i (142, 799-801); the NJV-di(cyclopropy1-
and Dap (a$-diaminopropionic acid) in posi- methyl) derivative exhibits higher K-receptor
tion i + 3, the constraint is well tolerated by K selectivity than that of the NJV-diallyl peptide
receptors between positions 2 and 5 (791) and (142, 801). Recently, novel analogs of 2',6'-
also between positions 6 and 9 (792, 793), dimethyltyrosine, which lack a basic m i n e
whereas moving the constraint to residues 3 (Dhp and Mdp, Fig. 7.43), have been incorpo-
and 6 markedly decreases affinity for opioid rated in place of Tyrl in dynorphin A-(1-
receptors (792, 793). Consistent with the re- 11)NH2, resulting in [(2S)-Mdpl]dynorphin
sults for the cyclic disulfide-containing ana- A-(1-11)NH2 (dynantin, Fig. 7.45), which is a
logs cyclized through position 5, c y c l o [ ~ - highly K-selective peptide that is a potent an-
Asp5,Daps]dynorphin A-(1-13)NH2 is a weak tagonist at K opioid receptors (see Table 7.17)
Narcotic Analgesics

(802). [Pro3]dynorphin A-(I-11)NH2 was also which exhibits antagonist activity and greatly
reported to be a highly selective, but relatively enhanced affinity for cloned K receptors (808).
weak, K-receptor antagonist (see Table 7.17) In spite of the structural similarities to dynor-
(781). phin A, the SAR of venorphin is completely
Chimeric dynorphin A analogs, in which different from that of dynorphin A, suggesting
the N-terminal "message" sequence of dynor- that these two peptides interact with K recep,
phin A is replaced by small peptides with opi- tors in different ways (809,810). In venorphin
oid antagonist activity (Fig. 7.45), have also only Trp3, and not Tyr' or a basic functional-
been prepared as potential antagonists. Addi- ity, is required in the N-terminal "message"
tion of the C-terminal "address" sequence in sequence for high affinity for K receptors
these peptides significantly enhances K-recep- (8091,and Arg9, which is not important for the
tor affinity, but the receptor preference of the K-receptor affinity of dynorphin A, is the most
N-terminal sequence still often predominates. critical residue in the C-terminus (810).
Thus incorporation of the &receptor antago-
nist TIPP (Tyr-Tic-Phe-Phe) in place of the 6.4 Opioid Peptides with the Tyr-Pro-Phe
N-terminal sequence of [ ~ - P r o ' ~ ] d ~ n o r ~ h iSequence
n
A-(1-11)NH2 or the corresponding acid re-
sulted in peptides with affinity and antagonist
activity at K receptors, but which still prefer- 6.4.1 P-Casomorphin Analogs and the En-
entially bind to 6 receptors (803, 804). Incor- domorphins. p-Casomorphin was identified
poration of only Tic2 in position 2 produced over 20 years ago, so a number of analogs of
similar results for the dynorphin A-(I-11)NH2 this peptide have been reported. The hep-
derivative (805) or a slight (twofold) prefer- tapeptide p-casomorphin (2101, although ex-
ence for 6 over K receptors for the hibiting some selectivity for p receptors, is a
[D-Prol0]dynorphinA-(1-11) analog (804); in- weak opioid agonist [IC,, in the GPI = 57 pit4
corporation of N-MePhe in position 2 of (811)l. Shortening the peptide to the pen-
[D-Prol0]dynorphin A-(1-11) resulted in a tapeptide and tetrapeptide increases potency
greater (eightfold) preference for K over 6 re- (811,812),so generally analogs have been pre-
ceptors but little selectivity for K over p recep- pared of one of these smaller fragments. Con-
tors (804). version of the tetrapeptide to the C-terminal
Attachment of the C-terminal "address" se- amide to give morphiceptin (226; see Table
quence from [D-Ala81dynorphinA-(1-11)NH, to 7.18) (812) substantially increases both po-
the acetylated hexapeptide [Arg6]acetalin, tency and p-receptor selectivity. Further mod-
which is a preceptor antagonist, to give the ification of morphiceptin by incorporation of
peptide extacet increases K-receptor affinity D-Pro at position 4 and N-methylation at posi-
65-fold, resulting in nanomolar affinity for K tion 3 yields PL017 (227) (813), which is sig-
receptors (Ki = 6.6 nM), but it still preferen- nificantly more potent than morphiceptin and
tially binds to preceptors (Ki = 1.1 nM)(804). more p selective (see Table 7.18). D-Pro or D-
Examination of analogs of this lead peptide by Pip (pipecolic acid) in position 4 of p-casomor-
use of a combinatorial library led to the iden- phin-(1-5) also enhances potency in the GPI
tification of arodyn, a novel dynorphin A ana- (814).
log with higher affinity, much higher selectiv-
ity, and antagonist activity at cloned K Morphiceptin (226) Tyr-Pro-Phe-ProNH,
receptors (see Table 7.17) (806).
A Boc-protected tetrapeptide derived from
a sequence found in Philippine cobra venom Cisltrans isomerization occurs around
has been reported to have weak antagonist ac- amide bonds involving the nitrogen of proline
tivity at K receptors (807). Attachment of the and other N-alkyl amino acid residues. NMR
C-terminal "address" sequence of [ ~ - & i ~ ] - studies of both morphiceptin and PL017 found
dynorphin A-(1-11)NH, to this sequence re- that, whereas the major isomers were the all-
sulted in a novel acetylated dynorphin A ana- trans conformers, the second most common
log, JVA-901 (now referred to as venorphin), isomer (25%) had a cis arnide bond between
1r 6 Opioid Peptide Analogs
I

C
Table 7.18 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of p-Selective
[ Opioid Peptide Analogs
kI K, (nM) K, Ratio IC,, (nM)
1
k
Peptide P 6 SIP GPI MVD Reference
1 P-Casomorphin analogs <

if Morphiceptin (226)
PL017 (227)
63
11
30,000
7,250
475
660
318
34
4800
240
813
130
i m-cyclo[~-Om-Phe-D-Pro-Gly]
I (232) 0.88 13.2 15 2.1 4.9 825
1
L T~~-c~c~o[D-O~-~-N~~-D-P~O-
1I Glyl (233) 5.9 17.2
Tyr-CyClo[ D - O ~ ~ - ~ - N ~ ~ - D - P ~ O - D -
2.9 384 K, = 200-270" 825
i
Alal 0.76 72 95 600 K, = 5.4-6.0" 828
I
I Dmt-cyclo[~-Om-2-Nd-~-Pro-
I Glyl (234) 0.46 0.46 1 7.9 K, = 2.1-3.3" 830
1 CHO-Dmt-cyclo[~-Om-2-Nd-~-
1 Pro-Glyl 218 33 0.15 K,=216" K,= 16" 829
Dermorphin analogs
TAPP (Tyr-D-Ala-Phe-PheNH,) 1.5 625 409 255 780 831
DALDA (242) 1.7 19,200 11,400 3.23 800 831
[DmtllDALDA (243)b 0.14 2,100 14,700 1.4 23 832
Tyr-cyclo[~-Om-Phe-AspINH,
(244) 10.4 2,220 213 36.2 3880 833
Tyr-cyclo[~-Om-Phe-GluINH, 0.98 3.21 3.3 1.2 1.1 834
Tyr-cyclo[~-Om-Aic-GluINH, 4.21 209 50 7.21 36.5 834
JOM-6 (246) 0.29 24.8 86 - - 835
JH-54 ([PhellJOM-6, 247) 1.36 1,020 750 9.1 - 835
[D-HatllJOM-6(248) 0.39 58 150 -C -C 836

"Antagonist.
*K,( K ) = 22 nM.
"EC,, = 1.4 and 1500 nMin GTPyS assays using cloned p and 6 receptors, respectively

Tyrl and Pro2 (815). Therefore, Goodman and ration, were inactive. This led Goodman and
coworkers incorporated 2-aminocyclopentane coworkers to propose that the cis conforma-
carboxylicacid (2-Ac5c, 228, Fig. 7.46) into po- tion around the Tyr-Pro amide bond is re-
sition 2 of morphiceptin analogs to eliminate quired for the opioid activity of morphiceptin
possible cisltrans isomerization (816, 817). Of and its analogs (817). A more detailed model
the four possible stereoisomers only morphi- for the bioactive conformation of morphicep-
ceptin analogs containing cis-(1S,2R)-2-Ac5c, tin was developed based on the comparison of
which exhibits a structure similar to the cis a series of active and inactive analogs (818).
conformation of the Tyr-Pro amide bond, are Like morphiceptin and PL017, cisltrans
potent opioids, whereas the analogs with cis- isomerization occurs around the Tyr-Pro
(1R,2S)-2-Ac5c,which is similar to morphicep- amide bond in endomorphin-1, with similar
tin with the Tyr-Pro bond in a trans configu-
populations (75%trans, 25% cis) found for the
two conformations (819). Based on structural
comparison of the cis and trans conformations
of endomorphin-1 to other p- and &selective
opioid peptides, Podlogar et al. proposed that
the trans conformation was the bioactive form
(819). Recently, Schiller and coworkers re-
ported endomorphin-2 and morphiceptin ana-
Figure 7.46. Proline analogs. logs containing a pseudoproline derivative in
424 Narcotic Analgesics

Figure 7.47. Cyclic P-casomorphin analogs.

place of Pro2 (820); analogs of both peptides


-
Tyr-cyclo[~-Om-Phe-Pro-Gly](230, Fig. 7.47)
containing the dimethylated pseudoprolines and Tyr-cyclo[~-Om-Phe-D-Pro-Gly] (232) ex-
Xaa[TMe,MeProl(Xaa = Cys or Ser, 229, Fig. hibit high affinity in p receptor binding assays
7.46), which exist almost exclusively in the cis and are potent agonists in smooth muscle as-
conformation, retain p opioid receptor affinity says (Table 7.18) (823). Peptides Tyr-cyclo[~-
and agonist activity, indicating that the cis X-Phe-D-Pro](X = D-Om or D-Lys)in which
conformation around the Tyr-Pro amide bond Gly5 has been removed, resulting in a smaller
is the bioactive form. Pro has been proposed to ring size, exhibited potency in the GPI similar
function as a stereochemical spacer, and in- to that of the corresponding peptides with a
version of its stereochemistrv" in endomor- larger ring, but decreased potency in the MVD
phin-1essentially abolishes agonist activity in (824). Substitution of Phe3 with 2-naphthyl-
the GPI (821). [D-Pro2]endomorphin-2, how- alanine (2-Nal) in the D-Pro-containing pep-
ever, was a much more potent analgesic than tides gave Tyr-cyclo[~-X-2-Nd-~-Pro-Gly]
endomorphin-2 in the tail flick assay after [X = D-Om(233, Table 7.18) or D-Lysl,which
i.c.v. administration; the analgesia produced are agonists in the GPI but antagonists in the
by both peptides was reversed by naloxone MVD (825), and thus are mixed p agonistsl6
(822). antagonists. Examination of Tyr-cyclo[~-Om-
Potent cyclic derivatives of P-casomorphin- X-D-Pro-Gly] [X = Phe (232) or 2-Nal (23311
(1-5) were prepared by cyclization between a and Tyr-cyclo[~-Om-2-Nal-Pro-Gly](231) by
D-amino acid in position 2 and the C-terminus. NMR indicated that the overall backbone con-
i 6 Opioid Peptide Analogs

Table 7.19 Opioid Receptor Affinities and Antagonist Activity in the GPI and MVD of TIPP
and Selected Analogsa
Ki (nM) Ki Ratio K, (nM)
Peptide 6 P 4 6 MVD GPI Reference(8)
TIPP (30) 3.0-5.9 -
TIPPNH, 14-18 IC,, = 1,700b
Tyr-D-Tic-Phe-PheNH, IC,, = 454b IC,, = 37'
TIPP[$I (31) 2.1-2.9 -
DIPP (236) 0.15 IC,, = 770'
DIPPNH2 (237) 0.20 IC,, = 18b
DIPP[$]-NH, (239) 0.54 IC,, = 7.7'
TICP (Tyr-Tic-Cha-Phe) 0.44
TICP[$I 0.22
Dmt-TicOH 5.7

- - - - - -

"Data for TIPP and TIPP[+] from Table 7.8 are included for comparison. Data for a number of other analogs are given in
Ref. 837.
'Agonist.
"Not active.
dIC,,.
'30% inhibition at 30 a.
fK, ((K)= 68 nM, EC5, = 0.18 nM for GTPyS binding at cloned preceptors.
SK, (K) = 1.3 nM;EC,, = 0.65 and 6.9 for GTPyS binding at cloned 6 and K receptors, respectively. Inactive at p receptors. ,

formations and preferred side-chain confor- workers to identify TIPP (Tyr-Tic-Phe-Phe,


mations were roughly similar for these pep- 30, Fig. 7.5) (111).TIPP is a potent 6 antago-
tides (826). Interestingly, substitution of nist in the MVD, with very high selectivity for
1-naphthylalaninein position 3 of (232) yields S receptors (Table 7.19). [Recently, however,
a compound with full agonist activity in the TIPP and its analog TIPP[W (31,Fig. 7.5, see
MVD (825). Substitution with other bulky ar- below) were reported to exhibit agonist activ-
omatic amino acids was generally well toler- ity in adenylyl cyclase assays using cells con-
ated by S receptors, but drastically decreased taining both endogenous and transfected S
5
preceptor affinity (827). Replacement of Gly opioid receptors (114).] The tripeptide deriva-
in (233) with sarcosine or D-Ala significantly tives TIP and TIP-NH, are also S-receptor an-
enhanced S-receptor affinity and antagonist tagonists in the MVD. In contrast, the tet-
potency (see Table 7.18) (828). Recently, de- rapeptide Tyr-D-Tic-Phe-Phe-NH, with D-Tic
rivatives of Dmt-cyclo[n-Om-2-Nal-D-Pro-Gly] in position 2 is a potent agonist that is selec-
(234) lacking a basic N-terminus were re- tive for p receptors. The amide derivative of
ported (see Table 7.18); these peptides exhibit TIPP, in addition to 6-antagonist activity in
antagonist activity at both 6 and p receptors the MVD, is afull agonist in the GPI (see Table
(829). 7.19), and was the first compound reported to
be a mixed p agonistIS antagonist (111).
6.4.2 TIPP and Related Peptides. Explora- The conformations of TIPP were examined
tion of a series of tetrapeptides consisting by molecular mechanics and X-ray crystallog-
solely of aromatic residues led Schiller and co- raphy (see Ref. 837 for a review). Examination
Narcotic Analgesics

of the 6 antagonist TIP and the p agonist Tyr- ity compared to the parent peptides and excep-
D-Tic-PheNH, by molecular mechanics found tional 6-receptor selectivity (see Table 7.19).
compact structures for both peptides, but with This modification also enhances the metabolic
different patterns of aromatic ring stacking stability of the peptides. Whereas the dike-
(838). Superimposition of low energy confor- topiperazine of Tyr-Tic is inactive, the Dmt
mations of these two peptides found that the analogcyclo[Dmt-Tic] (235, Fig. 7.48) exhibits
Phe3 residues were on opposite sides of the 6-receptor affinity (Ki = 9.6 nM) and weak h-
plane defined by the Tic residue, providing a tagonist activity (K, = 3.98 pI4) in the MVD
possible explanation for the differences in ac- (845).
tivity observed for the two peptides. Compar- A variety of structural modifications have
ison of TIP to the nonpeptide 6 antagonist nal- been made to all positions of TIPP (see Refs.
trindole found good spatial overlap of the 837, 846 for recent reviews), and these can
N-terminal m i n e and aromatic rings in the have a profound effect on the activity profile of
peptide with the corresponding groups in the these peptides. Numerous substitutions have
alkaloid. In this model the Tyr-Tic peptide been made in position 3, and the results indi-
bond is trans. In an alternative model based on cate that an aromatic residue is not required
the weak dipeptide 6 antagonist Tyr-TicNH, in this position for 6 antagonist activity. Thus
this bond is cis (839). the cyclohexylalanine (Cha) analogs of both
Further examination of the possible confor- TIPP and TIPP[qI (TICP and TICP[Vl, re-
mations of a series of TIPP analogs, including spectively) are approximately 10-fold more po-
derivatives of TIPP[qI (311, by molecular me- tent as 6-receptor antagonists than the parent
chanics found low energy conformations consis- peptides (847) (see Table 7.19). Interestingly,
tent with the model containing a trans Tyr-Tic incorporation of D-amino acids containing a
bond, but the model with a cis amide bond still P-methyl group can have a profound effect on
remained plausible (840). Other modeling stud- the efficacy at 6 receptors (848,849). Thus, the
ies involving TIPP found conformations consis- (2R,3R)-P-MePhe3derivative of TIPPNH, is a
tent with both the trans (841, 842) and the cis 6 antagonist, whereas the (2R,3S)-p-MePhe3
conformations (842). Therefore Schiller and isomer is a 6 agonist, and incorporation of
coworkers prepared TyrlIr[CH,NH]Tic-Phe- p-Me-~-Tic' derivatives in Tyr-D-Tic-Phe-
PheOH and Tyrq[CH,NH]MeTic-Phe-PheOH PheNH, converts the peptide from an agonist
(MeTic = 3-methyl-1,2,3,4-tetrahydroisoquino- to an antagonist. Iodination of Tyrl in TIPP
line-3-carboxylic acid, Fig. 7.43) in which a cis converts the peptide from an antagonist to a
amide bond between the first two residues is 6-selective agonist (850); the Tyr(3'-1)' ana-
sterically forbidden (843). The Sreceptor affin- logs of TIPP[qI, TICP, and TIP, however, are
ity and antagonist activity of these peptides, al- 6 antagonists, thus illustrating the subtleties
though 20- to 40-fold lower than TIPP, is consis- of the effects of modifications on efficacy at 6
tent with a trans conformation as the bioadive receptors (837,846).
conformation for TIPP. Interestingly, these Substitution of Dmt in position 1 of TIPP
modifications substantially increased p-recep- and analogs yielded DIPP (Dmt-Tic-Phe-Phe,
tor affinity, so that Tyrq[CH,NH]MeTic-Phe- 236, Fig. 7.48) and related peptides. DIPP is
PheOH was a nonselective antagonist at both p an extremely potent 6 antagonist (Table 7.19)
and 6 receptors (< a two-fold difference in K, and like TIPPNH, is also a full agonist in the
values in the GPI and MVD). GPI (851, 852). As noted earlier the nonpep-
During examination of TIPP by NMR in tide naltrindole can prevent the development
deuterated DMSO spontaneous degradation of morphine tolerance and dependence in mice
through diketopiperazine formation occurred (2251, and therefore compounds with mixed p
(844). This led Schiller and coworkers to pre- agonist/S antagonist activity could have ther-
pare TIPP[q] (31, Fig. 7.5) and the tripeptide apeutic potential. Thus, Schiller and cowork-
TIP[qI (112) containing a reduced peptide ers also incorporated Dmt into position 1 of
bond between Tic2 and Phe3. These analogs TIPPNH, and TIPP[YINH2 to enhance p ag-
exhibit increased 6-receptor antagonist po- onist activity; the resulting DIPP[q]-NH,
tency in the MVD and higher S-receptor affin- (239) was the first compound with balanced p
6 Opioid Peptide Analogs

X = =0, Y = OH (236) DlPP


X = =0, Y = NH2 (237) DIPPNH2
X = Hz, Y =OH (238) DIPP[Y]
X = Hz, Y = NH2 (239) DIPP[Y]NH2

HO.

Figure 7.48. Analogs of Dmt-Tic and TIPP.

agonistI8 antagonist properties (229, 853). consisted of only the Tyr-Tic dipeptide rather
DIPP[V]-NH, is a potent analgesic after i.c.v. than the tripeptide Tyr-Tic-Phe, Temussi and
administration (three times more potent than coworkers synthesized Tyr-IJD-Tic-NH, and
morphine) and produces less acute tolerance Tyr-LID-Tic-AlaNH,(839). Although they ex-
than morphine and no physical dependence hibited much lower potency than TIPP and
with chronic administration (229).The tripep- TIP, the shorter peptides containing Tyr-L-Tic
tide analogs Dmt-Tic-Ala-X (where X = OH or were &selectiveantagonists; peptides contain-
NH,) also exhibit high affinity for 8 receptors ing the Tyr-D-Tic sequence were nonselective
and are potent antagonists in the MVD; the agonists. Lazarus and coworkers explored the
arnide derivative retains appreciable p-recep- structure-activity relationships of Tyr-Tic in
tor affinity and is a weak agonist in the GPI considerable detail (see Refs. 837,855,856 for
(854). Replacement of Dmtl with N,2',6'-tri- reviews, including extensive tables of ana-
methyltyrosine (NMeDmt) in DIPPNH, de- logs). The dipeptide Dmt-TicOH was initially
creases efficacy at p receptors, so that reported to have exceptionally high 8-receptor
NMeDmt-Tic-Phe-PheNH, is a partial agonist affinity and selectivity (854), although other
and NMeDmt-TicV[CH,NH]Phe-Phe-NH, is researchers subsequently reported lower val-
an antagonist in the GPI (229). ues (857, 858) (see Table 7.19). Modifications
Based on the hypothesis that the "mes- examined have included N-terminal alkyla-
sage" domain in these 8 antagonist peptides tion, which enhances 8-receptor antagonism
Narcotic Analgesics

(859). Thus, N,N-Me2-Dmt-TicOH and N,N- similar (868). N,N-Me,-Dmt-Tic-NH-1-ada-


Me,-Dmt-Tic-AlaOH exhibit enhanced 6 an- mantane is both a potent &receptor antago-
tagonist potency in the MVD (K,= 0.2-0.3 nist and p-receptor agonist (Table 7.19) (868).
nM) (859); moreover, these derivatives cannot Interestingly, modification of the C-terminus
undergo diketopiperazine formation. In the of Dmt-Tic to yield m i n e , urea, and thiourea
GTPyS assay, N,N-Me2-Dmt-TicNH, is a full derivatives (e.g., 241) results in compounds
inverse agonist, whereas Dmt-TicOH is a par- with nanomolar affinity for K as well as p "and
tial inverse agonist and Dmt-TicNH, is a neu- 6 receptors, and agonist activity at all three
tral antagonist (860). (2S,3R)-Tmt-TicOH, receptor types (858).
with a P-methyl group added to Dmt (861), is
also a full inverse agonist in this assay (862). 6.5 Opioid Peptides with the Tyr-D-aa-Phe
Derivatives of Dmt-Tic with substitutions on Sequence
Tic2, with or without a C-terminal acid func-
tionality, have also recently been reported 6.5.1 Dermorphin Analogs and Related
(857, 863). Interestingly, substitution of Tic p-Selective Peptides
by D-Pheto give Dmt-D-PheNH, resulted in a 6.5.1.1 Linear Analogs. As indicated ear-
p-receptor antagonist (although its selectivity lier (Section 6. l . l ) , the amphibian heptapep-
was relatively low) (864), whereas substitu- tide dermorphin is a potent p-selective pep-
tion of Tic by 6-benzyl-1,2,3,4-tetrahydro- tide, and thus it has served as the lead
quinoline-4-amine to give (240) resulted in a compound for structural modification (see
p-selective agonist (Table 7.19) (865). Ref. 663 for a review). Dermorphin contains a
The C-terminal extension of Tyr-Tic and C-terminal amide, and deamidation of der-
Dmt-Tic can alter efficacy at 6 receptors, de- morphin or its shorter fragments to the corre-
pending on the substitution. Thus the efficacy of sponding acids decreases affinity for p recep-
the dipeptide amides Tyr-Tic-NH(CH,),Ph de- tors and potency in the GPI. Examination of
pends on the length of the amide chain (antago- shorter fragments indicated that the N-termi-
nist for n = 1 or 3, agonist for n = 2) (846). In nal tetrapeptide Tyr-D-Ala-Phe-Gly- NH,
Tyr-Tic-NH(CH,),Ph substitution on the phe- maintains significant opioid activity, and
nyl ring byp-fluorine or chlorine or replacement therefore a variety of tetrapeptide amide de-
of this phenyl ring by a cylohexyl ring converts rivatives have been prepared (see below)..The
the peptide from an agonist back to an antago- further truncated tripeptide amide Tyr-D-Ala-
nist (846). In contrast ortho substitution on the PheNH, also retains significant opioid activity
phenyl ring with chlorine enhances 6 agonist po- (25% of the potency of Met-enkephalin) (869),
tency 10-fold (846, 866). Introduction of a sec- and could be further simplified by removing
ond phenyl group and N-terminal methylation the C-terminal amide to give dipeptide aryl
also enhance agonist potency, so that NMeTyr- amides with maintenance of opioid activity.
Tic-NHCH,CHPh, is an extremely potent 6 ag- Tyr-D-Ala phenylpropylamide (DAPPA) was
onist (Table 7.19). Substitution of the P carbon further modified by incorporation of Dmt in
of the phenethyl group in Tyr-Tic-NH(CH,),Ph position 1 to give SC-39566 (870), which is
with C0,Et results in the most 6 selective ago- orally active (871).
nist within this class (Table 7.19) (846). Re- Extension of dermorphin with residues
moval of the C-terminal acid functionality from from the precursor sequence also yields potent
Tyr-Tic-AtcOHconverts the peptide from an an- p-selective peptides. Although introduction of
tagonist to an agonist (846). the additional residues through the Glu9 or
The C-terminal extension of Tyr-Tic and Ala1° residues decreases p-receptor affinity,
Dmt-Tic can also enhance p-receptor affin- apparently because of introduction of the
ity. The dipeptide derivative Dmt-Tic- NH acidic Glu9 residue, further extension of the
(CH,),Ph is a 6-receptor antagonist and p-re- sequence increases p-receptor affmity as basic
ceptor agonist (867). Interestingly, Dmt-Tic- residues are incorporated (872); the resulting
NH-1-adamantane is a weak agonist at 6 re- pentadecapeptide (Tyr-D-Ala-Phe-Gly-Tyr-
ceptors and potent agonist at p receptors, Pro-Ser-Gly-Glu-Ala-Lys-Lys-Ile-Lys-Arg-
although its affinity for the two receptors is NH,) has exceptional affinity for p receptors
6 Opioid Peptide Analogs

(Ki = 2.0 pM), but this C-terminal extension morphins (264). TAPP analogs in which either
does not enhance potency in the GPI. Dimeric Phe3 or Phe4 was nitrated were prepared to ex-
derivatives of dermorphin fragments have amine whether the Phe3 aromatic ring of der-
been prepared by bridging two monomers morphin interacts with a different subsite on
with hydrazine or diamines of various lengths opioid receptors than the Phe4 aromatic ring of
(873). Di-dermorphin, [(dermorphin-NH-),I, the enkephalins. Examination of Phe(p-NO,)-
in which two dermorphin molecules are linked containing analogs of dermorphin, morphicep-'
by hydrazine, exhibits fivefold higher affinity tin, and various enkephalin analogs found that
for preceptors and similar p-receptor selectiv- p-nitro substitution in Phe3 of dermorphin and
ity as dermorphin. Di-tetra-dermorphin, morphiceptin causes large decreases in potency
[(Tyr-D-Ala-Phe-Gly-NH-CH,),] and other in the GPI, whereas this substitution in Phe4 of
dimeric derivatives exhibit greater affinity for p- and &selectiveenkephalin analogs enhances
6 receptors, and hence decreased p-receptor potency in smooth muscle assays (880).Incorpo-
selectivity compared to that of the monomer. ration of Phe(p-NO,) in position 3 of TAPP de-
Glycosylated derivatives of dermorphin creases receptor affinity, whereas incorporation
were prepared by attaching p-D-glucoseto the in position 4 increases affinity, consistent with
hydroxyl of a Ser or Thr, or galactose through the concept of two distinct receptor subsites for
a C-alinkage to Ala in position 7 (874-876). these aromatic residues on opioid receptors
Although glycosylation decreased p-receptor (881). Bulky aromatic amino acids such as tryp-
affinity twofold, the penetration of the blood- tophan or naphthylalanine are well tolerated in
brain barrier was significantly higher for the positions 3 and 4 of TAPP and yield even more
glycosylated derivatives and they exhibited lipophilic peptides (881).
twice the antinociceptive activity of dermor- Incorporation of D-Arg in position 2 of der-
phin (875, 876). The enhanced BBB penetra- morphin and tetrapeptide analogs yields pep-
tion by the C-a-galactoside analog suggested tides that are potent opioids in antinociceptive
that the glucose transporter was not involved assays in mice (879,882). The tetrapeptide de-
in the transport (875). rivative Tyr-D-Arg-Phe-Sar(TAPS) is a potent
Amino acid substitutions have been exam- opioid in antinociceptive assays and causes re-
ined in every position of dermorphin (see Ref. spiratory stimulation, rather than respiratory
663 for a review). An alanine scan of the pep- depression, that is antagonized by naloxona-
tide indicated that substitutions in positions zine (883);TAPS also antagonizes the respira-
4, 6, and 7 are well tolerated, whereas substi- tory depression caused by dermorphin. On the
tution particularly in positions 1 or 2, but also basis of these results TAPS has been postu-
in positions 3 or 5, results in large decreases in lated to be a p, agonist and a p2antagonist in
potency in the GPI (877). A D-amino acid in vivo (883). In contrast, incorporation of L-Tic
position 2 is important for activity, and the in position 2 of dermorphin converts the pep-
~-Ala'peptide is virtually inactive (<0.1% the tide to a &receptor antagonist (884).
potency of dermorphin). Tetrapeptide analogs Schiller and coworkers postulated that pos-
containing D-methioninesulfoxide in position itively charged ligands should display p-recep-
2 are also potent p-selective agonists (878). tor selectivity (831) on the basis of Schwyzer's
Substitutions for Gly4 are well tolerated, proposal that p receptors are located in an an-
particularly in the tetrapeptide derivatives. ionic membrane compartment (885). Consis-
Sarcosine (NMeGly, Sar) at position 4 in tet- tent with this concept they found that incor-
rapeptide derivatives enhances opioid activity poration of a positively charged residue in
in antinociceptive assays (879). Substitution position 4 of tetrapeptide dermorphin deriva-
of Phe in position 4 of the tetrapeptide amide tives enhances p-receptor selectivity by de-
yields the dermorphidenkephalin hybrid TAPP creasing affinity for 6 receptors (831). The
(Tyr-D-Ala-Phe-PheNH,)(831), which is a po- combination of a D-Argin position 2 with a
tent p-selective agonist (see Table 7.18). This second basic residue in position 4 yielded
peptide can also be considered an analog of en- the polar peptide Tyr-D-Arg-Phe-LysNH,
domorphin-2, although TAPP was synthesized (DALDA, 242), which carries a net charge of
several years before the discovery of the endo- +3 (831) and exhibits exceptional p-receptor
Narcotic Analgesics

selectivity in binding assays (see Table 7.18). 6.5.1.2 Conformationally Constrained Ana-
Quaternization of the side chain amine of Lys4 logs. Dermorphin analogs containing a local
in DALDA and related analogs is well toler- constraint were prepared by incorporation of a
ated, and the resulting analogs retain potent dipeptide mimetic in place of Phe3-Gly4. The
in vivo antinociceptive activity in the mouse Aba3-Gly4 (see Fig. 7.43) analog of dermor-
writhing assay after S.C.administration (886). phin retains high affinity at p receptors and
The antinoceptive effects of DALDA and the potency in the GPI, whereas this structural
quaternary derivatives are substantially re- modification increases S-receptor affinity and
duced by the quaternized antagonist N-meth- potency in the MVD 17- to 25-fold (892). A
yllevallorphan, suggesting that these peptide number of heterocycles are also tolerated as
analogs have a high degree of peripheral an- bond replacements for the Phe3-Gly4 peptide
bond (893).
tinociceptive activity in this assay. The distri-
Cyclic tetrapeptide analogs of dermorphin
bution of DALDA to the CNS is limited (887),
with the structure Tyr-cyclo[~-X-Phe-ylNH2
and the antinociceptive activity of DALDA in were prepared by Schiller and coworkers. The
the hot plate test after S.C. administration is 13-membered ring cyclic peptide Tyr-cyclo[~-
low (888).The in vivo distribution of DALDA Om-Phe-AspINH, (244, Fig. 7.49) exhibits
has been examined in pregnant sheep (889), high selectivity for p receptors (see Table
and DALDA was not detected in any of the 7.181, whereas the more flexible peptide Tyr-
fetal plasma samples. This is in contrast to cyclo[~-Lys-Phe-GluINH, with a 15-mem-
meperidine and morphine, which undergo bered ring is nonselective (833). Peptides
rapid transfer across the placenta to the fetus, Tyr-cyclo[~-Asp-Phe-OrnINH, (894) and Tyr-
and suggested that DALDA could be a promis- cyclo[~-Asp-Phe-DablNH,(Dab = a, y-diami-
ing opioid for obstetrical use. nobutyric acid) (895) in which the lactam link-
Replacement of Tyrl by Dmt results in a age is reversed also exhibit high affinity and
peptide [DmtllDALDA (243) (832) with 10- p selectivity. The antiparallel cyclic dimers
fold higher affinities for both p and S receptors (Tyr-D-Om-Phe-AspNH,), and (Tyr-D-Asp-
and 200-fold higher affinity for K receptors Phe-OrnNH,),, obtained as by-products dur-
(890). [DmtllDALDA is 220 and 3,000 times ing the synthesis of the cyclic monomers, have
more potent than DALDA and morphine in similar affinities for both p and 8 receptors
the rat tail flick test after i.t. administration. (894).
[DmtllDALDA also inhibits norepinephrine Various modifications to Phe3 in these cy-
uptake in spinal cord synaptosomes, and this clic peptides have also been examined. Many
dual action may contribute to its antinoci- of the modifications (e.g., p-nitro or N-methyl
ceptive potency. Both [Dmtl]DALDA and substitution, or shortening the side chain) de-
DALDA exhibit longer durations of antinoci- crease preceptor affinity by 25-fold or more
ceptive action than morphine after i.t. admin- (895). Although the cyclic structure restricts
istration to rats (7 and 13 h, respectively, ver- the conformation of the peptide backbone,
sus 3 h) (890). In sheep these peptides have there is still considerable conformational flex-
longer elimination half-lives (1.5 and 1.8 h, ibility around the Tyrl and Phe3 side chains
respectively) than that of either morphine (896). Conformational constraint of Phe3 by
(20-30 min) or the much more hydrophobic incorporation of 2-aminoindan-2-carboxylic
p-selective peptide DAMGO (15 min) (891). In acid (Aic, Fig. 7.43) into the relatively nonse-
contrast to morphine and DALDA, [Dmt1]- lective peptide [Ki ratio (Sip) = 31 Tyr-cyclo[~-
DALDA did not cause respiratory depression Om-Phe-GluINH, markedly enhances p-re-
at the doses examined (832),suggesting that it ceptor selectivity (see Table 7.18) (834). This
could be a drug candidate for intrathecal anal- is a direct consequence of conformational re-
gesia. striction because incorporation of the acyclic
derivatives a-methylphenylalanine or 2'-
X-D-Arg-Phe-LysNH, methylphenylalanine in position 3 does not
DALDA (242) X=Tyr significantly change preceptor selectivity. In-
[DmtllDALDA (243) X = Dmt terestingly, the peptides containing L- and D-2-
6 Opioid Peptide Analogs

R =Tyr (246) JOM-6


R = Phe (247) JH-54
R = D-Hat (248)

Figure 7.49. Conformationally constrained dermorphin analogs.

aminotetralin-2-carboxylic acid (Atc, Fig. = 4.4 and 12 for the L-Leu and D-Leu analogs,
7.43) in position 3 had similar preceptor af- respectively]. The analog Tyr-cyclo[~-Dab-
finity and high p-receptor selectivity (834). Phe-gPhe-S-mLeu] containing a reversed
The restricted conformation of the side chain amide bond between Phe4 and Leu5 is also a
of residue 3 in the K c analogs was apparent p-receptor selective agonist. Interestingly, re-
from comparisons of molecular dynamics sim- versal of a second amide bond in the side chain
ulations for the Phe3 versus Kc3-containing lactam linkage to give Tyr-cyclo[~-Glu-Phe-
peptides (897). Further conformational con- gPhe-rLeu1 results in a &elective derivative
straint of Tyr-cyclo[~-Om-Kc-GluINH,by re- [IC,, ratio (GPIIMVD) = 111,which exhibits a
placement of Tyrl with L- or D-Hat yields pep- considerably different conformation from that
tides with only two freely rotatable bonds exhibited by the other retro-inverso analogs
(245, Fig. 7.49) (897); interestingly, both di- that preferentially interact with p receptors
astereomers exhibit reasonable preceptor af- (899).
finity and selectivity [Ki ( p ) = 20-30 nM, Ki In the case of peptides cyclized through a
ratio (Sip) = 12-191. disulfide or dithioether linkage, the receptor
Cyclic pentapeptide derivatives of Tyr-cy- selectivity depends on the linkage. The cyclic
C~O[D-Dab-Phe-Phe-(D- or L-)Leu] containing disulfide analog Tyr-cyclo[~-Cys-Phe-Cysl-
retro-inverso modifications were prepared by NH, exhibits 10-fold greater affinity for S re-
Goodman and coworkers (898). The parent ceptors than the corresponding lactam Tyr-
peptides 'lj~-cyclo[~-Dab-Phe-Phe-D/L-Leu] are cyclo[~-Asp-Phe-Om]-NH,and is therefore
potent agonists in the GPI with relatively low less p-receptor selective [IC,, ratio ( 6 1 ~=) 341
p-receptor selectivity [IC,, ratio (MVDIGPI) (895). The cyclic tetrapeptide JOM-13 Tyr-cy-
Narcotic Analgesics

C~O[D-Cys-phe-~-Pen]OH is a &selective ago- 6.5.2 Deltorphin Analogs and Related Pep-


nist (900) (see Section 6.5.2.2 below), but in- tides
corporation of an ethyl group between the two 6.5.2.1 Linear Analogs. Among the natu-
sulfurs and amidation of the C-terminus re- rally occurring deltorphins, [D-Ala2]deltorphin1
sult in the p-selective peptide JOM-6 (246, Ta- and I1are more potent and more &selectivethan
ble 7.18) (900). Comparison of JOM-13 and its deltorphin (see Table 7.13) and have a distinctly
p-selective amide derivative JH-42, which different C-terminal sequence (106). Like
contains E-dehydrophenalanine in position 3, dynorphin, the deltorphins have been divided
docked to computational models of 6 and p into two domains, the N-terminal "message" re-
receptors, respectively, found key differences gion and C-terminal "address" sequence. There
(182). The Phe3 side chain of the peptide are differences in the structure-activity relation-
ships for deltorphin and [D-Ala21deltorphin I and
adopts the gauche (- ) (- -60") conformation
11, particularly in the C-terminal "address" do-
and interacts with Leu3' in TM7 in the S re-
main, and therefore the SAR in this region of the
ceptor, whereas the presence of Trp in the cor-
peptides is discussed separately below. [D-A@]
responding position in the p receptor causes a deltorphin I and I1 are also metabolically more
shift of the entire peptide within the binding stable than deltorphin, apparently because of
pocket and reorientation of the Phe3 side the branched amino acid present in position 5 of
chain from gauche to the trans conformation. the former peptides (902).
The C-terminal acid in JOM-13 forms an ion A number of studies have examined possi-
pair with Lys214in TM5 of the S receptor in ble conformations of the deltorphins (see Refs.
the model, but because of the shift in the pep- 903-905 for reviews). A 0 turn in the N-termi-
tide in the binding site, its C-terminus is in nus has been observed for both the p-selective
close contact with G ~ in the u preceptor
~ ~ and ~ peptide dermorphin and the &selectivedeltor-
therefore amidation of the C-terminus re- phins, while differences in the conformations
moves unfavorable electrostatic repulsion. of the C-terminal sequences have been de-
The shift of the peptide lengthened the dis- scribed (see Refs. 903-905 and references
tance between the phenol of Tyrl of the pep- cited therein). These studies are complicated,
tide and Hiszg7in the preceptor binding site however, by the inherent conformational flex-
compared to the corresponding distance in the ibility of linear peptides, and very different.
S binding pocket, suggesting that the hydro- conformations can be observed for a given pep-
gen bond between these two groups may be tide (see, e.g., Ref. 906).
less important for binding to p receptors. Mos- Amino acid substitution has provided in-
berg and coworkers therefore prepared JH-54 formation on the contributions of different
(2471, the Phel analog of JOM-6, and found residues in the deltorphin sequence to S-recep-
that it retained high affinity for p receptors tor affinity and selectivity. A variety of substi-
but greatly reduced aMinity for 6 receptors tutions have been made in each position of the
(Table 7.18), consistent with the expected re- deltorphins, resulting in hundreds of analogs
sults from the modeling (835);this peptide is a reported in the literature. Only selected ana-
potent full agonist in the GPI. Even the aro- logs and structural modifications are dis-
maticity of the residue in position 1 was not cussed here to illustrate key SAR; for more
critical, and the Chal analog of JOM-6 retains detailed discussion readers are referred to re-
moderate p-receptor affinity (Ki = 32 nM) and cent detailed reviews (904,9051, which include
agonist potency (EC,, = 59 nM in the GTPyS extensive tables of analogs.
assay) (901). Incorporation of conformation- One of the first structural modifications
ally restricted tyrosine analogs in position 1 that was examined in the deltorphins was the
resulted in potent p agonists (see [D-Hat1]- chirality of residue 2. Along with the initial
JOM-6, 248, Table 7.18), but the potency descriptions of the deltorphin sequence, the
changes in the GTPyS assay did not always peptides with both D-Met and L-Met in position
correlate with affinity, suggesting that the 2 were synthesized to determine which was
conformations required for receptor activa- the naturally occurring sequence (666, 668,
tion versus binding were different (836). 669). Whereas the peptide containing D-Met
'E
i
6 Opioid Peptide Analogs
1
e
Table 7.20 Opioid Receptor Affinities and Opioid Activity in the GPI and MVD of Deltorphin
Analogsa
Ki(nM) Ki Ratio IC,, (nM)
Peptide 6 P d6 GPI MVD Reference

"Data for [D-Alaz]deltorphinI and I1 from Table 7.13 are included for comparison.
bPartial agonist.

exhibited high 8-receptor affmity and selectiv- acid causes a large decrease in 8-receptor af-
ity, the analog with L-Met had very low affinity finity (909). As with most opioid peptides,
and potency in the MVD, indicating the impor- other modifications of Tyrlare also generally
tance of a D-amino acid in this position. As was not tolerated, except for substitutions by con-
found for deltorphin, the D-Ala in position 2 of formationally restricted derivatives of Tyr
[D-Ala2]deltorphin1is also important for S-re- (see Section 6.5.2.2 below). A variety of struc-
ceptor affinity and selectivity, and the ~-Ala' tural modifications have been examined at po-
analog has extremely weak activity in the sition 3 of [D-Ala2]deltorphin I, including in-
MVD (IC,, > 1 a) (106). The exception to corporation of aromatic, heterocyclic, and
the requirement for a D-amino acid in position nonaromatic amino acids (see Ref. 904) and
2 is [Tic2]deltorphin I, which retains high af- conformationally constrained derivatives (see
finity and exhibits increased selectivity for 8 Section 6.5.2.2 below). The effects of substitu-
receptors (Table 7.20) (907); this substitution tion on the phenyl ring of Phe3 vary with the
decreases efficacy, however, and in the MVD substituent. para-Substitution with a halo-
this analog is a partial agonist. In deltorphin gen, but not an m i n e , nitro, hydroxyl, or
substitution of D-Ala, as is found in methyl group, in [ ~ A a ~ l d e l t o r p hIi nis well
[D-Ala2]deltorphinI and 11, for o-Met is well tolerated by 6 receptors, and p-bromo substi-
tolerated at 8 receptors, although it increases tution enhances 8-receptor selectivity in both
preceptor affmity and potency in the GPI binding and smooth muscle assays (910-912).
(908, 909). In contrast, substitution of D-Met The heterocyclic phenylalanine analog 342-
in position 2 of [D-Ala2]deltorphinI or 11 thieny1)alanine is well tolerated in position 3
causes a large decrease in 8-receptor aMinity by 8 receptors, but other heterocyclic aromatic
and selectivity (908, 909). amino acids, such as the pyridylalanine deriv-
Modifications to the aromatic residues in atives or His, significantly decrease 8-receptor
the N-terminal "message" sequence have been affmity (912). An aromatic residue is not re-
examined, mostly in [D-Ala2]deltorphinI or 11. quired in position 3 of [D-Ala2]deltorphinI,
Replacing either Tyrl or Phe3 by a D-amino and the analogs with Cha and even Leu or
Narcotic Analgesics

norleucine (Nle) exhibit &receptor affinity due in position 4. Replacement of Asp and Glu
only six- to sevenfold lower than that of the in this position with Asn and Gln, respectively,
parent peptide (Table 7.20). QSAR analysis of results in compounds that maintain brecep-
the effect of substitution in position 3 sug- tor affinity, but have enhanced p-receptor af-
gested that the binding site around this side finity and thus significantly decreased 6-recep-
chain is very similar for 6 and p receptors tor selectivity (908, 914, 915). A variety of
(913). Substitution of either the a-carbon or other amino acid substitutions in this position
3
nitrogen of Phe with a methyl group, which are well tolerated by 6 receptors but signifi-
can alter the conformation of the peptide cantly enhance p-receptor affinity (908, 919).
backbone, is not tolerated (911). Thus the negative charge at position 4 is not
The C-terminal truncation of the deltorphins necessary for &receptor interaction, but con-
can affect both &receptor affinity and selectiv- tributes significantly to 6-receptor selectivity
ity. Deamidation of both [D-Ala21deltorphinI by interfering with interaction with p recep-
and I1 causes significant decreases in &receptor tors. Consistent with this, substitution of Asp/
affinity (25- to 50-fold) and 6 selectivity (908, Glu by His, the residue found in this position
914, 915). Although there is one report of a of deltorphin, does not affect &receptor affin-
large (90-fold) decrease in 6-receptor affinity ity but increases preceptor affinity (908,919).
upon conversion of deltorphin to the C-termi- Replacement of Asp/Glu by hydrophobic resi-
nal acid (914),there are other reports that de- dues [e.g., Phe (see Table 7.20), a-aminobu-
amidation of this heptapeptide causes only a tyric (Abu), or a-aminoisobutyric acid (Aib),
small decrease (916), or even a slight increase and the conformationally restricted l-amino-
(9151, in &receptor affinity. Shortening of ei- cycloalkane derivatives1 substantially in-
ther [D-Ala21deltorphinI or deltorphin from creases p-receptor affinity, resulting in ana-
the C-terminus causes progressive decreases logs with nanomolar affinity for both 6 and p
in &receptor affinity and selectivity and po- receptors, which has been referred to as "opi-
tency in the MVD (908, 915, 916). The oid infidelity" (903). QSAR analysis of substi-
hexapeptide and pentapeptide derivatives of tutions in this position has also been per-
[D-Ala2]deltorphinI retain 6-receptor selectiv- formed (913), and suggests that the receptor
ity (908); the corresponding deltorphin frag- binding site for this residue is quite different
ments, although retaining high affinity for 6 for 6 versus preceptors. Analysis of binding to
receptors, are nonselective (916). The N-ter- 6 receptors suggested at least a partial positive
mind tetrapeptide amide derivative of deltor- charge in the binding pocket, with both elec-
phin is selective for preceptors (917,918) [the trostatic and van der Wads forces, but not hy-
tetrapeptide acid exhibits low affinity for both drogen bonding, contributing to receptor
p and 6 receptors (91811, indicating that the binding.
C-terminal "address" sequence is capable of In positions 5 and 6 of [D-Ala2]deltorphin11
changing receptor type selectivity. Indeed, replacement of Val5 and Val6 individually by
swapping the C-terminal tripeptide se- Ala suggested that Val5 is more important
quence of dermorphin and deltorphin re- than Val6 for &receptor selectivity (920). Re-
verses the receptor selectivity profile [i.e., placement of valine in both positions by nor-
5 6 7
p
[Leu ,Met ,As ]dermorphin is S selective leucine, Ile, or y-methylleucine enhances
(91611. The N-terminal tetrapeptide amide both 6-receptor affinity and selectivity four- to
fragment of [D-Ala2]deltorphin1 (Tyr-~-Ala- eightfold (920). Replacing Gly7 in [~-Ala']-
Phe-AspNH,) shows a slight preference for p deltorphin I with Asp, which is found in this
receptors (908,915), but its affinity (Ki = 100- position in deltorphin, decreases affinity for
195 nM) and selectivity for p receptors is both 6 and p receptors approximately 10-fold
much lower compared to that of the N-termi- (919).
nal tetrapeptide amide fragment of deltorphin Amino acid substitutions in the C-terminus
[Tyr-D-Met-Phe-HisNH,;Ki (p) = 8.0 nM]. of deltorphin have also focused mainly on the
In the C-terminal "address" sequence of charged residues His4 and Asp7. As was found
[D-Ala2]deltorphinI and I1 considerable atten- for Asp4/G1u4 in [D-Ala2]deltorphin I and 11,
tion has focused on the role of the acidic resi- His4 appears to play an important role in the
F
6
Ej

k1 6 Opioid Peptide Analogs

P
&receptor selectivity, but not affinity, of del- riety of other substitutions for Met6 in deltor-
torphin. Thus a variety of amino acid substi- phin are well tolerated (see Ref. 9041,
tutions for His4, including Gly and aromatic suggesting that residue 5 is more important
amino acids, are well tolerated by 6 receptors, for receptor interaction. However, incorpora-
but they enhance preceptor affinity and thus tion of an additional acidic residue in position
decrease 6-receptor selectivity (915). Interest- 6 decreases breceptor affinity (914,923).
ingly, substitution by Lys markedly decreases 6.5.2.2 Conformationally Constrained And-?
&receptor affinity (915), and substitution by logs. The conformationally restricted tyrosine
Asp, as is found in [D-Ala2]deltorphinI, de- analogs Dmt and Tmt (Fig. 7.43) have been in-
creases both 6- and preceptor affinity (908, corporated into position1of [D-Ala2]deltorphin 1-
914, 915). Replacement of His4 by D-H~s only or 11. Substitution of Dmt for Tyr in
decreases 6-receptor affinity and selectivity [D-Ala2]deltorphin I1 markedly enhances p-re-
4-6-fold, whereas des-His4 analogs have ceptor affinity, resulting in a compound with
markedly lower &receptor affinities and selec- nanomolar affinity for both receptors (Table
tivities (909),suggesting that His4 may play a 7.20) (924). In contrast [D-Ala2]deltorphinI
role in maintaining the necessary spatial ori- analogs containing either of the 2S isomers of
entation of the C-terminal sequence of deltor- Tmt, which has the additional P-methyl
phin relative to the N-terminus. Further mod- group, exhibited high Breceptor affinity and
ifications of His4 have been examined (921). selectivity; the 2S,3S isomer exhibited greater
N-Methylation on either nitrogen of the 6-receptor selectivity than that of the parent
imidazole enhances breceptor selectivity, peptide (IC,, ratio = 5,740 versus 3,500)
whereas N"-methylation of His4 decreases (728).
both &receptoraffinity and selectivity. Substi- Linear peptides containing conformationally
tution of the conformationally constrained constrained Phe analogs in position 3 have also
residue Tic for His4 is well tolerated by 6 re- been prepared. The conformationally restricted
ceptors, but decreases 6-receptor selectivity phenylalanine analogs Aic and both isomers of
(921).The charge on Asp7 also does not appear Atc (Fig. 7.43) are well tolerated at this position
to be critical for interaction with 6 receptors, by 6 receptors, although the Aic3 analog is less
but contributes to 6-receptor selectivity by ad- selective for 6 receptors than are the Atc3deriv-
versely affecting preceptor affinity. Thus re- atives of [D-Ala2]deltorphin I (907, 911). The
placement of Asp7 by a nonacidic amino acid similar potencies of both diastereomers of
decreases 6-receptor affinity by less than two- [D-A12,Atc3]deltorphinI are in sharp contrast
to threefold, but enhances preceptor affinity to the large (13- to 50-fold) decrease in potency
so that 6-receptor selectivity decreases (914, of the ~ - P h eanalog
~ compared to that of
2
915,919). [D-Ala ]deltorphin I, suggesting that the recep-
A number of residues have been incorpo- tor binding mode of the ~ - A t analog
c~ may be
rated in position 5 of deltorphin, and generally different from that of the ~ - P h derivative
e~
the 6 receptor affinities of these analogs corre- (907). The configuration of Atc in the diastereo-
late with the hydrophobicity of the residue in meric peptides was not determined in these ini-
this position (see Ref. 904). Branched hydro- tial studies, although it was in subsequent deriv-
phobic amino acids Val, Ile, and y-methyl- atives of [~-Ala~,Ile~,~]deltorphin 1and 11(929).
leucine have been incorporated into this posi- The four isomers of p-MePhe were incorpo-
tion of deltorphin to enhance metabolic rated into both [D-Ala2]deltorphinI and del-
stability; these analogs have Breceptor affini- torphin (930). The peptides containing the 2 s
ties and selectivities similar to those of the isomers exhibit higher Breceptor affinity
parent peptide (902). N-Alkyl amino acids and agonist activity in the MVD than the
were also introduced at position 6 to decrease analogs with the 2R isomers for both
metabolism of the Leu5-Met6 bond; these an- [~-Ala~]deltor~hin I and deltorphin, consis-
alogs possess the desired stability to degrada- tent with the preference for L- over D-Phein
tion by both rat brain and plasma, and the this position. The stereochemistry of the
N-nBuGly6 analog exhibits exceptional selec- methyl group at the P position, however, had
tivity for 6 receptors (Table 7.20) (922). A va- different effects on the 6 affinity and agonist
Narcotic Analgesics

activity of the two peptides, with the 3 s iso- reduced susceptibility to conformational per-
mer preferred in [D-Ala2]deltorphinI and the turbation, of the tetrapeptide. Other substitu-
3R isomer preferred in deltorphin. Substitu- tions that affect only the side chain of residue
3 4
tion with the dipeptide mimetic Aba -Gly is 3, particularly homophenylalanine (Hfe), had
also reasonably well tolerated in [ ~ - A l a ~ l - significantly different effects on &receptor af-
deltorphin I1 (IC,, = 5.0 nM) (892).Other con- finity in the two series. Hfe substitution does
strained residues in position 3 e . Tic or not adversely affect breceptor affinity or po-
NMePhe) result in drastic decreases in S-re- tency in the MVD when it is incorporated into
ceptor affinity (907,911). JOM-13 (although it does increase preceptor
As in the case of cyclic enkephalin analogs, affinity 20-fold so that &receptor selectivity
conformationally constrained &selective pep- decreases), but it decreases breceptor affinity
tides with the sequence Tyr-D-X-Phe were also
and potency in the MVD 100- and 25-fold
prepared by cyclization through a disulfide
when incorporated into DPDPE (932). para-
bond. Cyclization between D-Cys in position 2 3
and D-Pen in position 4 yielded the tetrapep- Substitution of Phe with fluorine, chlorine,
tide derivative Tyr-cyclo[~-Cys-Phe-D-Pen]-or a nitro group in JOM-13 is well tolerated by
OH (JOM-13, 249), which contains a fairly 6 receptors, similar to the results found for
DPDPE analogs (933). An aromatic residue at
position 3 is not essential for &receptor inter-
action, and incorporation of Cha at position 3
of JOM-13 causes less than a threefold de-
crease in breceptor affinity (934); not surpris-
ingly, this modification also enhances p-recep-
tor affinity so that [Cha3]JOM-13 exhibits
only a fourfold lower Kivalue for 6 receptors
than for p receptors.
The conformation of residue 3 has been re-
stricted by incorporation of p-MePhe (935)
and dehydrophenylalanine (APhe) (927) in
this position. Both the 3S and 3R diaste-
rigid 11-membered cyclic structure and which reomers of L-p-MePhe were compatible with
exhibits high affinity and selectivity for 6 re- interaction with S receptors, with the peptide
ceptors (Table 7.20) (900). Conformational containing the 2S,3S isomer exhibiting ap-
analysis by NMR, X-ray crystallography, and proximately eight-fold higher affmity than
computational analysis (931) indicated a sin- that of the peptide containing the 2S,3R iso-
gle preferred conformation for the cyclic tri- mer. Surprisingly, the peptide containing the
peptide portion of JOM-13, but the key phar- 2R,3R isomer of D-p-MePhealso exhibits high
macophoric elements, the exocyclic Tyrl and affinity and selectivity for 8 receptors. Exami-
3
the Phe side chains, still exhibit conforma- nation of this latter peptide by molecular mod-
tional flexibility. eling suggested a side chain conformation of
A variety of substitutions have been made Phe3 in JOM-13 with x1 about -60" when the
for Phe3 in JOM-13 (932-935). Comparison of peptide interacts with S receptors (935). On
3
Phe substitutions in JOM-13 to the same sub- the basis of these results, it was predicted that
4
stitutions for Phe in DPDPE found that mod- the JOM-13 analog containing AZPhe (Fig.
ifications that would be expected to affect the 7.43), but not AEPhe, could be superimposed
conformation of the peptide backbone (e.g., in- on the resulting proposed bioactive conforma-
corporation of NMePhe or D-Phe) had delete- tion of JOM-13; as predicted, [AZPhe3lJOM-
rious effects on breceptor affinity and potency 13 exhibited nanomolar affinity and higher
in the MVD in both series (932); the effects of &receptor selectivity than JOM-13, whereas
these substitutions were generally greater in incorporation of AEPhe in position 4 resulted
the pentapeptide series, however, which may in a 60-fold decrease in 8-receptor affinity
be due to the greater rigidity, and therefore (927).
6 Opioid Peptide Analogs

Mosberg and coworkers also examined Deltorphin and [D-Ala2]deltorphinI and I1


conformationally constrained tyrosine deriva- analogs cyclized by a disulfide linkage between
tives in position 1 of JOM-13 (926,936). Incor- residues 2 and 5 have also been reported. cy-
poration of trans- and cis-3-(4'-hydroxyphe- clo[n-Cys2,Cys5]deltorphinI exhibits affinity
ny1)proline (t-Hpp and c-Hpp, respectively; for 6 receptors similar to that of [ D - A ~ ~ I -
Fig. 7.43) yielded the analogs with the highest deltorphin I, but the cyclic peptide exhibits
-i'
Greceptor affinity and selectivity (Table 7,201, 400-fold higher preceptor affinity and thus
with the peptides containing Hat and Hai (2- very low 6-receptor selectivity (Table 7.20)
hydroxy-2-aminoindan-2-carboxylic acid) ex- (938). Substitution of Pen in position 5 or
hibiting modest 6-receptor affinities and se- preparation of the [D-Pen2,Pen51 derivative in
the deltorphin I series decreases preceptor af-
lectivities. Molecular modeling of the active
finity 730- and 5000-fold, respectively, while
Tyrl-substituted analogs suggested that in the
decreasing S-receptor affinity by only 3.5- to
receptor-bound conformation the side chain of
6-fold (928), thus restoring high breceptor
-
residue 1 is in the trans (x, 180") conforma- selectivity (Table 7.20). A series of cycb [D-QF?,I/
tion and that the exocyclic peptide group is in pPen51 derivatives of [~-Al2]deltorphinI1 and
an extended conformation (q, and @,- 160") deltorphin were also prepared (939); these an-
(926); a second low energy conformation dif- alogs, including some with D-Pen in position 5,
fering in @, (-70") also still remained a exhibit nanomolar affinity for 6 receptors, but
possibility. their selectivity for S over preceptors is much
These results led to a pharmacophoric lower (generally <60-fold) than the pen,,
model of the bioactive conformation of Pen5] peptides.
JOM-13 (926, 935). To distinguish between Schiller and coworkers prepared deriva-
the two remaining possible bioactive confor- tives of the p-selective lactam Tyr-cyclo[~-
mations for JOM-13, these conformations Om-Phe-Asp] with the C-terminal Val-Val-
were then compared and superimposed with GlyNH, sequence from [D-Ala2]deltorphin
DPDPE and other breceptor ligands (TIPP, (907).This C-terminal extension reduces p-re-
and the alkaloids SIOM and OMI) (841). Sim- ceptor affinity and increases 8-receptor affin-
ilar arrangements in space of the key pharma- ity 10-fold, resulting in similar affinities for
cophoric elements (the tyramine moiety and the two receptors. The peptide Tyr-cyclo[~-.
the second aromatic ring) were found with the Lys-Phe-Asp]-Val-Val-GlyNH, with a slightly
other ligands for JOM-13 in the proposed bio- larger ring size exhibits eightfold higher S-re-
active conformation (with @, - 160"),but not ceptor affinity and a slight preference for S
-
the alternative (a, 70") conformation. Dif- over p receptors.
ferent orientations were observed for the sec-
ond aromatic ring in agonists versus antago- 6.6 Other Peptides with High Affinity for
nists, but the same orientation of this Opioid Receptors
aromatic ring was found for both peptide and
alkaloid ligands with the same type of activity 6.6.1 Mu-Receptor Antagonists Derived
(i.e., agonists JOM-13, DPDPE, and SIOM). from Somatostatin. Potent p-opioid antago-
Subsequently, JOM-13 was docked to a com- nists have been identified that are derivatives
putational model of the S receptor (937); in of somatostatin rather than of an opioid pep-
contrast to the modeling based on superimpo- tide (see Ref. 656 for a review). Somatostatin
sition of different ligands, only the alternative exhibits low affinity for opioid receptors, and
-
conformation (a, 70"), and not the proposed the potent somatostatin analog SMS-201,995
conformation with @, about 160", was compat- (D-Phe-cyclo[Cys-Phe-D-Trp-Lys-Thr-Cysl-
ible with the receptor-binding pocket. These Thr-01) was found to be an antagonist at p
results are another indication that the recep- opioid receptors (940). Further structural
tor interactions may differ for different li- modification yielded a series of peptides with
gands, and caution against a simplistic view of the general structure D-Phe-cydo[Cys-Tyr-D-
a single common binding mode for different Trp-X-Thr-Pen]-ThrNH,, where X = Lys,
ligands (937). Om, or Arg in CTP, CTOP (19, Fig. 7.4), and
438 Narcotic Analgesics

Table 7.21 Opioid Receptor Affinities and Antagonist Activity in the GPI and MVD
of Peptide Antagonistsa
Ki (nM) Ki Ratio PA2 -
Peptide EL 6 alp GPI ($1
CTP 3.7 1,150 310 7.1
CTOP (19) 4.3 5,600 1,300 6.4"
CTAP (20) 2.1 5,310 2,530 7.1
TCTP 1.2 9,320 7,770 8.1
TCTOP 1.4 20,400 11,400 7.4 .
TCTAP 1.2 1,270 1,000 8.7
"Data from Ref. 944.

CTAP (20), respectively (105, 941), which ex- sequence of P-casomorphin,and the unrelated
hibit greatly reduced affinity for somatostatin peptides Trp-Trp-Pro-Lys-His-X-NH, (949)
receptors and enhanced affinity and selectiv- with affinity for p receptors. Hexapeptide li-
ity for p receptors. Analysis of CTP by NMR braries have also been examined for affinity
suggested that the central Tyr-D-Trp-Lys-Thr for 6 receptors, resulting in the identification
sequence adopts a type 11' P turn (942). The by positional scanning of several peptides that
conformation of these peptides was further re- share some similarity to the enkephalins [Tyr-
stricted and preceptor selectivity further en- X-Y-Z-Leu-ValNH,, where X-Y-Z = Gly-Met-
hanced by incorporation of the constrained His, His-Gly-Trp (9501, and Gly-Phe-His
amino acid D-Tic in position 1; the resulting (94611.
peptides TCTP, TCTOP, and TCTAP are po- A variety of novel acetylated peptides with
tent p antagonists with exceptional selectivity sequences unrelated to known opioid peptides
for p receptors (Table 7.21) (943,944). Incor- have been identified for all three opioid recep-
poration of either isomer of P-Me-~-phe in po- tors from combinatorial libraries (see Ref.
sition l decreases p-receptor affinity and se- 946). Initially, Houghten and coworkers used
lectivity 10- and 40-fold, respectively (945). p-receptor binding as the screening assay to
Other p-receptor antagonists have been identify peptides from an acetylated hexapep-
identified from combinatorial libraries (see be- tide amide library with affinity for p receptors.
low). These peptides, termed acetalins (250), are po-
tent p-receptor antagonists in the GPI (951).
6.6.2 Peptides and Peptidomimetics from Further exploration of the acetylated hexapep-
Combinatorial Libraries. Mixture-based com- tide library resulted in the additional identiha-
binatorial peptide libraries have been exten- tion of AcPhe-Arg-Trp-Trp-Tyr-X- NH, and
sively explored by Houghten and coworkers AcArg-Trp-Ile-Gly-Trp-X-NH,; AcPhe-Arg-
and have led to the identification of a variety of Trp-Trp-Tyr-MetNH, is an agonist, whereas
peptides with affinity for opioid receptors (see AcArg-Trp-Ile-Gly-Trp-Arg-NH, is an antago-
Ref. 946 for a review). Early hexapeptide li- nist at I*, receptors (949). Screening of an
braries, deconvoluted by binding to p opioid acetylated hexapeptide library of all D-amino
receptors and either iterative deconvolution acids led to the identification of Ac-arg-phe-
(947) or positional scanning (948; see Ref. 946 trp-ile-asn-lys-NH, (D-amino acids indicated
for a description of these deconvolution tech- by use of all lowercase letters for the amino
niques), identified sequences related to the en- acid) as a ligand for opioid receptors; inter-
kephalins. Other nonacetylated peptide li- estingly, this peptide is a potent agonist that
braries have identified more varied peptides, produces analgesia after peripheral adminis-
some that resemble opioid peptides and some tration (952). A nonacylated, all D-amino acid
that do not. Iterative deconvolution of a hexapeptide library also yielded peptides (ile-
hexapeptide library resulted in identification phe-trp-tyr-argNH, and ile-met-ser-trp-trp-
of both Tyr-Pro-Phe-Gly-Phe-XNH, (X = one glyNH,) with affinity for p opioid receptors
of 20 natural amino acids), reminiscent of the (946). An acetylated decapeptide library was
6 Opioid Peptide Analogs

used to identify AcTyr-Arg-Thr-Arg-Tyr-Arg-


Tyr-Arg-Arg-ArgNH, and AcArg-Gly-Trp-
Phe-His-Tyr-Lys-Pro-Lys-ArgNH2 as ligands
for K opioid receptors (946); like dynorphin A,
these peptides have a number of basic residues
in their C-terminal sequences.

Acetalins (250) X = Arg, Lys, or Thr

A single tetrapeptide library containing


both L- and D-amino acids, including a number
of unnatural amino acids (50 amino acids to-
tal), has been screened by positional scanning
for affinity for all three types of opioid recep-
tors (143).This led to the identification of pep-
tides with nanomolar affinity for each receptor
type. Based on screening of the mixtures, an lated hexapeptide library was subjected to ex-
aromatic L-amino acid (Tyr for p receptors, haustive reduction, and the resulting poly-
and Tyr or Trp for 8 receptors) was incorpo- amine library was screened by positional
rated in position 1 in the individual peptides scanning for affinity for p opioid receptors
prepared for these two receptor types. In the 4 (955). The polyamine with the highest affinity
position, an aromatic L-amino acid was also was the fully reduced heptamine of AcTyr-
incorporated in peptides with affinity for p re- Tyr-Phe-Pro-Thr-MetNH2 (IC,, = 14 nM).
ceptors, whereas either Arg or Trp was found The fifth and sixth residues could be truncated
in this position in peptides with 8-receptor af- to yield the pentamine without loss of affinity;
finity. Interestingly, some of the peptides pre- this derivative is an antagonist in both the
pared as ligands for the 8 receptor exhibited GPI and MVD (K,values of 13.6 and 163 nM,
higher affinity for p receptors. The most un- respectively). Further modifications were
usual results were those obtained for the K made to the pentamine to enhance preceptor
receptor. In this case at each position the mix- affinity (see Ref. 946). A bicyclic guanidine li-
tures exhibiting the highest affmity contained brary was also prepared, and after screening
a D-amino acid in the defined position, so that for binding at y receptors, a ligand with mod-
the resulting peptides contained all D-amino est affinity (252, IC,, = 37 nM) was identified
acids. The peptides with the highest affinity (956).
for p and K receptors were tested in adenylyl
cyclase assays and found to be full agonists.
Peptidomimetic ligands for opioid recep-
tors have also been identified from combinato-
rial libraries. Screening of an N-(substi-
tuted)glycine peptoid library for affinity for p
opioid receptors yielded novel structures (251)
with high affmity for these receptors (Ki =
6-46 n M ) (953). A library of dipeptide amides
with alkyl substituents on both the interior
and C-terminal amides were prepared, and
high affinity agonists for all three opioid recep-
tors identified from the library (see Ref. 946).
Peptide libraries can also be further modified
["libraries from libraries" (954)l to yield new
potential ligands for receptors. Thus an acety-
Narcotic Analgesics

6.7 Peptide Affinity Label Derivatives binds with high affinity to 6 receptors and has
been used to characterize 6-receptor subtypes
Peptide-based affinity labels have been princi-
(see Section 3.2.4.3). 3-Nitro-2-pyridinesulfe-
pally photoaffinity labels, including the azide nyl (Npys)-containing derivatives of cysteine
derivatives of several enkephalin analogs and were incorporated into opioid peptides to yield
CTP (see Refs. 286,594 for detailed reviews). potential affinity label derivatives (969-972).
As noted earlier (Section 5.11.21, the use of S-Activated enkephalin analogs containing
photoaffinity labels, however, has been lim- the Npys group attached to the C-terminus
ited because opioid receptors are susceptible label p opioid receptors in a dose-dependent
to inactivation by UV irradiation (643). manner (969),whereas the Npys-protected de-
The preparation of opioid peptide deriva- rivative of DALCE reacts with 6 receptors
tives containing electrophilic affinity labels (971). Incorporation of Cys(Npys) into posi-
has been limited to a few compounds. The tion 8 of dynorphin A-(1-9) yields a peptide
chloromethyl ketone DALECK (Tyr-D-Ala- that decreases the B,, value, but does not
Gly-Phe-LeuCH,Cl) (957, 958) is one of the affect the K, value, for binding to K receptors
best studied electrophilic peptide derivatives. (970); recovery of binding after treatment
It selectively alkylates p opioid receptors (959, with dithiothreotol suggests that the dynorphin
960),and [3HlDALECKhas been used to label analog binds to K receptors through a disulfide
and characterize these receptors (959, 961, bond. [D-Ala2,Cys(Npys)8]-dynorphinA-(1-9)-
962). DAMK (Tyr-D-Ala-Gly-MePheCHfl), NH, is reported to label all three opioid recep-
the chloromethyl ketone derivative of tors, whereas [D-Al$,Cy~(Npys)~~ldynorphin
DAMGO, was also prepared and binds selec- A-(1-13)NH, apparently labels p and 6, but not
tively to p opioid receptors (963). The chlo- K , receptors (972).
romethyl ketone of dynorphin A-(1-10) (964)
6.8 Peptidase Inhibitors
inhibits binding to frog brain membranes in a
wash-resistant manner, although the affinity All of the ligands discussed so far in this chap-
of this peptide for K receptors is relatively ter interact directly with opioid receptors. An
weak (apparent IC,, for irreversible blockade alternative approach to producing analgesia is
-10 m. The C-terminal maleamide deriva- to inhibit the metabolism of the endogenous
tive of DSLET was recently reported to exhibit opioid peptides, thus increasing their concen-
wash-resistant inhibition of binding to 6 re- tration and occupancy of opioid receptors (see
ceptors at micromolar concentrations (965). Refs. 973-976 for reviews). The two major en-
Enkephalin analogs containing melphalan zymes involved in metabolism of the opioid
(Mel), the nitrogen mustard derivative of p- peptides are the aminopeptidases, especially
aminophenylalanine, were also prepared (see the bestatin-sensitive aminopeptidase-N
Refs. 286, 966). Recently, the first isothiocya- [APN (EC 3.4.11.2)], and the neutral endo-
nate derivatives of opioid peptides were de- peptidase-24.11 [NEP or neprilysin (EC
scribed (738, 967); the Phe(p-N=C=iSI4 de- 3.4.24.11) (974)1,which cleaves at the Gly-Phe
rivative of N,N-dibenzyl enkephalin and both bond. NEP has been cloned, and the crystal
the Phe(p-N=C=S)3 and p h e ( ~ - N = = C + 3 ) ~ structure of the extracellular domain of the
derivatives of TIPP exhibited wash-resistant enzyme complexed with the inhibitor phos-
inhibition of binding to cloned 6 opioid recep- phoramidon has recently been reported (977).
tors. The Phe(p-br~moacetamide)~ derivative Both of these enzymes have a broad substrate
of TIPP is even more potent than the p-iso- specificity and cleave other peptides in addi-
thiocyanate derivative at inhibiting binding to tion to the opioid peptides. NEP particularly
cloned 6 opioid receptors in a wash-resistant exhibits much lower activity toward longer
manner (968). opioid peptides, and thus the opioid effects re-
Thiol-containing derivatives of opioid sulting from inhibition of this enzyme are
peptides have been prepared that potentially probably mainly due to interfering with the
can form disulfide linkages with cysteine resi- metabolism of the enkephalins and possibly
dues on opioid receptors. DALCE ([D- the heptapeptide Met-enkephalin-Arg6-Phe7
Ala2,Leu5,Cys6]enkephalin, 45, Fig. 7.8) (194) (973). Other minor metabolic routes include
6 Opioid Peptide Analogs

cleavage of the Gly-Gly bond by dipepti- oxone-reversible antidiarrheal effects (9821,


dylarninopeptidase (DAP).
-
and is in clinical use for this indication in
Studies of peptidase inhibitors in brain France (983).
slices indicate the importance of inhibiting In order to more completely inhibit en-.
both enzymes in order to significantly increase kephalin degradation, mixed inhibitors that
can inhibit more than one of the metabolizin
the concentrations of the endogenous opioid
enzymes have been designed. Roques and co-
%
peptides (see Refs. 973-976). Thus, inhibiting
NEP with thiorphan decreases the formation workers developed hydroxamate mixed inhib-
of [3H]Tyr-Gly-Glyfrom [3HlMet-enkephalin, itors, based on the hypothesis that the
strength of the hydroxamate coordination to-
but increases the production of C3H]Tyr,
the zinc could overcome less than perfect fit of
whereas the opposite results were found with
the inhibitor side chains to the active sites of
the APN inhibitor bestatin. Both APN and the different metallopeptidases (973, 974).
NEP, as well as the other enzymes involved in This led to the preparation of kelatorphan
enkephalin metabolism, are zinc metallopep- (256), the first virtually complete inhibitor of
tidases. Thus it is possible to design mixed in- enkephalin metabolism (984). Kelatorphan,
hibitors capable of blocking multiple enzymes which is the R,S isomer, potently inhibits
that more effectively protect the opioid pep- NEP, DAP, and APN (IC,, values of 1.8, 0.9,
tides from metabolism (see below). and 380 nM, respectively),whereas its S,S iso-
Because these enzymes are zinc metal- mer is a potent selective inhibitor for NEP
lopeptidases, all of their inhibitors contain a (IC,, = 1.8, 100, and 29,000 nM for NEP,
metal coordinating group such as a thiol, car- DAP, and APN, respectively) (985). An analog
boxylic acid, or hydroxamic acid. The first po- of kelatorphan RB38A (257) exhibits similar
tent synthetic inhibitor of NEP, thiorphan potency for NEP and DAP, but greater po-
(253;Ki = 4.7 nM) (9781, was based on a model tency against APN than that of kelatorphan
of the binding of enkephalins of the active site (IC,, = 0.9, 2.5, and 120 nM, respectively)
of NEP (Fig. 7.50). Thiorphan exhibits antino- (986).
ciceptive activity in mice that is blocked by Although kelatorphan and related inhibi-
naloxone. This inhibitor also inhibits angio- tors exhibit nanomolar potency for both NEP
tensin converting enzyme (ACE, Ki = 150 and APN, these derivatives have high water
nM),so a variety of modifications to thiorphan solubility and do not readily cross the blood-
were made in attempts to increase selectivity brain barrier (973-975). When attempts to im-
prove the bioavailability of these inhibitors
for NEP (see Refs. 973, 974 and references
met with little success, an alternative strategy
cited therein). Structural modifications of the
was explored. In this approach potent inhibi-
PI1and P,' moieties generally led to mixed
tors of NEP- and APN-containing thiol groups
inhibitors of NEP and ACE, so changes were were linked by a disulfide bond (987). The di-
then made to the PI1-P,' amide bond. Retro- sulfide bond, although stable in plasma, is
inversion of this amide bond yields retrothior- readily cleaved in the brain. The dual inhibitor
phan (254) (979), which has similar affinity prodrug RBlOl (259) is very active in antino-
for NEP (Ki= 6 nM) as thiorphan, but greatly ciceptive assays after either i.v. or S.C.admin-
reduced affinity for ACE (Ki > 10,000 nM). istration at low doses (988). The RBlOl analog
The bioavailability of thiorphan is improved RB120 (258) has been reported to be orally
by protecting the thiol and carboxylic acid active (989). The antinociceptive response to
functionalities to give the prodrug acetorphan RBlOl is potentiated by a CCK-B (cholecysto-
(255) (980),which is rapidly hydrolyzed to thi- kinin) antagonist, presumably due to reversal
orphan by esterases. Acetorphan was the first of the physiological antagonism of the opioid
NEP inhibitor examined in clinical studies, system by CCK (975, 976). Unlike morphine
but it had no effect on flexion reflexes or pain and preceptor analgesics, both RBlOl and ke-
sensation in humans (981), emphasizing the latorphan are devoid of respiratory depressant
importance of inhibiting both NEP and APN effects (990). RB120 at analgesic doses also
to obtain analgesia. Acetorphan produces nal- does not produce a discriminative response
Narcotic Analgesics

II
-C- HNCHC-HNCHC02- Enkephalin (enzyme substrate)
I
0
0
II
X = CNH (253) Thiorphan

0
II
X = NHC (254) Retrothiorphan

(255) Acetorphan

(256) Kelatorphan .

(257) RB38A

(258) RBI 20

(259) RBI 01

Figure 7.50. Inhibitors of opioid peptide metabolism.


7 Recent Developments

and does not generalize to morphine, suggest- kinetics for the hydrolysis of the two lipophilic
ing that this inhibitor may have low abuse po- groups were different, with the carboxylate es-
tential (991). These major differences in the ter undergoing much more rapid hydrolysis in
side effect profile of these enzyme inhibitors plasma than in rat brain membranes; the
compared to morphine has been attributed to deprotection of the phosphinate group was
the low tonic release of the endogenous en- slower, resulting in approximately 55 and 80%
kephalins in brain regions relevant to these of the completely deprotected compound after
side effects of morphine (see Refs. 975, 976 a 1-h incubation with plasma and rat brain
and references cited therein). membranes, respectively (995).
Recently, a-aminophosphinic derivatives
(260) have been identified as both selective
7 RECENT DEVELOPMENTS

7.1 Opioid Receptor Structure: Receptor


Dimerization
As discussed earlier in Section 3.2.4.3, al-
though pharmacological studies have sug-
gested multiple subtypes of each of the opioid
receptors, cloned opioid receptors consistently
represent only a single subtype for each recep-
tor type. Recently, an alternative explanation
for opioid receptor subtypes has appeared in
the literature, which could explain these dis-
crepancies (see Ref. 996). Receptor dimeriza-
tion has been described for both cloned 6 (997)
APN inhibitors (992) and dual inhibitors of and K receptors alone (998) (homodimers),as
both APN and NEP (993-995). The phos- well as for heterodimers between K and 6 re-
phinic moiety binds to the zinc in the active ceptors (998) and between p and 6 receptors
site and mimics the tetrahedral transition (999, 1000). The K-6 opioid receptor het-
state formed during peptide bond cleavage. erodimers exhibit a ligand binding profile that
Optimization of the groups in the P,, P,', and is virtually identical to that previously re-
P,' sites resulted in the first true dual inhibi- ported for the proposed K,-receptor subtype
tors of APN and NEP with low nanomolar af- (9981. The p-6 heterodimers exhibit a distinct
finity for both enzymes (993,994). These com- binding profile (999, 1000),binding some 6 re-
pounds are much more potent antinociceptive ceptor ligands (the $-selective antagonist
agents than kelatorphan after i.c.v. adminis- BNTX and the 6,-selective agonist deltorphin
tration (ED,, = 12-20 nmol versus 158 nmol 11) but not others (the 6,-selective agonist
in the hot plate test), most likely as a result of DPDPE and the 6,-selective antagonist nal-
the more efficient inhibition of APN; they are triben) (999). Receptor dimerization has been
also more potent than RBlOl (ED,, = 72 observed for other G-protein-coupled recep-
nmol), illustrating the advantage of a single tors and may be a universal phenomenon for
compound with dual action (993). Large doses receptor modulation (1001, 1002); this fasci-
(100 mg/kg), however, were required to pro- nating area was the subject of a recent sympo-
duce an antinociceptive response after i.v. ad- sium summarized in a special supplemental
ministration (995), which was attributed to issue of Neuropsychopharmacology (vol. 23,
poor penetration of the blood-brain barrier by number S4,2000). Based on results for adren-
these polar compounds. Therefore prodrug de- ergic-muscarinic chimeric receptors (10031,
rivatives were prepared by protecting both the Reynolds and coworkers proposed that the
carboxylic acid and phosphinic functionalities dimerization interface includes transmem-
with lipophilic groups (995). These derivatives brane helices 5 and 6 (see Ref. 1004 and refer-
produced a long-lasting (-2 h) antinociceptive ences cited therein), although these studies
response after i.v. or i.p. administration. The cannot distinguish between the contact dimer
Narcotic Analgesics

and domain-swapped dimer modes of dimer- There is also high sequence homology with
ization (1004). The growing evidence for opioid receptors in the intracellular loops, con-
dimerization of opioid receptors prompted sistent with ORLl receptors coupling to the
Portoghese to revisit some of his earlier work same G-proteins as opioid receptors. Splice
on bivalent ligands and their possible interac- variants of the ORLl gene have been reported
tions with dimeric receptors (321). Computa- (see Refs. 87,90 for reviews), and the results of
tional models of possible dimeric opioid recep- some pharmacological studies have suggested
tors are only beginning to appear in the receptor heterogeneity (see Ref. 871, but the
literature (321). existence of subtypes of the ORLl receptor
has not been firmly established.
7.2 Opioid-Receptor-Like 1 (ORL1) Receptor
The ORLl receptor exhibits high selectiv-
and Its Endogenous Ligand Orphanin
ity for its endogenous ligand, and has very low
FQ/Nociceptin (OFQ/N)
affinity for most opioid ligands. Site-directed
During attempts to clone different opioid re- mutagenesis and chimeric receptor studies
ceptor types, several laboratories isolated a have examined possible structural reasons for
cDNA for a receptor with high homology to this selectivity of the ORLl receptor. Point
opioid receptors (see Refs. 87,89,90 for recent mutations of only four residues in TM6
reviews). Because this receptor, referred to by CVQV276-278IHIl and TM7 LT302II of the
Mollereau et al. as opioid-receptor-like 1 ORLl receptor were sufficient to impart bind-
(ORL1) receptor (911, did not display affinity ing affinity for Dyn A fragments without af-
for classical opioid ligands, it was classified as fecting the affinity or potency of OFQ/N (176).
an "orphan receptor." Subsequently, two The additional mutation of a residue in TM5
groups isolated a 17-residue peptide as the en- [A213K] enhanced affinity for several opioid
dogenous ligand for this receptor (see Fig. 7.9) alkaloids, particularly antagonists (1007), but
(92,93).This peptide was referred to as orpha- this mutant no longer bound OFQ/N. Alanine
nin FQ by one group because it was the ligand mutation of several TM residues that are con-
for the orphan receptor (F and Q are the N- served with opioid receptors yielded mutant
and C-terminal residues, respectively, of the receptors with reduced affinity for OFQ/N
peptide) (92) and named nociceptin by the (1008), suggesting that the binding pocket in
other group, since in the initial studies this the ORLl receptor may be similar to that
peptide was reported to produce hyperalgesia found in opioid receptors. Alanine replace-
(93). The OFQ/N precursor protein preprono- ment of GlnZa6at the C-terminus of TM6 in
ciceptin (93) contains additional biologically hORLl results in a mutant to which OFQIN
active peptides related to OFQ/N. Nocistatin still binds with high affinity, but which cannot
(Fig. 7.9) (271) blocks a number of the effects mediate inhibition of forskolin-stimulated
of OFQ/N (see Ref. 1005 for a review), but no- CAMPformation (1008),implicating this resi-
cistatin does not interact with ORLl recep- due in ORLl receptor signal transduction.
tors. A second 17-residue peptide, referred to OFQ/N and the ORLl receptor exhibit the
as orphanidnociceptin 11,is also found in pre- greatest similarity to dynorphin A and K opi-
pronociceptin (2701, along with a longer pep- oid receptors, respectively, but OFQ/N exhib-
tide OFQN160-187 (1006); these peptides, its very low affinity for K receptors and, con-
however, have not been as well characterized versely, Dyn A exhibits low affinity for ORLl
as OFQ/N (see Ref. 87 for a recent review). receptors. To study the structural reasons for
Like opioid receptors, the ORLl receptor is this selectivity, chimeric receptors have been
a G-protein-coupled receptor, consisting of constructed between ORLl and K receptors
seven transmembrane (TM) regions plus ex- (1009, 1010). Replacement of the N-terminal
tracellular and intracellular domains. The region of the K receptor up through the top of
ORLl receptor exhibits high sequence homol- TM3 with the corresponding sequence of the
ogy to opioid receptors, with 60-62% identity ORLl receptor imparted affinity for OFQ/N,
for the whole transmembrane domain (resi- but low potency in an adenylyl cyclase assay,
dues 52-342 in the human ORLl receptor) without affecting the binding or potency of
(90) and higher homology in TM2, 3, and 7. Dyn A. Further incorporation of extracellular
7 Recent Developments

loop 2 (EL21from the ORLl receptor restored fects, however, were subsequently classified as
efficacy for OFQ/N, again without affecting antianalgesic effects (89, 1011) based on re-
the ability of Dyn A to bind and activate the evaluation of the controls and the effects of
receptor. Thus, EL2 appears to be required for stress-induced analgesia accompanying the.
activation of ORLl receptors, but not K opioid experimental procedures. Effects reported for
receptors. OFQ/N administered i.c.v. have ranged f r o q
Based on the experimental data, a compu- hyperalgesia, analgesia, or anti-analgesic ac-
tational model of OFQ/N bound to ORLl re- tivity to a combination of these effects (87,89,
ceptors has been proposed (189).In this model 1011). A similar range of activities have been.
the N-terminal sequence containing the two reported after spinal (intrathecal) administra-
Phe residues binds in a highly conserved
tion (87,89,1012).A number of factors appear
pocket formed by TM3, 5, 6, and 7, which is
to influence these often contradictory find-
similar to that proposed for opioid receptors.
ings, including the noxious stimuli studied,
Residues 5-7 (Thr-Gly-Ala)of OFQIN are then
positioned at the TM-EL2 interface in a the species and strain of animal used, the dose
largely nonconserved region; unfavorable of OFQ/N, stress, and the physiological state
side-chain interactions in this region of the of the animal (see Ref. 87 for a detailed discus-
receptor are then used to explain the selectiv- sion). The most robust and consistently ob-
ity of the ORLl receptor for OFQ/N over Dyn served effects of OFQ/Nare the anti-analgesic
A. The positively charged C-terminus of the effects after supraspinal administration.
peptide is proposed to make multiple contacts OFQ/N acts as a functional antagonist of opi-
with the highly acidic EL2. oid receptors and blocks analgesia produced
by a wide variety of opioids (see Refs. 87, 89).
7.2.1 Physiological and Pharmacological Ef- At the spinal level the predominant effect of
fects. Since their discovery, interest in this re- OFQ/N appears to be inhibitory, resulting in
ceptor and its endogenous ligand has in- analgesia and/or anti-hyperalgesidanti-allo-
creased exponentially. There have been a dynia (see Refs. 87, 89, 1012). Several studies
number of excellent reviews covering the com- have reported anti-hyperalgesic or anti-allo-
plex pharmacology of this system (see Refs. dynic activity for OFQ/N in rat models of in-
87-89 for recent reviews), including a special flammation and nerve injury (89, 1012). Be-
issue of the journal Peptides (Vol. 21, Number cause morphine appears to have reduced
7, 2000) devoted solely to the ORLl receptor effectiveness in treating neuropathic pain af-
and OFQ/N. ter nerve injury, the activity of OFQ/N in this
Consistent with the sequence similarities type of pain could have important therapeutic
between the ORLl and opioid receptors, acti- implications. OFQ/N has also been implicated
vation of the ORLl receptor triggers the same in the development of tolerance to morphine
signal transduction mechanisms as used by (see Refs. 87, 89).
the opioid receptors. Thus activation of ORLl OFQ/N and the ORLl receptor are also in-
receptors inhibits both forskolin-stimulated volved in a number of other physiological ef-
adenylyl cyclase and Cat+ currents and acti- fects (see Refs. 87,891. One of the most signif-
vates several other effectors, including inward icant effects is the anxiolytic activity of
rectifying K+ channels, protein kinase C, mi- OFQ/N (1013), which has been postulated to
togen-activated protein kinase (MAP kinase) be one of OFQ/N's most fundamental actions,
and phospholipase C (see Ref. 89 for a review). and may help explain the effects of OFQ/N on
There has been considerable controversy other phenomena [e.g., locomotion, reward,
over the roles of ORLl receptors and OFQ/N and feeding (8711. A small molecule ORLl ag-
in response to painful stimuli (see Refs. 87,89, onist has also demonstrated anxiolytic activity
1011 for recent reviews). When administered (10141,demonstrating an important potential
by intracerebroventricular (i.c.v.) injection therapeutic application of these compounds.
OFQ/N was initially reported to produce hy- Like opioids, OFQ/N inhibits electrically in-
peralgesia (92,93),hence the name nociceptin duced contractions in the GPI and MVD
for the endogenous peptide ligand. These ef- smooth muscle preparations; these effects are
Narcotic Analgesics

not naloxone reversible, indicating that they oid receptors, particularly K and p receptors
are not mediated by opioid receptors (see Ref. (see Refs. 1015, 1016). Unlike in the opioid
89 for a review). peptides, an aromatic amino acid is not re--
quired in position 1, and Phel can be replaced
7.2.2 Structure-Activity Relationships of by the aliphatic residues cyclohexylalanine
OFQ/N and Other Peptidic Ligands for the and leucine (1022). In contrast, an aromatic
OR11 Receptor. Shortly after the identifica- residue is required in position 4, and replace:
tion of the endogenous ligand, several re- ment of Phe4 with an aliphatic residue results
search groups began exploring the SAR of this in loss of activity (1022). An Arg in position 8
peptide. Several recent reviews (88, 1015, appears to be critical, and replacement with
1016) have described the details of the SAR of Lys results in large decreases (>loo-fold) in
OFQ/N, so the discussion here focuses on affmity and potency (1016). Incorporation of
some of the key findings. Tyr in place of Leu14 was used to obtain an
Truncation studies have been performed to analog that could be radioiodinated or triti-
identify the minimum sequence required for ated for use in radioligand binding assays (92);
ORLl affinity and activation. These studies both labeled derivatives are commercially
revealed that, like opioid peptides, the N-ter- available.
minal aromatic residue was important for bi- A series of chimeric peptides between
ological activity (1017, 1018), although one OFQ/N and Dyn A were prepared to explore
study (1017) reported that the further N-ter- the structural reasons for the selectivity of
minal truncated fragments OFQ/N-(6-17) OFQ/N for ORLl over K opioid receptors
and OFQ/N-(12-17) retain affinity and activ- (1023). The results from this study suggested
ity for ORLl receptors. In contrast to dynor- that residues Thr 5 and Gly6, in addition to
phin A, where shorter fragments retain opioid Phel, are responsible for the activity and se-
activity (263), 13 of the 17 residues of OFQ/N lectivity of OFQIN for ORLl receptors; the
appear to be required for ORL1-receptoraffin- chimera Dyn A-(1-5)/OFQ/N-(6-17) (261)
ity and activation (1017, 1018). The amide de- was able to bind and activate both ORLl and K
rivative of OFQ-(1-13) is a considerably more opioid receptor.
potent agonist in the mouse vas deferens assay
than the acid derivative, apparently because of
decreased metabolism (1016); therefore this
fragment is typically used as the parent struc-
ture in further SAR studies (see below). OFQ/
N-(1-ll), however, has been reported to be Ser-Ala-Arg-Lys-Leu-Ala-Am-Gln
active both in vitro (1019) and in vivo (10201,
despite its low affinity for cloned ORLl recep- Early studies of the pharmacology of the
tors in binding assays, resulting in the pro- ORLl system were hindered by the lack of an-
posal of receptor heterogeneity for OFQIN tagonists for this receptor. Therefore there
(1019). Results from binding studies have also was considerable excitement in the field when
suggested receptor heterogeneity (see Ref. the first report of an antagonist appeared in
87). the literature (1024). The reduced amide de-
A number of analogs of OFQ/N have been rivative of OFQ/N [ P ~ ~ ~ I ) ( C H , N H ) G ~ ~ ~ ] O F Q /
examined for their pharmacological activity N-(1-13)NH2 (262, Fig. 7.51; referred to as
(see Refs. 88, 1015, 1016 for recent reviews). [F/G]NC(l-13)NH, by Calo and coworkers),
Shortly after identification of the endogenous which was synthesized to protect the peptide
ligand the results of an alanine scan of OFQ/N from metabolism by aminopeptidases, was ini-
were reported, identifying Phel, Phe4, and tially reported to be an antagonist of OFQ/N-
Ar$ as critical residues in the sequence (1017, (1-13)NH2 in smooth muscle preparations
1021). Phel can be replaced by tyrosine (1018, (1024). Subsequent examination of this com-
1021), resulting in an analog that retains af- pound in a variety of assays, however, indi-
finity and potency at ORLl receptors, but also cated that the activity observed depended on
exhibits increased affinity and activity at opi- the assay and that although (262) was an an-
tagonist in some assays, it was a partial or full literature, with leads identified from screen-
agonist in a number of other assays, including ing assays (see Refs. 1015, 1016, 1029 for re-
forskolin-stimulated CAMP accumulation in cent reviews). Starting from a lead (267, Fig.
Chinese hamster ovary cells expressing cloned 7.52), identified by high throughput screening
ORLl receptors (see Refs. 88,1015 for detailed as a nonselective ORLl ligand, a group from
reviews). Subsequently, the N-substituted Hoffmann-La Roche explored a number ofr
glycine analog [NphellOFQ/N-(1-13)NH2
(263) was reported to be an ORL1-receptor to identify more selective and potent ORLl
antagonist (1025).Although the potency of the agonists (1030-1033). The pharmacology of- -
compound is weak (PA, < 6 in most assays), it one of these compounds, Ro 64-6198 (268),
is an antagonist in all of the assays examined
has been examined in considerable detail
to date (see Refs. 88, 1015 for reviews).
(1014,1033-1036), including determination of
The use of combinatorial libraries has re-
sulted in the identification of peptidic and pep- the affinities of the different stereoisomers for
tidomimetic ligands for the ORLl receptor opioid receptors as well as ORLl receptors
that are not structurally related to OFQ/N. (1033).The stereochemistry at positions 1 and
Houghten and coworkers identified acetylated 3a has significant effects on ORL1-receptoraf-
hexapeptides with high affinity for the ORLl finity, whereas the affinities for the opioid re-
receptor, with Ac-RYYRXK-NH, (264; X = W ceptors are comparable for the different iso-
or I) having the highest affinity (1026); in mers; the 1S,3aS isomer exhibits the highest
most assays these peptides exhibit partial ag- affinity for ORLl receptors (pKi = 9.41) and
onist activity (see Ref. 1015). A combinatorial therefore the highest selectivity for ORLl over
library of conformationally constrained pep- opioid receptors (1033). This compound is a
tides resulted in the identification of 111-BTD full agonist at ORLl receptors and produces
(265) that exhibits moderate affinity (K, = 24 dose-dependent anxiolytic effects in several
nM) but only modest selectivity [Ki ratio rat models of anxiety, with an efficacy and po-
(oRLl/p/~/a)= 1/4.6/6.1/221 for ORLl recep- tency after systemic administration compara-
tors; this compound acts as an antagonist at ble to those of benzodiazepine anxiolytics such
ORLl receptors, whereas it exhibits partial as diazepam (1014).
agonist activity at opioid receptors (1027). The Researchers from the Banyu Tsukuba Re:
related conformationally constrained peptide search Institute reported the first nonpeptide
111-Haic (266) was nonselective, exhibiting antagonist for ORLl receptors (1037). Start-
modest affinity for ORLl and the three opioid ing from a lead (269) from their chemical li-
receptors (K, = 50-125 nM) (1027). brary, which again exhibited reasonable affin-
ity but poor selectivity for ORLl receptors,
7.2.3 Nonpeptide Ligands for the OR11 Re- these researchers identified 5-113397 (270),
ceptor. Because of the potential therapeutic which exhibits high affinity (Ki = 1.8 nM) and
applications of ORLl receptor ligands, there high selectivity for ORLl receptors over opioid
has been considerable interest in identifying receptors (1037-1039). This compound is an
nonpeptidic compounds that interact with this antagonist of OFQ/N in uitro and in viuo after
receptor. Several opiates have been reported subcutaneous administration (1038, 1039). A
to exhibit some affinity for ORLl receptors series of 4-aminoquinolines (271) has also
(see Refs. 1015,1016) with some opiates, most been examined for antagonist activity, based
notably the fentanyl analog lofentanyl(1018), on the weak affinity of the lead compound
naloxone benzoylhydrazone [Nal(BzO)H, 501 (271)in a random screen (1040). JTC-801
(see Refs. 1015,1016),the naltrexamine deriv- (272) was selected because it showed the best
ative TRK-820 (65, Fig. 7.16) (311), and bu- bioavailability. After oral administration this
prenorphine (1028), exhibiting reasonable af- compound was shown to antagonize the ef-
finity andlor potency. Reports by groups from fects of OFQ/N and to produce an analgesic
the pharmaceutical industry of both nonpep- effect that was not antagonized by naloxone;
tidic selective agonists and antagonists have this compound is reported to be undergoing
begun to appear in the scientific and patent clinical trials (1040).
Narcotic Analgesics

Ac-Arg-Tyr-Tyr-Arg-X-LysNH2

(264) X = Trp or lle

(265) Ill-BTD (266) Ill-Haic

Figure 7.51. Peptidic ligands for ORLl receptors.

8 THINGS TO COME ment of peripheral opioid receptors in inflarn-


matory pain (see Section 3.3) has resulted in
Several advancements in opioid pharmacology the search for peripherally selective analgesics
during recent years could have a significant (see Section 5.9.2), which would be free from
impact on the types of compounds used as nar- serious centrally mediated side effects. The
cotic analgesics in the future. The involve- challenge in this area may be to obtain com-
8 Things to Come

(271) R = Ph (272) JTC-801

Figure 7.52. Nonpeptidic ligands for ORLl receptors.

pounds that do not cross the blood-brain bar- This approach is still in its infancy, however,
rier, but that are still orally bioavailable. The so its therapeutic application in clinical trials
peripherally selective antagonists methylnal- still remains to be demonstrated.
trexone and alvimopan are currently undergo- There has also been considerable advance-
ing clinical trials for treatment of opioid-in- ment in the identification of agents that pro-
duced constipation and related GI side effects. duce analgesic effects through different mech-
The ability of 6-receptor antagonists to de- anisms than interaction with opioid receptors
crease the development of tolerance and de- (see Refs. 1041-1044 for reviews). Thus
pendence to morphine (see Section 3.3.1) has NMDA (N-methyl-D-aspartate) antagonists,
considerable therapeutic potential and has GABA (y-aminobutyric acid) agonists, nico-
prompted the search for compounds with both tinic acetylcholine receptor agonists (e.g., epi-
p agonist and 6 antagonist activity. Although batadine), antagonists of substance P at NK-1
peptide derivatives with both activities have receptors, and a number of other compounds
been studied in some detail (see Section 6.4.2)... targeting different receptors exhibit antinoci-
nonpeptide opioids with this activity profile ceptive activity in animal models. These com-
have been reported only recently. This ap- pounds do not cause the side effects associated
proach of using S antagonism together with p with the clinically used opiates, but they have
agonism, either combined in a single drug or their own distinct side effect profiles, which in
by coadministering two agents, to minimize some cases (e.g., NMDA antagonists, which
the side effects of p agonists is very exciting. cause psychotomimetic effects) have resulted
Narcotic Analgesics

in termination of clinical studies (see Ref. structures exhibiting affinity for opioid recep-
1042). Also, the promising antinociceptive ac- tors, there is still ample opportunity for the
tivity observed in animal models has not al- development of new therapeutic agents that,
ways translated into clinical efficacy in hu- hopefully, will bring us closer to the goal of
mans. Thus a number of NK-1-receptor identifying optimal analgesics.
antagonists are highly effective in animal
models of pain and exhibit excellent pharma- 9 WEB ADDRESSES AND RECOMMENDED
cokinetic profiles in humans, but have failed in READING FOR FURTHER INFORMATION
phase I1 clinical trials for treatment of pain
and migraine (see Ref. 1042). Thus, whether 9.1 Clinically Used Agents
any of these novel targets will ultimately re-
sult in clinically used agents for pain remains Drug Facts and Comparisons, Wolters Klu-
to be determined. wer, St. Louis, 2001. May be accessedat www.
Clearly, one very exciting target for the de- factsandcomparisons.com
velopment of potential therapeutic agents is C. Stein, Ed., Opioids in Pain Control: Basic
the ORLl receptor (Section 7.2). Because of and Clincial Aspects, Cambridge University
the complexity of ORLl receptor involvement Press, Cambridge, 1999. This book contains
in pain perception, however, it is not clear at several chapters discussing the clinical use
this time whether ligands for this receptor will of opioids in different types of pain and clin-
prove to be clinically useful analgesics. The ical settings in addition to chapters discuss-
anxiolytic activity of ORLl agonists, however, ing the pharmacology of opioids.
represents a promising approach for the devel-
opment of novel clinically useful agents for 9.2 Pharmacology
this indication.
A major unmet therapeutic need is effective 0 H. B. Gutstein and H. Akil in J. G. Hard-
treatments for substance abuse, including man, L. E. Limbird, and A. G. Gilman, Eds.,
abuse of opioids, cocaine, and amphetamines. Goodman and Gilman's The Pharmacolog-
Results for ligands interacting with either 6 or ical Basis of Therapeutics, 10th ed.,
K receptors hold some promise in this area (see McGraw-Hill Medical Publishing Division,
Section 3.31, but whether such agents will be New York, 2001, pp. 569-619.
clinically useful remains to be demonstrated. A. Hem, H. Akil, and E. J. Simon, Eds., Opi-
Although the results of some initial studies in oids I and Opioids 11, Handbook of Experi-
humans have been promising [e.g., an im- mental Pharmacology, Vols. 104/I and 1041
proved positive response of opioid-dependent 11, Springer-Verlag, Berlin, 1993. Two
individuals to a "functional" K antagonist (bu- volumes containing comprehensive reviews
prenorphine in the presence of naltrexone to of opioid pharmacology.
block p-agonist activity) as compared to nal-
trexone alone (24911, other studies have been 9.2.1 Opioid Receptor Structure and Molec-
disappointing [although the K-selective ago- ular Biology
nist enadoline reduced the positive subjective
effects of cocaine, neither enadoline nor the 0 University of Minnesota Center for Opioid
mixed agonist butorphanol modified self-ad- Research and Design (CORD), http://www.
ministration of cocaine in humans (255)l. opioid.umn.edu. This site includes computa-
The goal of identifying potent analgesics tional models of the opioid receptors, a com-
free of the side effects of morphine and other plete list of chimeric receptors and point
narcotics has remained elusive. As more infor- mutations in opioid receptors with pharma-
mation has become available about opioid re- cological data and literature references, and
ceptor structure, opioid pharmacology, and re- links to other relevant sites.
lated systems (i.e., the ORLl receptor), this 0 P. Y. Law, Y. H. Wong, and H. H. Loh, Mu-
has provided new challenges to medicinal tational Analysis of the Structure and Func-
chemists to prepare compounds with unique tion of Opioid Receptors, Biopolymers, 51,
pharmacological profiles. With the diversity of 440-455 (1999).
9 Web Addresses and Recommended Reading for Furtht?r Information 45 1

9.2.2 Dimerization of Opioid and Other C- (Parts I and 111,Expert Opin. Ther. Patents,
Protein-Coupled Receptors 7,1075-1098 (1997); 9,353-374 (1999).

a L. S. Brady and L. Devi, Eds., Dimerization 9.4.2 Kappa-Receptor-Selective Ligands


of G-Protein-Coupled Receptors: Implica-
tions for Drug Design and Signaling, Neuro- 0 A. Barber and R. Gottschlich, Novel Develop-*
psychopharmacology, 2 3 (Suppl. 4), S1-S77 ments with Selective, Non-Peptidic Kappa-
(2000). This special issue of Neuropsycho- Opioid Receptor Agonists, Expert Opin. In-
pharmacology contains reviews of dimeriza- vest. Drugs, 6,1351-1368 (1997).
tion of opioid and other G-protein-coupled G. Giardina, G. D. Clarke, M. Grugni, M.
receptors. Sbacchi, and V. Vecchietti, Central and Pe-
0 L. A. Devi, Heterodimerization of G-Pro- ripheral Analgesic Agents: Chemical Strate-
tein-Coupled Receptors: Pharmacology, Sig- gies for Limiting Brain Penetration in
naling and Trafficking, Trends Pharmacol. Kappa-Opioid Agonists Belonging to Differ-
Sci., 22,532-537 (2001). ent Chemical Classes, Farmaco, 50,
I. Gomes, B. A. Jordan, A. Gupta, C. Rios, N. 405-418 (1995).
Trapaidze, and L. A. Devi, G-Protein Cou- 0 J. Szmuszkovicz, U-50,488 and the K Recep-
pled Receptor Dimerization: Implications in tor: A Personalized Account Covering the
Modulating Receptor Function, J. Mol. Period 1973 to 1990 and Part 11: 1991 to
Med., 79,226-242 (2001). 1998, Prog. Drug Res., 52, 167-195 (1999);
53,l-51 (2000).
9.3 SAR of Classical Nonpeptide Opiates 9.5 Opioid Peptides

a A. F. Casy and R. T. Parfitt, Opioid Analge- P. W. Schiller, Ed., Peptide and Peptidomi-
sics: Chemistry and Receptors, Plenum metic Ligands of Opioid Receptors, Biopoly-
Press, New York, 1986. mers, 51, 377-458 (1999). This issue of
0 G. R. Lenz, S. M. Evans, D. E. Walters, and Biopolymers contains reviews covering opi-
A. J. Hopfinger, Opiates, Academic Press, oid receptor structure as well as peptide and
Orlando, FL, 1986. peptidomimetic ligands for these receptors:
9.6 OR11 Receptor and Orphanin
The above two comprehensive books con-
FQ/Nociceptin
tain detailed reviews of the early literature.
0 M. Nassi, C. Polidori, G. Cal6, and D. Regoli,
0 A. F. Casy and G. H. Dewar, The Steric Fac-
NociceptinIOrphanin FQ and Its Receptor,
tor in Medicinal Chemistry: Dissymmetric
Peptides, 21,891-1154 (2000). This issue of
Probes of Pharmacological Receptors, Ple-
Peptides contains reviews of all aspects of
num Press, New York, pp. 429-501 and
ORLl receptor and orphanin FQInociceptin
503-548.
pharmacology.
0 G. Calb, R. Guerrini, A. Rizzi, S. Salvadori,
9.4 Delta and Kappa Opioid Receptors and and D. Regoli, Pharmacology of Nociceptin
Selective Ligands and Its Receptor: A Novel Therapeutic Tar-
get, Br. J. Pharmacol., 129, 1261-1283
9.4.1 Delta Opioid Receptor Pharmacology (2000).
and 6-Receptor-Selective Ligands 0 L. M. Harrison and D. K. Grandy, Opiate
Modulating Properties of NociceptinlOr-
0 A. Coop and K. C. Rice, Role of 6-Opioid Re- phanin FQ, Peptides, 21, 151-172 (2000).
ceptors in Biological Processes, Drug News 0 J. S. Mogd and G. W. Pasternak, The Molecu-
Perspect., 13,481-487 (2000). lar and Behavioral Pharmacology of the Or-
0 G. Dondio, S. Ronzani, and P. Petrillo, Non- phanin FQJNociceptin Peptide and Receptor
peptide 6 Opioid Agonists and Antagonists Family, P h a m o l . Rev., 53,381-415 (2001).
Narcotic Analgesics

10 ACKNOWLEDGMENTS 19. WHO, Cancer Pain Relief-With a Guide to


Opioid Auailability, 2nd ed., World Health
The authors thank John Traynor for his help- Organization, Geneva, Switzerland, 1996.
ful comments on part of the manuscript and 20. American Pain Society, Principles of Analge-
Matthew Leighty for his assistance in its prep- sic Use in the Treatment of Acute Pain and
Cancer Pain, 4th ed., American Pain Society,
aration.
Glenview, IL, 1999,64 pp. -Z

21. M . Levy, N. Engl. J. Med., 335, 1124-1130


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CHAPTER EIGHT

Antidepressants

University of Oxford
F Department of Pharmacology
Oxford, United Kingdom
i

g RICHARD A. GLENNON
Virginia Commonwealth University
School of Pharmacy
;, Richmond, Virginia

Contents
1 Introduction, 484
2 Clinical Use, 484
2.1 Available Agents and Classification, 484
2.2 Clinical Efficacy of Antidepressants, 486
2.3 Adverse Side Effects, 490
2.3.1 Introduction, 490
2.3.2 Monoamine Oxidase (MA01 Inhibitors,
491
2.3.3 Tricyclic Antidepressants, 492
2.3.4 Serotonin-Selective Reuptake
Inhibitors, 493
2.3.5 Other Agents, 494
2.4 Pharmacokinetics, 496
2.4.1 Tricyclic Antidepressants, 496
2.4.2 SSRI, 496
2.4.3 MA0 Inhibitors, 497
2.4.4 Other Antidepressants, 498
3 Physiology and Pharmacology, 498
3.1 Monoamine Transporters, 498
3.1.1 Discovery, 498
3.1.2 Monoamine Transporters, 498
3.1.3 Drugs as Inhibitors of Monoamine
Transporters, 499
3.2 Serotonergic Agents, 502
3.2.1 Receptor Populations, 502
3.2.2 5-HT, Receptors, 503
3.2.3 5-HT,, Receptors, 503
3.2.4 Mixed-Function Ligands, 505
3.2.5 Other 5-HT Receptors,
- 506
3.3 Alpha Adrenergic Receptors, 506
Burger's Medicinal Chemistry and Drug Discovery 3.4 Monoamine Oxidase, 507
Sixth Edition, Volume 6: Nervous System Agents
-
3.5 Other Proposed Mechanisms of Action, 507
Edited by Donald J. Abraham 4 History, 508
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 4.1 Discovery of the First Antidepressants, 508
Antidepressants

4.2 Case History: Fluoxetine (Prozac), 509 6.1 Monoaminergic Drugs, 516
5 Structure-Activity Relationship and Metabolism, 6.2 NMDA Receptor Antagonists, 516
510 6.3 Drugs Acting at Neuropeptide Receptors,
5.1 Reuptake Inhibitors, 510 517
5.2 Monoamine Oxidase Inhibitors, 512 6.3.1 Substance P-NK1 Receptor
5.3 Serotonergic Agents, 513 Antagonists, 517
5.4 Other Agents, 515 6.3.2 CRF Antagonists, 517
6 Recent Developments and Things to Come, 516

1 INTRODUCTION ical recognition and treatment of depression


to a much greater number of people than be-
The term depression refers to a depression of fore. At the same time, new indications have
mood than can be a transient but, more com- been demonstrated and officially approved for
monly, is a chronic condition. The symptoms the SSRIs, including syndromes associated
are distressing; patients report an ineffable with anxiety and panic, extending still further
and all-pervading depth of despair and hope- the wide use of these agents in psychopharma-
lessness far beyond normal experience (1, 2). cology. There is even a growing veterinary use
Depressed mood is typically accompanied by of such agents for companion animals who ap-
low energy or fatigue and sleep disturbances. pear depressed!
Physical, social, and personal functioning are
greatly impaired, leading to a t least as much
handicap as such physical illnesses as diabetes 2 CLINICAL USE
or arthritis. The risk of suicide is greatly in-
creased. Depression is an important and com- 2.1 Available Agents and Classification
mon disorder: each year about 100 million
people worldwide develop depression (2, 3), Table 8.1 lists the 26 antidepressant drugs
with the prevalence in women being about currently registered for use in the United
twice that in men. Depression can also be States and Europe. All are administered
associated with other psychiatric disorders, orally, usually on a once-a-day dosing regime.
such as anxiety disorders, or with physical A typical course of treatment lasts 3 months.
illnesses that can worsen the prognosis. Al- Why do we have so many antidepressants, and
though a partial remission of symptoms why does there still exist a need for additional
rather than full recovery is the usual out- agents? There are four primary reasons.
come of drug treatment, the availability of
safe and effective antidepressants is a major 1. The initial selection of an antidepressant
achievement of twentieth century psycho- for the treatment of depressed patients de-
pharmacology. Worldwide sales of antide- pends to a large extent on diagnostic crite-
pressants already exceed US$10 billion an- ria. Often, however, the first agent selected
nually, making them the single most is not the most therapeutically beneficial or
important group of psychopharmaceuticals, best tolerated by the patient. Subsequent
and include some of the most widely used selection is empirical and involves trials
prescription drugs (e.g., fluoxetine; Prozac). with different agents from different classes
The new wave of safer antidepressants in- (and sometimes even from within the same
troduced in the 1990s, led by fluoxetine class), to identify the most suitable agent
(Prozac),is dominated by drugs that are sero- (i.e., the most effective agent with the few-
tonin-selective reuptake inhibitors (SSRIs). est undesirable side effects) for a given
The SSRIs exhibit some adverse side effects, patient.
notably in impaired sexual function in both 2. Although effective, many of the presently
men and women, but because they are rela- available agents, particularly the tricyclic
tively safe physicians have been less inhibited antidepressants (TCAs), produce undesir-
about using them. This has extended the clin- able side effects. Patients who initiate ther-
2 Clinical Use

Table 8.1 Antidepressants: Drugs Currently on the Market (6,7)


Proprietary Name
Daily Dose
Generic Name United States Europe Manufacturer Range (mg)
Amitriptyline (1) Elavil Lentizol Astra Zeneca 50-200
Amoxapine (2) Asendin Asendis Wyeth Ayerst 100-250
Bupropion (3) Wellbutrin Wellbutrin GlaxoSmithKline 300456
Citalopram (4) Celexa Cipramil Lundbeck 20-60
Clomipramine (5) Anafranil Anafranil Novartis 30-150
Desipramine (6) Norpamin - HMR 100-300
Dothiepin (7) - Prothiaden Knoll 75-150
Doxepine (8) Sinequan Sinequan Pfizer 10-100
Fluoxetine (9) Prozac Prozac Eli Lilly 20-60
Fluvoxamine (10) Luvox Faverin Solvay 100-200
Imipramine (11) Tofranil Tofranil Novartis 50-200
Lofepramine (12) - Gamanil Merck 140-210
Maprotiline (13) Ludiomil Ludiomil Novartis 25-75
Mirtazapine (14) Remeron Zispin Organon 1545
Moclobemide (15) - Manerix Roche 300-600
Nefazodone (16) Serzone Dutonin BMS 100400
Nortriptyline (17) Aventyl Allegron King 75-150
Paroxetine (18) Paxil Seroxat GlaxoSmithKline 20-60
Phenelzine (19) Nardil Nardil Parke Davis 30-45
Protriptyline (20) Vivactil - Merck 15-60
Reboxetine (21) Edronax Edronax PharmaciaAJpjohn 8-12
Sertraline (22) Zoloft Lustral Pfizer 50-200
Tranylcypromine (23) Parnate Parnate GlaxoSmithKline 20-30
Trazodone (24) Desyrel Molipaxan HMR 150-300
Trimipramine (25) Surmontil Surmontil Wyeth Ayerst 150-300
Venlafaxine (26) Effexor Effexor Wyeth Ayerst 75-150

apy on an SSRI, for example, are more time of existing agents, are required to
likely to complete a course of adequate dose overcome this problem.
and duration of antidepressant therapy 4. Finally, there is a certain population of pa-
than patients who initiate therapy with a tients who are resistant to current therapies.
TCA (4). In a review of more than 100
cases, patients receiving SSRIs tended to
Most antidepressants in clinical use today
discontinue medication less often than
act by enhancing the neurotransmission of se-
those on TCAs or heterocyclic antidepres-
sants. The difference was statistically sig- rotonin [5-hydroxytryptamine (5-HT)], nor-
nificant when SSRI use was compared with epinephrine [NE; noradrenaline (NA)], or
use of TCAs, but the differences were not as both. They do so either by blocking the re-
significant when the SSRIs were compared uptake (transport) of neurotransmitter,
to the heterocyclic antidepressants. The blocking the metabolism of neurotransmitter
findings were attributed more to the side [i.e., monoamine oxidase (MAO) inhibitors],
effects associated with the TCAs than with or by direct action on a neurotransmitter re-
the therapeutic efficacy of the agents (5). ceptor. Hence, the antidepressants can be
3. Most antidepressants have a delayed time classified on the basis of their putative mech-
of onset; currently available antidepres- anisms of action (Table 8.2 and Figs. 8.1-8.4).
sants require administration for at least Agents that block neurotransmitter reuptake
2-4 weeks before effects are evident. can be further divided into those that are non-
Newer agents with shorter onset times, or selective (e.g., tricyclic antidepressants with
newer strategies for enhancing the onset mixed action), serotonin-selective reuptake
486 Antidepressants

Table 8.2 Mechanistic Classification of Antidepressants and Other Types of


Agents/MechanismsCurrently Being Explored for the Treatment of Depression
-- -

Transport Blockers (reuptake inhibitors)


Tricyclic antidepressants (TCAs)
Mixed 5-HT/NE Amitriptyline (1)
Arnoxepine (2)
Clomipramine (5)
Dothiepin (7)
Doxepin (8)
Imipramine (11)
Trimipramine (25)
NE-Favoring Desipramine (6)
Maprotiline (13)
Nortriptyline (17)
Protriptyine (20)
Lofepramine (12)
Serotonin-selective reuptake inhibitors (SSRIs)
Citalopram (4)
Fluoxetine (9)
Fluvoxamine (10)
Paroxetine (18)
Sertraline (22)
Venlafaxine (26)
Norepinephrine-selective reuptake inhibitors (NSRIs; NaRIs)
Reboxetine (21)
Monoamine oxidase (MAO) inhibitors
Irreversible MA0 inhibitors
Phenelzine (19)
Tranylcypromine (23)
Reversible (RIMAS)
Moclobemide (15)
Serotonergic agents
Nefazodone (16)
Trazodone (24)
Other agents
Bupropion (3)
Mirtazepine (14)

inhibitors (SSRIs), and norepinephrine-selec- from other known antidepressants (most of


tive reuptake inhibitors (NSRI; referred to in which also happen to be heterocyclic!). For the
Europe as noradrenergic-selective reuptake most part, their mechanism(s) of action is not
inhibitors or NaRIs). Nomenclature has re- known with certainty; there is evidence, how-
cently become a bit unwieldy, in that the ever, that many of these agents interact di-
newer nonselective agents are referred to as rectly with serotonin receptors in the brain.
serotonin- and norepinephrine-selective re- The term "heterocyclic antidepressants" will
uptake inhibitors (SNRIs), to distinguish not be used herein. Finally, some newer
them from the nonselective tricyclic antide- agents, with potentially unique mechanisms
pressants. Furthermore, some investigators of action, are currently being explored; some
now classify the norepinephrine-favoring tri- of these agents are discussed.
cyclic antidepressants as NSRIs; however, this
2.2 Clinical Efficacy of Antidepressants
latter nomenclature will not be used here to
refer to the tricyclic antidepressants. A newer Antidepressants are given orally usually for
category of antidepressants is the "heterocy- extended periods of treatment ranging from
clic antidepressants," to differentiate them a few weeks to many months in duration.
2 Clinical Use

Amitriptyline (1) Amoxepine (2) Clomipramine (5)

a0
\ I

CH2CH2CH2N(CH3)2
Dothiepin (7)
\ I

CH2CH2CH2N(CH3)2 lmjpramjne R
Doxepin (8)
YR I /CH3
CH3
= -H (11)
Trimipramine R = -CH3 (25)

'I
I

NH-CH3
Desipramine (6)
9
a
0 NH-CH3
Maprotiline (13)

1 I
\ CHCH2CH2NH-CH3
I

Nortriptyline (17)

QQJ
1 I N \
I
CH2CH2CH2NH-CH3 CH3 0
Protriptyline (20) Lofepramine (12)
Figure 8.1. Structures of tricyclic antidepressants.

Clinical trials invariably employ self-report- drug treatment is usually defined as a de-
ing of symptoms, using standardized ques- crease of at least 50% in the baseline HAM-D
tionnaires, the tool most often used being score.
the 17- or 21-item Hamilton Rating Scale for There are several puzzling features of anti-
Depression (HAM-D). A positive response to depressant drug action. The first is that re-
488 Antidepressants

Citalopram (4) Fluoxetine (9) Fluvoxamine (10)


F
NH-CH3

CI H
Paroxetine (18) Sertraline (22) Reboxetine (21)

Venlafaxine (26)
Figure 8.2. Structures of the SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline),
the NSRI reboxetine, and the SNRI venlafaxine.

gardless of which drug is used, one-third or


more of those treated fail to show any signifi-
cant response. All drugs seem effective in
about 60-70% of those treated, but placebo
response rates range from 30% to 50%. Thus
the true efficacy of antidepressant drugs may
Phenelzine (19) Tranylcypromine (23) only be seen in less than 50% of those treated
(8).The reasons for the high placebo response
are partly because some patients show a spon-
taneous remission from their depression dur-
ing the 6-8 weeks of the drug trial, but partly
also because of the genuine power of the pla-
0 L o cebo effect, which is particularly noticeable in
Moclobemide (15) the treatment of psychiatric illnesses. The
magnitude of the placebo effect is exception-
Figure 8.3. Structures of common monoamine ox- ally large in trials of antidepressants, at least
idase (MAO)inhibitors. as great as that attributable to the antidepres-
2 Clinical Use

Bupropion (3) Nefazodone (16)


0

Mirtazepine (14) Trazodone (24)

Figure 8.4. Structures of some of the newer atypical antidepressants: bupropion, mirtazepine,
nefazodone, and trazodone.

sant drug (9). The placebo effect is variable; it tween the drug-treated and placebo groups.
is larger, for example, in patients with milder The various classes of antidepressant drugs
depression than in those with more severe exhibit few differences in their clinical effi-
forms of the illness. It is not uncommon for cacy; the advantages of the newer compounds
clinical trials of antidepressant drugs to fail to are related to their improved side-effect
show a statistically significant difference be- profiles rather than to a more powerful anti-

Table 8.3 Efficacy of Antidepressants Compared with Placebo in


Controlled Clinical Trials(11)
Drug Treated Placebo % Drug-Placebo
Antidepressant % Responders Responders % Treated
Tricyclics (n= 3327)
Amitriptyline (1) 60 25 35
Amoxepine(2) 67 49 18
Imipramine (11) 68 40 28
SSRIs (n= 2463)
Paroxetine (18) 45 23 22
Fluoxetine(9) 60 33 27
Fluvoxarnine (10) 67 39 28
Sertraline (22) 79 48 31
MA0 inhibitors (n = 1944)
Phenelzine (19) 64 30 34
Moclobemide (15) 64 24 40
Other (n= 277)
Mirtazapine (14) 48 20 28
490 Antidepressants

Table 8.4 Additional Indications for SSRI Antidepressants


Agent Additional Indications Approved by U.S. Food and Drug Administration
Fluoxetine (9) Bulimia nervosa, obsessive compulsive disorder (OCD),
panic disorder
Fluvoxamine(10) OCD
Paroxetine(18) OCD,panic disorder, social anxiety disorder
Sertraline (22) OCD,panic disorder, posttraumatic stress syndrome

depressant action (8, 10). The results of a SSRIs in particular have come to be used in-
meta-analysis of antidepressant drug trials il- creasingly in a variety of conditions other than
lustrate this point (Table 8.3). major depression. Table 8.4 summarizes the
A meta-analysis of 186 randomized con- uses for which SSRIs have been approved,
trolled trials with amitriptyline (1)indicated based on the finding of significant beneficial
that although this drug is less well tolerated effects in controlled clinical trials. In addition,
than other tricyclic or SSRI antidepressants agents in this class in controlled trials have
there was a small but significant 2.5% higher shown usefulness in premenstrual dysphoria,
proportion of responders compared to that of the borderline personality disorder, obesity,
other drugs (12). A systematic search of 108 smoking cessation, and alcoholism (17).
other meta-analyses suggested that combined The remarkable success of the SSRIs has
serotoninlnorepinephrine reuptake inhibitors prompted the question of whether genetic de-
have slightly superior efficacy to that of the fects in the serotonin (SERT) transporter
SSRIs (13). Recent studies of the norepineph- gene or in the regulation of its expression
rine-selective reuptake inhibitor reboxetine (21) might explain the etiology of mood disorders.
showed it to have comparable efficacy to that of The gene coding for human SERT is localized
other antidepressants, but it improved social on chromosome 17q11.2. It spans over 35 kilo-
functioning more than did the SSRIs (14,15). bases and is organized in 14 introns. No ge-
A second unexplained feature of antide- netic variations have been found in the coding
pressant drug action is that the maximum region of the SERT gene in depressed pa-
clinical benefit is not seen until treatment has tients, but a number of studies have found
been continued for several weeks (10). Al- that certain variants in a polymorphic region ,

though a significant improvement in HAM-D flanking the 5' region or in the second intron
scores can sometimes be detected after 2 are associated with depressive illness, anxiety-
weeks of treatment, it takes 4-6 weeks to ob- related personality traits, or suicidal alcohol-
tain the maximum response. Boyer and Feigh- ism (6).
ner (16) performed a meta-analysis of six trials
to determine the predictive value of nonre- 2.3 Adverse Side Effects
sponse to medication early in a clinical trial.
They found that patients who failed to achieve 2.3.1 introduction. The antidepressants
at least a 20% reduction in HAM-D scores at include a wide range of compounds with differ-
any point during the first 4 weeks of a study ing modes of action (Table 8.2). It is not sur-
had less than a 5% chance of becoming a "re- prising to find that they display a plethora of
sponder," as defined by a 50% or more reduc- differing side effects (18, 19). These range
tion in HAM-D score by the end of the 6-week from adverse effects that can be unpleasant
trial. The authors concluded that a full 6 but relatively harmless, to rarer and often un-
weeks' trial of antidepressant medication is predictable serious adverse reactions. Partic-
usually not justified if patients fail to respond ularly in the older, so-called first-generation
during the first 4 weeks. A number of explana- antidepressants, these can be life threatening.
tions have been proposed to explain the de- Because depressed patients are often suicidal,
layed clinical response to antidepressant it is not surprising that these drugs were often
drugs, and these are discussed below. implicated in deaths resulting from inten-
Depression is often associated with anxiety tional overdose (20,21). Some antidepressants
or other forms of psychiatric disorder, and the caused rare, idiosyncratic adverse effects that
2 Clinical Use

were, nevertheless, so severe as to lead to from pulmonary and cerebral edema. Despite
withdrawal of the drugs from the market (e.g., the relatively low risk of food interactions, a
nomifensine, zimelidine). wide range of foodstuffs is prohibited to paz
tients taking MA0 inhibitors, including ma-.
2.3.2 Monoamine Oxidase (MAO) Inhibi- ture cheeses, meat or yeast extracts, mature
tors. The first-generation MA0 inhibitors fish, pickled fish, smoked foods, and broad
tended to cause hypotension (often causing bean pods. Because of the long-lasting inhibir
dizziness), headache, and mild anticholinergic tion of MA0 caused by these irreversible en-
effects such as dry mouth, constipation, zyme inhibitors, the dietary precautions have
blurred vision, and difficulty in micturition. to be maintained for at least 14 days after ces-
Phenelzine (19) can cause mild sedation, but sation of drug treatment. These restrictions
tranylcypromine (23)is more likely to act as a make these drugs unpopular with both pa-
psychostimulant with mild amphetamine-like tients and physicians. At least as important as
properties, thereby leading to agitation and the food-interaction risk is that of drug in-
insomnia (18). These effects are dose depen- teractions. MA0 inhibitors are dangerous to
dent and tend to lessen in severity with time. use in conjunction with a number of other
In fact, although antidepressants are not typ- clinically important drugs (18, 24). Serious
ically associated with abuse potential, 16 of 21 interactions (usually hypertensive crises)
case reports of antidepressant abuse involved may occur with pethidine, levodopa, sympa-
tranylcypromine (22). More serious adverse thomimetic amines such as amphetamine
effects are related to the fact that the first- and ephedrine, and other antidepressants
generation MA0 inhibitors are compounds including the tricyclics and SSRIs.
that irreversibly inhibit the enzyme in the The second-generation MA0 inhibitor mo-
brain and other organs. With chronic drug clobemide (15)was designed to lessen the risk
treatment, inhibition of enzyme activity is cu- of the food and drug interactions seen with
mulative and may become almost complete. earlier MA0 inhibitors. Moclobemide selec-
The enzyme is abundant in the liver, where it tively targets one form of the enzyme, mono-
serves the function of detoxifying a variety of m i n e oxidase A, leaving monoamine oxidase
pharmacologically active organic amines that B in the liver active and capable of detoxifying
are absorbed from the diet. tyramine and other dietary vasoactive amines
Inhibition of liver MA0 leaves the patient (25). Moclobemide is also a reversible inhibi-
vulnerable to the so-called wine-and-cheese tor of the enzyme, so its effects are not cumu-
syndrome, with adverse cardiovascular effects lative and are more rapidly reversible on ter-
caused by absorption of such vasoactive mination of drug treatment. Adverse effects
amines as tyramine into the general circula- are few and infrequent, with dropouts because
tion [for review, see Blackwell et al. (23)l. The of side effects in clinical trials uncommon.
syndrome can include severe headache and Nausea, insomnia, headache, and dizziness oc-
hypertension and may lead to cerebral hemor- curred in some patients taking the drug, and
rhage and death. Although this is a real risk, it others experienced agitation and restlessness
seems likely that fears of MAO-food interac- (25, 26). Despite the improved selectivity of
tions may have been grossly exaggerated. Pare moclobemide, there have been a small number
(24) reviewed the evidence in 1985 and noted of reports of hypertension when moclobemide
that despite the widespread use of MA0 inhib- was combined with tyramine-rich foods (27).
itors in the previous decade there had only Moclobemide exhibits fewer adverse drug in-
been 17 reports of food interactions with teractions than first-generation compounds,
phenelzine (19) and none of these proved fa- although combination with SSRIs is not rec-
tal. With tranylcypromine (23) seven deaths ommended because of the danger that a "sero-
had been reported, but in only two of these tonin syndrome" could result (28). Moclobe-
could a definite relationship with diet be mide does, however, appear to be safe when
established. given in conjunction with sympathomimetic
MA0 inhibitors when taken alone in over- amines, found in many common cough and
dose can be fatal, with death usually resulting cold remedies. The drug appears to be safe if
Antidepressants

taken in overdose. Moclobemide represents a In therapeutic doses, the tricyclic antide-


real advance in terms of its safety profile over pressants also cause a variety of less serious
the earlier MA0 inhibitors, but the class as a unwanted side effects. Many of these are asso-
whole remains largely out of favor. ciated with the ability of many of these drugs
to act as antagonists at various monoamine
2.3.3 Tricyclic Antidepressants. The older receptors (see Table 8.6 below). Antidepres-
antidepressant drugs in this class exhibit a vari- sants interact with a large number of neuro-
ety of adverse side effects, most of which are transmitter receptors. Some of the targets
related to their secondary pharmacological ac- listed in Table 8.6 represent multiple subtype;
tions on targets other than the monoamine for example, "5-HT2" is in fact a composite of
transporters (29, 30). Although some of these effects of 5-HT,,, 5-HT,,, and 5-HT,,. (For a
side effects are uncomfortable but not serious, more complete and up-to-date summary of
others are life threatening, and the tricyclic an- drug interactions with neurotransmitter re-
tidepressants have only anarrow therapeutic in- ceptors visit the online database http://pdsp.
dex. Serious toxicity can occur at doses that are cwru.edu/pdsp.asp.) Several of the tricyclic
only 2-6 times therapeutic. Thus, a single bottle agents bind with high affinity at muscarinic
of tablets can prove lethal. Given the increased receptors, and the blockade of these cholin-
risk of suicide in depressed patients, it is not ergic receptors causes a range of side effects;
surprisingthat tricyclic overdose was among the again, there are five different subtypes of mus-
commonest causes of drug-related death in the carinic receptors. Anticholinergic side effects
United States in the early 1980s (20). Leonard include dry mouth, blurred vision, constipa-
(21) analyzed the number of deaths attributable tion, urinary retention, and sinus tachycardia.
to antidepressant overdose in England and The most -potent effects of all are seen at his-
Wales for the period 1977-1983, a total of more tamine H1 receptors, where several tricyclic
than 1500 deaths. It was possible to calculate an drugs bind with subnanomolar affinities.
estimated death rate per million patients Blockade of these receptors probably contrib-
treated for each antidepressant. The rates were utes to the sedative effects of some of these
arnitriptyline = 166, dothiepin = 147, maproti- agents. Sedation is also a side effect caused by
line = 115, imipramine = 105, doxepine = 99, blockade of alpha-adrenergic receptors, an-
trimipramine = 93, and clomipramine = 34. To other common feature in this class of drum. -
put these data into perspective, however, the Orthostatic hypotension is another side effect
deaths associated with tricyclic antidepressants related to alpha,-adrenergic blockade, leading
represent only approximately 10% of the risk of to dizziness on rising in young adults, but pos-
death through overdose with barbiturates, sibly causing syncope and falls in the elderly.
which were then widely used as hypnotics (31). Another unwanted feature of the older drugs
The most serious effects of the older drugs are is their tendency to cause significant weight
attributed to direct quinidine-like actions on the gain, which may reduce patient compliance
heart, interfering with normal conduction and with the drug treatment regime. Tricyclic an-
causing prolongation of the QRS or QT interval. tidepressants also reduce seizure threshold,
Death is most commonly the result of cardiac and this can lead to drug-induced seizures in
arrhythmia and arrest. Other toxic effects in- 0.1-0.5% of patients, usually early in treat-
clude respiratory depression, delirium, seizures, ment (19). CNS side effects include a propen-
shock, and coma. It is worth noting that the sity to cause mania or hypomania in patients
newer tricyclic antidepressant lofepramine (12) suffering from bipolar depression. Sexual dys-
has very little cardiotoxicity. In a review of fatal function may be associated with tricyclic use.
poisonings associated with antidepressants in Decreased libido and delayed orgasm can be
England and Wales for the period 1993-1995, it seen in men and women, and men may expe-
was associated with fatal overdose in only 4.3 rience erectile dysfunction. These effects,
per million treatment episodes (of 3 months' du- however, are much more common in patients
ration), comparable to the fatalities associated treated with the newer SSRIs (see Table 8.5).
with SSRIs (2.4 per million treatment episodes) The tricyclic drugs are extensively metabo-
(32,331. lized in the liver by the cytochrome p450 en-
II 2 Clinical Use
i
?

Table 8.5 Summary of Side Effect Profiles of Antidepressant Drugs (34)


Anticholinergic Cardiac Weight
Generic Name Sedation Effects Hypotension Effects Gain
Amitriptyline (1) +++ ++++ +++ +++ +++
Arnoxepine (2) + ++ + ++ +
Bupropion (3) 0 0 0 + 0,
Citalopram (4) + + O/+ O/+ 0
Clomipramine (5) ++ +++ ++ +++ +
Desipramine (6) + + + ++ +
Doxepine (8) +++ ++ +++ ++ ++
Fluoxetine (9) O/+ 0 0 0 0
Fluvoxamine (10) 0 0 0 0 0
Imipramine (11) +++ ++ ++ +++ ++
Maprotiline (13) ++ ++ ++ ++ +
Mirtazapine (14) +++ + 0/+ + +
Moclobemide (15) 0 0 0 0 0
Nefazodone (16) + 0 + O/+ O/+
Nortriptyline (17) + + + ++ +
Paroxetine (18) + + 0 0 0
Phenelzine (19) + 0 +++ 0 ++
Protriptyline (20) 0/+ ++ + +++ +
Sertraline (22) 0 0 0 0 0
Tranylcypromine (23) + 0 ++ 0 O/+
Trazodone (24) +++ 0 ++ O/+ +
Trimipramine (25) +++ +++ ++ +++ ++
Venlafaxine (26) 0/+ O/+ 0 + 0

zymes. Consequently, other drugs that induce has, however, been reported in six patients
such enzymes or compete with the tricyclic an- taking citalopram (4) (37), although the cause
tidepressants for metabolism may alter their of death was disputed (38). The symptoms of
actions. Calcium channel blockers, cimetidine, SSRI overdose include nausea, agitation, sei-
phenothiazines, haloperidol, methylphenidate, zures, and sometimes loss of consciousness
glucocorticoids, oral contraceptives, and most (18).The relative safety of the SSRIs has led to
SSRIs may inhibit the metabolism of the tricy- their being prescribed more freely than the
clics. This will tend to exacerbate the adverse earlier antidepressants, and their use in a
side effects of the tricyclics. Conversely, carba- number of indications in addition to the treat-
mazepine, phenytoin, barbiturates, primidone, ment of major depression (Table 8.4).
and alcohol may induce liver cyhchrome p450 There are, however, some hazards associ-
enzymes and accelerate metabolism, making tri- ated with the use of these drugs. SSRIs de-
cyclics less effective (8,19). crease serotonin uptake from the blood by
platelets. Because platelets cannot synthesize
2.3.4 Serotonin-Selective Reuptake Inhibi- serotonin, which is involved in platelet aggre-
tors. Since their introduction in the mid- gation, SSRIs may impair platelet function. A
1980s SSRIs have become the most widely case-controlled study found that the risk of
used of all antidepressants. This is largely be- gastrointestinal bleeding was three times
cause of their improved safety and tolerability greater in SSRI users than in controls (39).
in clinical use. Although the SSRIs are no This conclusion was confirmed by a retrospec-
more efficacious or rapid in onset of action tive cohort study of 317,824 SSRI users, which
than the tricyclics, they lack most of the seri- emphasised that the risk of gastrointestinal
ous toxicity and adverse side effects associated bleeding was particularly important for el-
with the first-generation drugs. The relative derly patients (40).
absence of cardiac toxicity makes the SSRIs The SSRIs exhibit only low affinities for
relatively safe in overdose (36). Fatal overdose muscarinic and most other monoamine recep-
Antidepressants

tors (Table 8.6). Consequently at therapeutic Given concurrently with TCAs they may cause
doses they are relatively free from the cholin- serious adverse effects. Fluvoxamine may
ergic side effects associated with the TCAs, raise levels of caffeine and theophylline, and
and are less likely to cause sedation and fluoxetine can interfere with the metabolism
drowsiness or hypotension. Instead of promot- of clozapine, cyclosporin, and tefenadine (18,
ing weight gain, the SSRIs tend to suppress 46). SSRIs should never be given with MA0
appetite and this can lead to weight loss. The inhibitors because a fatal "serotonin syn-
most common side effect in the acute use of drome" has been reported with fluoxetine in
SSRIs is nausea, which clinical trial data indi- this combination (18).
cate affects about 20% of patients taking flu-
oxetine (9),fluvoxamine (101, paroxetine (l8), 2.3.5 Other Agents
and citalopram (4) (18). The risk of nausea is Bupropion. Bupropion (3)is a weak inhibi-
reduced if the SSRIs are taken with a meal. tor of dopamine reuptake that has not been
Most SSRIs tend to cause CNS "activation," widely used outside the United States as an
leading to insomnia, agitation, or anxiety. Par- antidepressant. It has received a new world-
adoxically, paroxetine (18)tends to cause se- wide lease on life as an effective means of
dation and drowsiness to such an extent that treatment for tobacco smoking cessation (47).
in several countries the drug is prescribed It has little sedative, cholinergic, hypotensive,
with a warning not to drive (18). All SSRIs or cardiotoxic properties (48). There are some
tend to cause sexual dysfunction, including adverse side effects, however, related to the
loss of libido, erectile dysfunction, and delayed ability of this drug to enhance dopaminergic
or absent orgasm. Both men and women are function. These include insomnia, agitation,
affected, and the incidence of these side effects nausea, weight loss, and sometimes psychosis
is quite high. Although initial clinical trial (49). The drug decreases seizure threshold
data suggested that only a small proportion of and so should not be given to those at risk of
patients suffered sexual dysfunction, more re- seizures (49). In overdose acute toxicity is less
cent reports suggest that these side effects serious than that seen with tricyclics (50). Bu-
may occur in as many as 50-70% of patients propion (3) should not be given with MA0 in-
taking SSRIs, and 30-40% of all those on an- hibitors, levodopa, or dopaminergic receptor
tidepressant medication of any kind (41, 42). agonists (49).
Patients are reluctant to volunteer informa- Venlafmine. Venlafaxine (26) is an inhibi-
tion on sexual dysfunction, but when asked tor of serotonin and norepinephrine uptake,
specifically a truer picture emerges. but unlike the TCAs it has little affinity for
A debate has raged for several years over muscarinic, histamine, or alpha-adrenergic
the alleged association between the use of receptors. Consequently, it does not exhibit
SSRIs and the occurrence of suicidal thoughts the cholinergic, sedative, or hypotensive side
and suicide. However, meta-analysis of the effects seen with the earlier compounds (18,
available clinical data has failed to show any 19). Nevertheless, the side-effect profile in-
such association (43, 44). Nevertheless, the cludes headache, dry mouth, sedation, and
UK Medicines Control Agency as recently as constipation in up to 15% of patients (51).
October 2000 advised manufacturers of SSRIs During the first 2 weeks of treatment as many
to include a warning in patient information as 30% of patients receiving the drug may ex-
leaflets about the possibility of suicidal perience nausea (52).At high doses close mon-
thoughts when they begin taking the prod- itoring of blood pressure is needed, given that
ucts, before the antidepressant effects become the drug tends to cause hypertension (52).
apparent (45). Venlafaxine (26) appears to have little cardiac
SSRIs are metabolized by cytochrome p450 toxicity and seems to be safe in overdose, al-
enzymes in the liver. Most SSRIs inhibit though seizures have been reported (53).
CYP2D6, fluvoxamine (10) inhibits CYPlA2, Trazodone. Trazodone (24) is a weak inhib-
and fluoxetine (9) inhibits CYP3A4. Conse- itor of serotonin uptake and is an antagonist
quently, these drugs may interfere with the at 5-HT and alpha,-adrenergic receptors (Ta-
metabolism of a number of other agents. ble 8.5). These properties appear to be related
Table 8.6 Affinities of Antidepressant Drugs for Human Monoamine Receptors"
Generic Name Histamine H l Muscarink a,-Adrenergic a,-Adrenergic Dopamine D2 5-HT,, 5-HT,
Amitriptyline
Amoxepine
Bupropion
Citalopram
Clomipramin
Desipramine
Dothiepin
Doxepine
Fluoxetine
Fluvoxamine
Imipramine
Lofepramine
Maprotiline
Nefazodone
Nortriptyline
Paroxetine
Protriptyline
Reboxetine
Sertraline
Trazodone
Trimipramine
Venlafaxine
"Equilibrium dissociation constants are nanomolar. Data were obtained from binding studies using the following: Histamine HI: 3H-doxepin (29) or 3H-pyrilamine (35);
Muscarinic: 3H-quinuclidinylbenzilate; a,-Adrenergic: 3H-prazosin; a,-Adrenergic: 3H-rauwolscine; Dopamine D2: 3H-spiperone;5HT1,: 3H-8-OH-DPAT;5-HT,: 3H-ketanserin.
Data are from Refs. 29,30, and 35. The four compounds with the highest &ty for each receptor are highlighted in bold type. For a more complete and up-to-date summary of drug
interactions with neurotransmitter receptors see http://pdsp.cwry.edu/pdsp.asp.
Antidepressants

to the side effects of sedation and hypotension from 1 to 12 h according to both the drug and
(leading to dizziness) seen with the drug, and the individual. Most of these compounds have
common at high doses (54). Trazodone lacks long half-lives, and many are metabolized by
cardiac toxicity, although dysrhythmias have demethylation in the liver, to yield biologically
been reported (18); the drug appears safe in active desmethyl metabolites, which further
overdose. Trazodone sometimes causes an un- extend their duration of action (62,63) (Table
usual type of sexual dysfunction, that can in- 8.7). For example, imipramine (11)is metabo-
clude increased libido, priapism, and sponta- lized to desipramine (6). In the case of lofepra-
neous orgasm (55, 56). These symptoms, mine (12), its metabolite, desipramine (61,
plays an important role in the overall actions
although rare, are dramatic and have received
of the drug, in that desipramine has a consid-
considerable attention. Combination with
erably longer elimination half-life than that of
SSRIs or MA0 inhibitors should be avoided
the parent compound (27,34) (Table 8.7). The
because of the risk of "serotonin syndrome" drugs are extensively metabolized in the liver
(18). by demethylation, hydroxylation, and gluc-
Nefazodone. Nefazodone (16) is chemically uronide conjugation of the hydroxy metabo-
related to trazodone but acts in a different lites. The lipid-soluble drugs are thus con-
manner, largely through inhibition of seroto- verted to water-soluble conjugates that are
nin uptake and antagonism at 5-HT, recep- readily excreted by the kidney (64). There is
tors. Adverse effects are mild and infrequent. increased renal clearance in children and de-
They include sedation, dry mouth, and dizzi- creased clearance in older people, factors that
ness in around 10% of patients (57). The drug need to be taken into account in determining
causes less hypotension than does trazodone, optimum dosage levels. Clearance is also re-
and is unlikely to cause sexual dysfunction duced in patients with compromised liver or
(18).It is considered safe to use in epilepsy and kidney function.
there appears to be no overdose risk (18). Ne- There is considerable individual variation
fazodone is a potent inhibitor of cytochrome in the metabolism of the tricyclics, and this is
p450 CYP3A4 and so should not be given with largely attributed to genetically determined
alprazolam, astenizole, terfenadine, cisapride,
-
differences in liver enzymes. Some 7 to 9% of
or cyclosporin (58). Caucasians are classified as "slow metaboliz-
Reboxetine. Reboxetine (21) is a norepi- ers," measured by the rate of hydroxylation of
nephrine-selective reuptake inhibitor that the drug debrisoquin. This is caused by ge-
lacks affinity for most of the monoamine re- netic polymorphism in the cytochrome p450
ceptors. It thus does not exhibit the typical enzyme CYP2D6 (65). This enzyme plays an
side-effect profile of the tricyclics. Neverthe- important role in the aromatic hydroxylation
less, side effects include increased sweating, of tricyclic antidepressants. The tricyclic
postural hypotension (leading to dizziness), drugs have a narrow therapeutic window, so
dry mouth, constipation, blurred vision, impo- individual variations in drug metabolism can
tence, and dysuria. Tachycardia and urinary be important in determining the correct ther-
retention have also been reported (59). There apeutic dose and avoiding toxic overdose (66,
is no evidence of cardiotoxicity and sexual dys- 67).
function seems to be rare. In contrast to some
of the earlier tricyclics that are sedative, re- 2.4.2 SSRI. All the SSRIs are well absorbed
boxetine is nonsedating and can cause insom- and most have long half-lives, compatible with
nia (60, 611.. their use as once-a-day drugs (68-70). The for-
mation of biologically active desmethyl metab-
2.4 Pharmacokinetics olites is again a factor in prolonging the dura-
tion of action of some of these drugs. This is
2.4.1 Tricyclic Antidepressants. The tricy- particularly important for fluoxetine (91,
clic antidepressants are, by and large, well ab- which is metabolized in part to form norfluox-
sorbed after oral administration, although etine, an active metabolite that has a half-life
time to peak plasma concentration can vary of 4-16 days (71, 72). The desmethyl metabo-
2 Clinical Use 497

Table 8.7 Pharmacokinetic Parameters for Antidepressant Drugsa


Time to Peak Percentage
Plasma Elimination Plasma Protein
Generic Name Concentration (h) Half-Life (h) Binding Important Metabolite.
Amitriptyline (1) 1-5 10-26 94 Nortriptyline (17)
Amoxepine (2) 1-2 8-30 90 8-Hydroxyamoxapine ? .
Bupropion (3) 3 10-21 85 BP-threoamino-alcohol
Citalopram (4) 1-6 33 80 Desmethylcitalopram
Clomipramine (5) 2-6 21-31 97 Desmethylclomipramine.

Desipramine (6) 3-6 11-31 90 2-OH-desipramine


Dothiepin (7) n.a. 1624 n.a. Desmethyldothiepin
Doxepine (8) 14 11-23 80 Desmethyldoxepine
Fluoxetine (9) 4-8 24-120 94 Norfluoxetine
Fluvoxamine (10) 2-8 15-26 77 None
Imipramine (11) 1-3 11-25 92 Desipramine (6)
Lofepramine* (12) n.a. 4-6 n.a. Desipramine (6)
Maprotiline (13) 4-12 28-58 88 Desmethylmaprotiline
Mirtazapine (14) 2-3 2040 85 None
Moclobemide (15) 1-1.5 1.4 n.a. Numerous
Nefazodone (16) 1 2 4 99 mCPP (28)
Nortriptyline (17) 3-12 18-44 92 10-OH-nortriptyline
Paroxetine (18) 5-7 24-31 95 None
Phenelzine (19) 2 4 n.a. n.a. n.a.
Protriptyline (20) 6-12 67-89 93 None
Reboxetine** (21) 2 4 12 97 Various
Sertraline (22) 6-8 27 99 N-Desmethylsertraline
Tranylcypromine (23) 1.5-3 1.5-3.5 n.a. n.a.
Trazodone (24) 1-2 6-11 92 mCPP (28)
Trimipramine (25) 3 9-11 95 None
Venlafaxine (26) 2 5 30 0-Desmethylvenlafaxine
"Data are from Refs. 29, *27, **81, and 82; n.a., data not available.

lite of sertraline (22), although less potent the individual enantiomers may be metabo-
than the parent drug (681, also has an ex- lized and eliminated differently (70, 77).
tended half-life (73, 74). The desmethyl me-
tabolite of citalopram (4) is formed in rela- 2.4.3 M A 0 Inhibitors. The MA0 inhibi-
tively small amounts and appears to tors are rapidly absorbed and are extensively
contribute less importantly (34, 75). The long degraded by first-pass metabolism in the liver.
duration of action of fluoxetine (9) and sertra- For the irreversible enzyme inhibitors phenel-
line (22) make long drug-free periods neces- zine (19) and tranylcypromine (23) the elimi-
sary when switching patients to other drugs. nation half-lives are relatively unimportant,
All of the SSRIs are metabolized by cyto- given that enzyme inhibition persists for
chrome p450 CYP2D6 in the liver, so individ- many days after the drug has been eliminated.
ual genetically determined differences exist in A minimum of 7-14 days is needed after stop-
rates of drug clearance and there is the poten- ping treatment with these drugs before it is
tial for interaction with other drugs that are safe to switch to other agents. The reversible
metabolized by this enzyme (69, 70). Citalo- MA0 inhibitor moclobemide (15) is rapidly
pram (4) and fluvoxamine (10) are also sub- absorbed and extensively metabolized in the
strates of p450 CYP 2C19, which exhibits a liver. It has an elimination half-life of approx-
particularly high rate of genetic polymor- imately 12 h (78). Because enzyme inhibition
phism in Asians (76). The pharmacokinetics of is reversible, the time to recover after stopping
fluoxetine and citalopram are complicated by moclobemide treatment is much shorter,
the fact that they are racemic compounds and 16-24 h (79).
Antidepressants

2.4.4 Other Antidepressants. The other an- It was not until high specific activity
tidepressant drugs in Table 8.7 are rapidly ab- tritium-labeled radioactive catecholamines
sorbed and vary in their half-lives, with some became available in the late 1950s, however,
requiring multiple daily dosing. Trazodone that experiments could be performed using
and nefazodone (16)are metabolized in part to quantities of monoamine small enough to
m-chlorophenylpiperazine (m-CPP; (28), a mimic the very low concentrations of epineph-
compound that acts as an agonist at some se- rine or norepinephrine normally encountered
rotonin receptors (80). The metabolite may, in body fluids. When the first experiments
thus, contribute to the biological action of were performed in the Axelrod laboratory at
these drugs. m-CPP (28) also has a longer the National Institutes of Health with 3H-epi-
half-life than the parent drugs and readily nephrine (85) and later with 3H-norepineph-
penetrates the CNS. rine (861, they yielded an unexpected result.
The norepinephrine selective uptake inhib- Although in laboratory animals most of the
itor reboxetine (21) is rapidly and completely injected dose of labeled catecholamine was
absorbed, and is metabolized mainly by the rapidly metabolized (mainly by COMT), a sub-
cytochrome p450 3A4; because it does not in- stantial proportion of the injected monoamine
teract with CYP 2D6 there is less risk of inter- (30-40%) was removed from the circulation
actions with other drugs (81-83).Mirtazepine by a rapid uptake into tissues, where it re-
(14) also shows little interaction with p450 cy- mained for some time unchanged. A key obser-
tochrome isozymes and there is only a low risk vation was that the uptake of 3H-norepineph-
of drug interactions (84). Mirtazepine is a rine into the heart was virtually eliminated in
racemate, and the two enantiomers are elimi- animals in which the sympathetic innervation
nated at different rates, with a twofold higher had been destroyed by surgical removal of the
rate of elimination of the (S)-enantiomer than superior cervical ganglion (87). This led Hert-
of the (R)-enantiomer (84). ting and Axelrod (88) to propose that the re-
uptake of norepinephrine by the same nerves
from which it had been released might repre-
sent a novel mechanism for inactivating this
3 PHYSIOLOGY AND PHARMACOLOGY
neurotransmitter.
The discovery of norepinephrine uptake
3.1 Monoamine Transporters was followed by the finding that similar but
distinct transporters were involved in the in-
3.1 .I Discovery. The majority of both old activation of 5-HT and do~amine,and that
and new antidepressants act by virtue of their similar mechanisms existed for the inactiva-
ability to inhibit monoamine transporter tion of the amino acid neurotransmitters
mechanisms in the brain. The concept that GABA, glycine, and L-glutamate (89, 90). Re-
neurotransmitters are inactivated by uptake search interest has focused on these mecha-
of the released chemical into the nerve termi- nisms, including in recent years the identifica-
nal from which it had been released or into tion and cloning of the genes encoding the
adjacent cells is less than 40 years old. Before transporter proteins involved and the develop-
this it was generally assumed that the inacti- ment of knockout strains of genetically engi-
vation of norepinephrine and the other mono- neered mice lacking one or other of these gene
amine neurotransmitters after their release products. The family of neurotransmitter
from nerves was likely to involve rapid enzy- transporters has turned out to be far more
matic breakdown, akin to that seen with ace- extensive than previously imagined, with
tylcholinesterase. The degradation of mono- more than 20 different members (for review,
amines by the enzyme monoamine oxidase see Ref. 91).
was known early on, and in the 1950s a second
enzyme catechol-0-methyl transferase (COMT) 3.1.2 Monoamine Transporters. The nor-
was discovered and was thought to play a key epinephrine transporter (NET) was cloned by
role in inactivating norepinephrine and other Pacholczyk et a]. in 1991 (92) and this soon led
catecholamines. to the discovery of other related members of
3 Physiology and Pharmacology

the transporter gene family. Separate trans- sively in monoaminergic neurons SERT is ex-
porters exist for serotonin (SERT) and dopa- pressed in both neurons and glia.
mine (DAT).The monoamine transporters are
dependent on sodium and chloride ions for 3.1.3 Drugs as Inhibitors of Monoamine
their function. They use the electrochemical ~ r a n s ~ o r t e r sfar
. ~ ~the most important
gradient of sodium between the outside and group of CNS drugs that target the NE and *
inside surfaces of the cell membrane to pro- serotonin neurotransmitter transporters (i.e.,
vide the thermodynamic energy required to NET and SERT, respectively) is the tricyclic
pump neurotransmitters from low concentra- antidepressants and their modern counter-
tions outside the cell to the much higher con- parts. The discovery by the Axelrod group in
centrations inside the cell. Chloride ions ac- 1961 (94) that imipramine (11)potently inhib-
company the entry of neurotransmitter and ited the uptake of norepinephrine led to the
sodium, and there is a net movement of posi- first understanding of the mechanism of ac-
tively charged ions into the cell, although not tion of the first-generation tricyclic antide-
in sufficient amounts to appreciably alter the pressants. After the discovery of the serotonin
resting membrane potential of the cell. uptake system in the brain it soon became ap-
The vesicular neurotransmitter trans- parent that the classical tricyclic drugs imip-
porters represent another family (91) whose ramine (11)and amitriptyline (1)were potent
function is to maintain the very high concen- as inhibitors of both NE and 5-HT uptake (Ta-
trations of monoamine and amino acid neu- ble 8.2). This reinforced the monoamine hy-
rotransmitters in storage vesicles. They use pothesis of depression as a monoamine-defi-
the proton gradient that exists across the ciency state, and stimulated much further
vesicular membrane as the motive force. The research in the pharmaceutical industry to
vesicular monoamine transporters (VMAT) discover new inhibitors of monoamine uptake.
recognize serotonin, dopamine, norepineph- The debate as to whether inhibition of either
rine, epinephrine, and histamine. VMAT-1 NE or 5-HT was the more important in con-
is present chiefly in amine-containing endo- ferring antidepressant efficacy has swung one
crine and paracrine cells in peripheral or- way and the other over the past 40 years and
gans, whereas VMAT-2 is the predominant there is no definitive answer to this question.
form found in monaminergic neurons in the An early effort to improve the selectivity of
CNS. It is also expressed in the histamine- antidepressants was made in the 1970s by sci-
containing cells of the stomach, and in the entists at the Ciba-GeigyCompany in Switzer-
adrenal medulla and in blood cells. The Na+/ land (now Novartis), who developed the selec-
C1'-dependent transporters and the vesicu- tive NE uptake inhibitor maprotiline (13)
lar transporters are membrane proteins con- (95). This proved to be clinically effective as an
sisting of a single polypeptide chain of 5-600 antidepressant but it was not a great success
amino acid residues, with a 12 a-helical mem- commercially and had few clear advantages
brane-spanning domain (91). The molecular over the classical TCAs. This idea was also
mechanisms underlying the function of the swept away by the wave of enthusiasm for se-
neurotransmitter transporters remain un- rotonin-selective reuptake inhibitors (SSRIs)
clear. Unlike flux through an open ion chan- that started with the success of fluoxetine (96,
nel, there must be a gating cycle every time 97). Table 8.8 summarizes the affmities of cur-
solute is transported, although the exact mo- rently used antidepressants on cloned human
lecular details of this are not understood. No monoamine transporters expressed in tissue
doubt selective mutations of amino acids in culture cell lines (98). The availability of the
the transporter molecules will throw light on human transporter proteins for screening rep-
these questions in the future (93). resents a considerable advance. Although
Immunocytochemical and in situ hybrid- there are many published accounts of the ef-
ization techniques have been used to study the fects of antidepressants on monoamine trans-
cellular distribution of the transporters (91). porter mechanisms, most of these employed
Whereas NET and DAT are expressed exclu- animal tissues and there are few reported
Antidepressants

studies in which a large number of drugs were


tested under the same experimental protocols.
Ironically, some of the most recently intro-
duced antidepressants hark back to the nonse-
lective compounds of the earlier era. Thus ven-
Maxine (26) is described as a drug that
combines both NE and serotonin reuptake inhi-
bition (99) [although in vitro binding data show
that v e n l a f k e binds with more than 100 times
higher affinity to human SERT than to NET
(98) (Table 8. 'i')]. The compound sibutramine
(29) is also an inhibitor of both NE and seroto-
nin uptake, but it has been approved for use as
an antiobesity agent rather than an antidepres-
sant (102). At the same time reboxetine (21) is
the first antidepressant drug in a new class of (29) Sibutramine
NET-selective inhibitors (35). Reboxetine is re-
ported to be as effective as the SSRIs or older justment of depressed patients (101). The older
tricylics, but is not associated with sexual dys- antidepressant bupropion (31,acts as a weak in-
function (60,61).It is claimed to be more effec- hibitor of NE and dopamine uptake, with little
tive than fluoxetine in improving the social ad- effect on serotonin uptake, but it and some of its

Table 8.8 Antidepressants: Inhibition of Human Serotonin(SERT),Norepinephrine (NET),


and Dopamine (DAT) Transportersa
Human SERT, Human NET, Human DAT, Selectivity:
Generic Name Kd (nM) Kd (nM) Kd (nM) SERT vs. NET
Amitriptyline (1) 4.3 35 3250
Amoxepine (2) 58 16 4310
Bupropion (3) 9100 52,000 520
Citalopram (4) 1.2 4070 28,100
Clomipramine (5) 0.3 38 2190
Desipramine (6) 17.6 0.8 3190
Dothiepin (7) 8.6 46 5310
Doxepine (8) 68 29.5 12,100
Fluoxetine (9) 0.8 240 3600
Fluvoxamine (10) 2.2 1300 9200
Imipramine (11) 1.4 37 8500
Lofepramine (12) 70 5.4 18,000
Maprotiline (13) 5800 11.1 1000
Mirtazapine (14) >100,000 4600 >100,000
Nefazodone (16) 200 360 360
Nortriptyline (17) 18 4.4 1140
Paroxetine (18) 0.13 40 490
Protriptyline (20) 19.6 1.4 2100
Reboxetine* (21) 129 1.1 -
Sertraline (22) 0.29 420 25
Trazodone (24) 160 8500 7400
Trimipramine (25) 149 2450 780
Venlafaxine (26) 8.9 1060 9300
"Data are from Refs. 98 and *35. The results are equilibrium dissociation constants (Kd)in nM,using 3H-imipramine
binding to human serotonin transporter, 3H-nisoxetinebinding to human norepinephrine transporter, and 3H-WIN35428
binding to human dopamine transporter (98), or for reboxetine (35), 3H-citalopram binding to human serotonin transporter
and 3H-nisoxetinebinding to the human norepinephrine transporter.
3 Physiology and Pharmacology

metabolites may indirectly activate noradrener- the importance of serotonin. There is some ev-
gic mechanisms (see Section 5.4 below). The idence that NET-selective drugs are subtly
compound has had little success as an antide- different in their clinical profiles from those of -
pressant, but has been approved in the United SSRIs. Healy and McMonagle (106) have sug-
States and Europe as an aid to smoking cessa- gested that these drugs affect overlapping
tion (47). clinical domains. They suggest that NET-se-
.-@

What are we to make of these twists and lective agents tend to promote levels of energy
turns? How can drugs that are selective NE re- and interest, whereas SSRIs affect impulse
uptake inhibitors be equally effective as those control and both categories of drug treat
that selectively target SERT? In practice it is mood, anxiety, and irritability.
The molecular mechanisms in the brain
difficult to know how selective the monoamine
that are triggered by the antidepressants,
uptake inhibitors are in vivo. None of the anti-
however, remain obscure. The fact that all
depressants is completely selective for either
drugs require a period of several weeks before
NET or SERT. The SSRIs have some affinity for they become fully effective suggests that they
NET, and some (e.g., paroxetine) are quite po- modify gene expression in the brain and that
tent inhibitors of NET (102). In some cases the the resulting altered biochemical state takes a
formation of active metabolites alters the drug long time to become stabilized. Many theories
selectivity profile. Thus the nonselective com- have been proposed, including alterations in
pound imipramine (11)and the partially NET- the expression of alpha- and beta-adrenergic
selective compound lofepramine (12) are exten- receptors, changes in transcription factors
sively metabolized to desipramine (61,a highly and/or neurotrophic factors, and even mor-
potent and selective NE reuptake inhibitor. phological alterations in the connectivity of
Similarly, whereas amitriptyline (1)has little se- monoaminergic nerves.
lectivity for either NET or SERT, the metabolite It is possible that antidepressant drugs
nortriptyline (17) is a selective NET inhibitor. It have other targets in addition to their actions
seems likely that both NET-selective agents and at cell surface monoamine transporters. Al-
SSRIs exert their effects through some common Damluji and Kopin (107) have described a
final pathway in the brain. Perhaps the SSRIs novel amine uptake process in peptide-con-
a d indirectly to modulate noradrenergic func- taining hypothalamic neurons, which they.
tion (103,104). Experimental data from animal named "transport-P." Like the vesicular
experiments using microdialysis probes showed transporters this process is driven by a proton
increased levels of extracellular norepinephrine gradient, but it is distinct from the vesicular
transporters in being insensitive to reserpine,
in rat hippocampus aRer chronic treatment
but sensitive to a variety of tricyclic antide-
with paroxetine (18)(103). The original mono-
pressants at micromolar concentrations (108).
amhe hypothesis of depression as formulated It is not clear, however, what role if any trans-
by Schildkraut in 1965 (105) stated: port-P plays in the inactivation of the mono-
amine neurotransmitters.
"Some, if not all, depressions are associated with Some antidepressants, notably mazindol
an absolute or relative deficiency of catechola- and bupropion (3), inhibit the dopamine
mines, particularly norepinephrine, at function- transporter (DAT) as well as NET or SERT.
ally important adrenergic receptor sites in the
The DAT is best known, however, as one of the
brain. Elation conversely may be associated with
principal sites of action of the psychostimu-
an excess of such amines."
lant drug cocaine. Mice that are genetically
engineered to knock out the expression of the
European opinion currently seems to be DAT gene are profoundly hyperactive and fail
swinging back in support of the view that an to show any further stimulation of activity in
upregulation of noradrenergic function may response to cocaine or (+)-amphetamine
be the key element underlying the efficacy of (109). Such animals, nevertheless, will con-
antidepressant drugs (103, 104), but most tinue to self-administer cocaine (110), sug-
American researchers continue to emphasize gesting that the rewarding properties of the
Antidepressants

drug cannot be explained entirely by its ability


to inhibit DAT. Cocaine (30) is also a potent
inhibitor of both serotonin and NE reuptake.
It retains some rewarding properties even in
combined SERT and DAT knockout mice
(Ill),suggesting that inhibition NE reuptake
may also contribute importantly to its phar-
macology. A corollary of the understanding
that cocaine owes important parts of its over-
all CNS profile to mechanisms other than in-
hibition of DAT is that more selective inhibi-
tors of dopamine reuptake might be useful and
free of dependency liability. One such com-
pound, brasofensine, is in clinical develop- sitized to the behavioral stimulant effects of
ment for the treatment of Parkinson's disease dopaminergic drugs, and there is evidence for
(112). Other selective DAT inhibitors have increased dopamine release in the brain (115).
been proposed for the treatment of the with- The neurotransmitter transporter family
drawal phase of CNS drug abuse. On the other has provided many valuable targets for psy-
hand, the structure of cocaine (30) has been chopharmacology. There is every prospect
modified in such a manner [e.g., (31)and (3211 that this will continue. It might seem that the
that the resulting agents behave primarily as monoamine transporters had already been
selective 5-HT reuptake inhibitors (113, 114). fully exploited, but the reemergence of NET-
Some have suggested that a supersensitiv- specific antidepressants and the possible ap-
ity of central dopaminergic mechanisms may plications of selective inhibitors of DAT sug-
play an important role in the actions of anti- gest that there may still be room for
depressant drugs (115). Animals treated innovation even in such a crowded field.
chronically with antidepressants become sen-
3.2 Serotonergic Agents

3.2.1 Receptor Populations. Seven major


families or populations of serotonin receptors
have been identified: 5-HT,-5-HT, receptors.
Several of these populations are divided into
subpopulations (119-121). For example, 5-HT,
(5-HTIA,5-HTIB,5-HT,,,, 5-HT,,, 5-HT,,) and
5-HT, (5-HT,,, 5-HT,,, 5-HTZc)receptors rep-
resent serotonin receptor populations for which
subpopulations exist. With the exception of the
5-HT, receptors, which are directly linked to an
(30) Cocaine ion channel, all the other 5-HT receptors belong
to the G-protein-coupled superfamily of recep-
tors. 5-HT, receptors are negatively coupled to
an adenylate cyclase second-messenger system,
whereas the 5-HT,, 5-HT,, and 5-HT, receptors
are positively coupIed. 5-HT, receptors are cou-
pled to a phosphatidylinositol second-messenger
system. There is evidence that 5-HT, receptors
and 5-HT, receptors are involved in depres-
sion. Certain of the other 5-HT receptors may
also play a role in depression and there is evi-
dence for functional interactions between 5-HT
receptors.
3 Physiology and Pharmacology

3.2.2 5-HT, Receptors. The exact mecha- (e.g., Ref. 125). Mechanistically, then, it is rea-
nism of action of some antidepressants is cur- sonable that 5-HT, antagonists display anti-
rently unknown. For example, the atypical anti- depressant activity. Ritanserin (33)is a newer
depressant trazodone (24) is a weak 5-HT
reuptake inhibitor, whereas nefazodone (16) is a
weak inhibitor of both 5-HT and NE reuptake
(Table 8.7). Inhibition of neurotransmitter re-
uptake does not seem to account for the antide-

-
pressant actions of these two agents. Both bind
at 5-HT, receptors with high CK, 25 nM) af-
finity (30) and are 5-HT, antagonists (122) (Ta-
ble 8.6). A plausible mechanism of action for
these drugs is that they enhance noradrenergic
and serotonergic function by their ability to
block presynaptic 5-HT receptors that normally (33) Ritanserin
exert an inhibitory effect on monoamine release
in the brain, or by blockade of postsynaptic example of a 5-HT, antagonist. In humans,
5-HT, receptors (see below). Mianserin ritanserin has been found to be as effective as
("Tolvan") (27) is a nonselective 5-HT, and amitriptyline (I), and superior to trazodone
(241, as an antidepressant (126). The SSRI flu-
oxetine (9) is metabolized to norfluoxetine
(34). (-1-Norfluoxetine retains antidepres-

(27) Mianserin

5-HT, antagonist with antidepressant activity sant activity and displays only slightly lower
(123);it binds with high affinity (Ki < 10 nM) at affinity for 5-HT,, receptors than it displays
5-HT, receptors (124). Hence, trazodone (24), for the 5-HT transporter (127). Results from
nefazodone (16), and mianserin (27) represent an animal behavioral model predictive of anti-
atypical antidepressants that have in common a depressant activity (the forced swim test) sug-
high a i t y for 5-HT,,receptors and 5-HT2an- gest that compounds that activate 5-HT,, re-
tagonist action. It might be noted that certain ceptors have antidepressant-like profiles
tricyclic antidepressants also bind at 5-HT, re- (128). m-Chlorophenylpiperazine (mCPP; (28),
ceptors; imipramine (111, desipramine (61,nor- which has significant affinity as an agonist at
triptyline (17), and maprotiline (13), for exarn- 5-HT,, receptors, was among the compounds
ple, bind with submicromolar Ki values (124) that were positive in this test. Because mCPP
(Table 8.6). is an important and long-lasting metabolite of
5-HT receptors are upregulated in depres- both trazodone (24) and nefazodone (16), it
sion. Hence, agents that downregulate 5-HT may also contribute to their antidepressant
receptors might be of benefit in the treatment profiles.
of this disorder. According to receptor adapta-
tion theory, neurotransmitter antagonists 3.2.3 5-HT,, Receptors. 5-HT,, receptors
should upregulate neurotransmitter recep- have been implicated as playing roles both in
tors. However, paradoxically, 5-HT2 antago- depression and in anxiety (129). Postsynaptic
nists generally downregulate 5-HT, receptors 5-HT,, (partial) agonist effects may be more
Antidepressants

important for antidepressant action, whereas studies. These agents are full agonists at pre-
agonist effects at presynaptic 5-HT,, recep- synaptic 5-HT,, receptors, but partial ago-
tors may be more important for antianxiety nists at postsynaptic 5-HT,, receptors (126).
activity (130-132). Furthermore, postsynap- An alternative approach is to develop postsyn-
tic 5-HT,, receptors have been shown to be aptic 5-HT,, agonists with greater efficacy
hypersensitive in depressed patients, whereas than that of those currently available.
presynaptic receptors are hyposensitive (133). Flesinoxan (38),an example of such an agent,
Also, electroconvulsive therapy has been dem- is currently in clinical trials. A newer agent of
onstrated to upregulate cortical 5-HT,, recep- this type is exemplified by (39) (1391, which
tors (134). binds at 5-HT,, receptors with high aMinity
Certain long-chain arylpiperazines (LCAPs) (Ki = 1 nM).
(135) have been demonstrated to possess both A problem associated with many antide-
anxiolytic and antidepressant actions. For ex- pressants is their delayed onset of action.
ample, the anxiolytic agents buspirone (351, Agents typically require 1-3 or more weeks
gepirone (36) (136),and ipsapirone (37) (137) before effects are realized. It has been hypoth-
showed antidepressant activity in clinical esized that the delay might be related, in part,
to the initial elevation in synaptic 5-HT levels,
which reduces the firing of serotonergic neu-
rons by activating autoreceptors, mainly of
the 5-HT,, subtype (139). During treatment
with antidepressants these autoreceptors are
desensitized and proper firing of 5-HT neu-
rons is restored; many believe this to be one of
the key changes elicited by antidepressant
(35) Buspirone
drugs of many different categories. 5-HT,, se-
rotonin receptors are found both presynapti-
cally and postsynaptically. Agents that behave
as antagonists at presynaptic 5-HT,, recep-
tors ( i . . , somatodentritic autoreceptors)
could, in theory, shorten the time of onset of
those antidepressants that act by increasing
synaptic levels of serotonin. In animal studies
the combination of acute treatment with an
(36) Gepirone SSRI together with a 5-HT,, antagonist led to
a larger increase in 5-HT release, as predicted
(140). Although no 5-HT,, antagonists are
available for human use, the beta-blocker pin-
do101 has appreciable affinity as an antagonist
at 5-HT,, receptors (K, value of approxi-
mately 10 nM). To date, the results of 15 pla-
cebo-controlled clinical trials, involving some
(37) Ipsapirone 800 patients, using pindolol in treating de-

(38) Flesinoxan
3 Physiology and Pharmacology

pression have been published (141, 142). Pin- tagonist with high affinity for the 5-HT trans-
do101 significantly accelerated the onset of ac- porter (K, = 12 nM)(1491, whereas compound
tion of SSRIs in five out of seven trials (42) displays somewhat higher affinity for
designed to test this concept. The combination
of pindolol with fluoxetine (9), for example,
reduced the median period required to obtain
a clinical response (50% reduction in baseline
score) from 29 to 19 days (142). A similar ac-
celeration of rate of onset has been shown with
a combination of pindolol and paroxetine (181,
and citalopram (4) (143-146 and references
therein). A role for P-adrenergic involvement
in these actions of pindolol has been ruled out
(147).

3.2.4 Mixed-Function Ligands. Recently,


both sites (5-HTlAIC5, = 4.6 nM; SERT ICE,
attempts have been made to incorporate mul- = 1.7 nM)(150).
tiple actions into the same molecule. For ex- Compounds combining high affinity both
ample, compound (40) (YM-35992) is a 5-HT, for 5-HT,, and 5-HT, receptors would be po- .
tentially useful for the treatment of depres-
sion. RK-153 (43) (151, 152) and adatanserin
(44) (153) are examples of such agents. RK-
153 (43) binds at 5-HT,, and 5-HT,, recep-
tors with high affinity (Ki values of 0.4 and 34

antagonist (IC,, = 86 nM) and a 5-HT re-


uptake inhibitor (SERT IC,, = 20 nM)(148).
Compound (41) is a 5-HT,, (Ki = 2.3 nM)an-

(44) Adatanserin
Antidepressants

nM,respectively)and displays reduced aMinity pressant perspective are the 5-HT, receptors.
for a,-adrenergic receptors (Ki => 1000 nM) 5-HT, receptors are known to be involved in
but high affinity for dopamine D2 receptors the release of several neurotransmitters, in-
(Ki= 2.7 nM), whereas adatanserin (44) binds cluding norepinephrine, serotonin, and dopa-
at 5-HT,, and 5-HT, receptors with compa- mine, and there are preclinical data indicating
rable affmity (Kivalues of 1 and 73 nM,respec- 5-HT, antagonists might play a role in anxiety
tively), but displays substantially reduced af- and, to a lesser extent, in depression (reviewed
finity for dopamine D2 receptors (Ki = 166 in ref. 158). It might be noted that mirtazepine
nM).Both agents are 5-HT,, partial agonists, (14), although its antidepressant properties
and adatanserin (44) has been demonstrated have been attributed primarily to its antago-
to be a 5-HT,, antagonist and is being devel- nist action at a,-adrenergic receptors and
oped as an antidepressant (153). 5-HT, serotonin receptors, is also a 5-HTIA
agonist and a 5-HT, antagonist (159).
3.2.5 Other 5-HT Receptors. Although so- Two of the most recently discovered popu-
matodendritic serotonin receptors are of the
-
lations of 5-HT receptors are the 5-HT, and
5-HT,, type, terminal autoreceptors are of 5-HT, receptors. Of interest is that certain
the 5-HTIDllBtype. These latter receptors are typical and atypical antidepressants, as well as
involved in the modulation of serotonin re- typical and atypical antipsychotic agents, bind
lease, and blockade of these receptors has been at both populations of receptors (160, 161). A
proposed as a possible means of developing role for either receptor population in the ac-
novel antidepressants or of enhancing the ef- tions of these agents has yet to be firmly estab-
fects of SSRIs (reviewed in Refs. 154, 155). lished, but the nanomolar affinity of the
SSRIs require 1 or more weeks before their agents for these receptors has heightened in-
antidepressant actions are evident; this delay terest in them.
corresponds to the time required to desensi-
3.3 Alpha Adrenergic Receptors
tize 5-HT,, and 5-HTlDlIBreceptors (156).
Hence, a 5-HT,,,, autoreceptor antagonist Although several antidepressant drugs have
might hasten the onset of effects of an SSRI by weak affbity for alpha-adrenergic receptors
mimicking its desensitizing action. Compound (Table 8.6) only one compound is thought to
(45), a 5-HT,,,, antagonist, has been demon- owe its antidepressant activity to such an in-
strated to augment citalopram-induced effects teraction. This is mirtazepine (14), which has
in rat ventral hippocampus and provides some nanomolar affinity as an a,-adrenergic recep-
support for this concept (157). tor antagonist (162, 163). The a,-adrenergic
A population of receptors that has yet to re- receptors are located presynaptically on both
ceive extensive investigation from an antide- noradrenergic and serotonergic nerve endings
3 Physiology and Pharmacology

and cell bodies, and exert an inhibitory effect The first-generation MA0 inhibitors
on monoamine neuronal firing and mono- phenelzine (19)and tranylcypromine (23) act .
mine release. Administration of mirtazepine as substrates for MAO-A and MAO-B but are
to animals has been reported to increase the converted by the enzyme to highly reactive in-
spontaneous rate of firing of noradrenergic termediates that then react irreversibly with
neurons in rat locus coeruleus, and serotonin the enzyme to cause an irreversible inhibition,
neurons in the raphe nucleus (164), and to of activity. Recovery of MA0 activity after ex-
increase levels of 5-HT release in hippocam- posure to these MA0 inhibitors requires the
pus (165),although this was not confirmed in synthesis of new enzyme protein, a process .
another publication (166). Clinical trials have that takes some weeks to completely restore
shown that mirtazepine is equivalent to ami- activity (173, 174). A clinical antidepressant
triptyline and other tricyclics in antidepres- response is associated with an inhibition of
sant efficacy (167). Some of these studies platelet MA0 activity of approximately 80%,
showed a clinical improvement within the first and measurement of platelet MA0 activity
week of treatment (167).Mianserin (27) is an- can be used to monitor treatment dose re-
other agent whose effects, at least in part, gimes (175).
might involve a,-adrenergic antagonism A new series of MA0 inhibitors are selec-
(168). Many adrenergic agents possess an im- tive for MAO-A and cause reversible inhibi-
idazoline ring. Imidazolines have been found tion of the enzyme, thus leaving MAO-B in the
to bind at nonadrenergic imidazoline binding liver intact to detoxify dietary amines, and
sites and this has led to speculation that such showing rapid recovery of enzyme activity af-
sites might play a role in depression (see Sec- ter discontinuation of drug treatment. The
tion 5.4). only drug of this type so far available for hu-
man use is moclobemide (15).
3.4 Monoamine Oxidase 3.5 Other Proposed Mechanisms of Action
Monoamine oxidase (MAO) is an enzyme - lo- Although many lines of evidence point to a
cated in the outer mitochondria1 membrane. common mode of action of antidepressant
As its name implies, it catalyzes the oxidative drugs by an enhanced release of the mono-
deamination of a varietv" of monoamines. The m i n e norepinephrine and serotonin in the'
enzyme is particularly abundant in liver, brain, many questions remain unanswered. If
where it serves to detoxify a variety of amines the monoamines themselves were responsible
that are absorbed from the diet; these include for regulating mood, why do depressed pa-
the vasoactive monoamines tyramine, octo- tients not feel an improvement immediately
pamine, phenylethanolamine, and phenyleth- after receiving the first dose of antidepres-
ylamine. The enzyme is also present in mono- sant? The fact that the clinical response is
mine-containing neurons, where it serves to delayed by several weeks suggests that the im-
regulate levels of cytoplasmic monoamine mediate effects of the drugs on monoaminer-
neurotransmitters (169). There are two forms gic mechanism in turn trigger longer-term
of MAO: MAO-A and MAO-B (170). Both are changes in the brain, probably involving alter-
present in the liver, and in most monoaminer- ations in gene expression. One possibility al-
gic neurons, although MAO-A is predominant ready discussed is that the early effects of in-
in norepinephrine and dopamine-containing creased monoamine release are counteracted
neurons, and MAO-B in serotoninergic cells. by brain mechanisms that downregulate
Both forms of the enzyme have a wide and monoamine release in response to the imme-
overlapping range of substrates, but MAO-A diate effects of the drugs. Thus, receptor de-
shows some preference for the catecholamines sensitization is required before the full effect
norepinephrine and epinephrine, and sero- of the antidepressants on monoamine release
tonin, and MAO-B for tyramine, phenyl- can be seen.
ethylamine, phenylethanolamine, and benzyl- However, there are other alternative expla-
mine. - Both enzymes metabolize dopamine nations for the delayed clinical response.
and tryptamine (169-171). There have been many studies of the neuro-
Antidepressants

chemical changes caused in animal brain by mechanisms could provide a novel approach to
chronic treatment with antidepressants. One antidepressant drug discovery in the future
of the changes elicited by many antidepres- (186).
sants is a downregulation in the expression of Another possibly important change in re-
P-adrenergic receptors (176-178). This is of ceptor sensitivity associated with chronic
interest because one of the most consistent treatment with antidepressants concerns re-
findings in depressed patients has been that ceptors for glucocorticoids. Antidepressant
P-adrenergic receptors are upregulated in pe- treatment produces an improvement in the
ripheral lymphocytes and in the brains of sui- function of the hypothalamic-pituitary axis, in
cide victims (179). It was proposed that the which several neuroendocine responses are
downregulation of P-receptors represents a blunted in depressed patients (187, 188).
marker of antidepressant efficacy (176, 177).
The validity of this concept was soon chal-
lenged, however, because it was found that the 4 HISTORY
newer SSRIs did not consistently downregu-
late P-adrenergic receptors, and citalopram
4.1 Discovery of the First Antidepressants
(4)actually caused an increase (146). p-Adren-
ergic receptors are coupled to cyclic AMP for- Before 1954, except for the use of electrocon-
mation but, although the receptors may be vulsive therapy, there were no effective treat-
downregulated by antidepressant drugs, other ments for depression. The two major classes of
components of cellular signaling that are reg- antidepressants, the monoamine oxidase in-
ulated by cyclic AMP are upregulated, notably hibitors and inhibitors of monoamine trans-
the cyclic AMP response element protein port, were discovered by accident in the 1950s.
(CREB), a prominent transcription factor in The drug iproniazid used for the treatment of
the brain (180).Another way of increasing lev- tuberculosis was found to have a mood-elevat-
els of cyclic AMP is to inhibit its degradation ing property (189) and clinical studies by
by phosphodiesterases. George Crane and Nathan Kline in the United
The compound rolipram is a phosphodies- States showed it to be effective in treating ma-
terase inhibitor and has been found to have jor depression (190, 191). Its actions were
clinical antidepressant activity (181). Al- traced to its ability to inhibit the monoamine-
though rolipram is not well tolerated because degrading enzyme MA0 (192). Although this
it causes severe nausea. it is ~ossiblethat in- and other subsequently developed MA0 inhib-
hibitors with more selectivity k r phosphodies- itors proved highly effective in the treatment
terase subtypes could be of future interest. In of depression, the possible dangers associated
animals chronic treatment with SSRIs leads to with their use led to their being largely re-
increased expression of the PDE4A and placed by the safer inhibitors of monoamine
PDE4B subtypes (183). Among the many transport. The first examples of the latter
genes that may be regulated by CREB are drugs to be widely used were imipramine (11)
those encoding neurotrophic factors (183). An in Europe and amitriptyline (1)in the United
important new finding is that chronic treat- States. Imipramine was synthesized originally
ment with antidepressants leads to increased by the Swiss company Geigy as a chlorproma-
expression of the neurotrophic factor BDNF zine-like molecule with potential as an anti-
(brain-derived neurotrophic factor) in rat hip- psychotic drug. The Swiss psychiatrist Roland
pocampus, and this may underlie the recent Kuhn, however, found it to be an effective an-
finding that chronic antidepressant treatment tidepressant (193, 194). On the other side of
causes a proliferation of progenitor cells in the the Atlantic, Merck first made amitriptyline
rat hippocampus (180, 184, 185). Neuroimag- also as a chlorpromazine-like molecule. It was
ing and postmortem histological studies have shown subsequently to be an antidepressant
reported reductions in neuronal and glial den- by Frank Ayd (195). For a detailed and enter-
sities in dorsolateral prefrontal cortex in pa- taining account of the history of the discovery
tients with mood disorders (185a,b). Com- of antidepressant drugs see Healy's The Anti-
pounds that targeted neurotrophic factor depressant Era (1997) (196).
4 History

4.2 Case History: Fluoxetine (Prozac) zimelidine as an antidepressant in 1980 (199).


Zimelidine was initially successful in Europe
-
One of the earliest theories of how antide~res-
and was to be marketed in the United States
sant drugs work was that they caused an in-
by Merck, who had completed extensive clini- -
creased availability of serotonin in the brain.
cal trials and submitted the results to the FDA
This was supported by data from the British
in 1983, although the drug was withdrawn,
psychiatrist Alec Coppen, that combining an
shortly thereafter following reports of drug-
MA0 inhibitor with the serotonin precursor
induced Guillain-Bar6 syndrome (peripheral
tryptophan was a more effective antidepres-
nerve damage) in Europe. Carlsson also took -
sant treatment than the MA0 inhibitor alone
the SSRI idea to the Danish company Lund-
(197),a result repeated by the Dutch psychia-
beck, which subsequently launched the highly
trist Herman van Praag. The serotonin hy-
selective and potent compound citalopram (4)
pothesis was largely lost sight of, however, af-
in 1986. Meanwhile at Ciba-Geigy in Switzer-
ter the discovery that imipramine (11)and
land, Peter Waldmeier and colleagues had
related tricyclic antidepressants were potent
been working on the serotonin idea since the
inhibitors of norepinephrine uptake (11)and
early 1970s and discovered several potent
the idea that norepinephrine was the key
SSRIs, but were unable to persuade the com-
player in antidepressant drug actions domi-
pany to develop any of them further (95).
nated thinking, particularly in the United
David Wong and colleagues at Eli-Lilly were
States (198). The norepinephrine-selective
more fortunate, but only after a long delay (96,
uptake inhibitor desipramine (6) from Merck
97). They had also been stimulated by Carls-
proved highly successful, and in Europe the
son's ideas and started screening for SSRIs in
Swiss company Ciba launched its norepineph-
1972. They discovered fluoxetine (9) and re-
rine-selective uptake inhibitor maprotiline
ported its biochemical profile in 1974 (96), but
(13) (95). Lilly was not at all clear what the drug would
Nevertheless, the "mixed" norepinephrine1
be used for. At one of the meetings of clinical
serotonin uptake inhibitors imipramine and
experts that the company convened, Alec Cop-
amitriptyline continued to be very popular,
pen suggested that it might be tested in de-
particularly in Europe. In Sweden, the neuro-
pression, only to be told that this was defi-
pharmacologist Arvid Carlsson, originally a
nitely not the target the company had in mind!'
champion of the norepinephrine hypothesis,
(196). It was only in the 1980s, when the anti-
became interested in the idea of developing
depressant profile of zimelidine was reported,
selective inhibitors of serotonin uptake. Hav-
that Lilly began to speed up the development
ing failed to interest any major pharmaceuti-
of fluoxetine (9), and it was 1985 until the first
cal company in this idea, he collaborated with
positive clinical trial results in depression
the chemist Hans Corrodi at the Swedish com-
were reported (97), followed by registration in
pany Astra. They produced the first SSRI,
the United States in 1987.
zimelidine (46), which was more potent than
Several other SSRIs were registered: flu-
voxamine (10)in 1983, sertraline (22) in 1990,
and paroxetine (18)in 1991. It was fluoxetine
(9), however, that captured the public imagi-
nation and became the single most important
psychopharmaceutical product of the late
twentieth century. Physicians liked it because
it was safe in overdose, the dosage regime was
(46) Zimelidine simple (not requiring any gradual titration)
and the side-effect profile was an improve-
clomipramine (51, the best SSRI then avail- ment over that of the earlier tricyclics. Prozac
able, and unlike clomipramine zimelidine did was on the cover of Time and Newsweek and it
not break down in the body to form a norepi- gained a number of additional medical uses
nephrine-selective active metabolite. Astra re- (Table 8.4). Some people also used it for non-
ported the first positive clinical trials with medical purposes, just to make them feel bet-
Antidepressants

ter, or to enjoy the opera more! A whole liter- 5-HT and NE reuptake, whereas the second-
ature was spawned around the drug, most ary amines are typically more selective at in-
famously in Peter Krmer's book, Listening to hibiting NE reuptake. In vivo, however, one of
Prozac (200). A new market was even found the major routes of metabolism of the tertiary
for the drug in the treatment of depression in amines is by demethylation to a secondary
companion animals. By the turn of the cen- amine.
tury, sales of Prozac were earning Lilly in ex- Doxepine (8) is related in structure to the
cess of $2 billion annually. antipsychotic agent pinoxepin (47). However,

5 STRUCTURE-ACTIVITY RELATIONSHIP
AND METABOLISM

5.1 Reuptake Inhibitors


The SAR of the tricyclic antidepressants has
been studied for over 40 years and numerous
reviews are readily available on these and re-
lated agents (168, 201-203). Only the high-
lights of some of the pertinent SAR studies
are presented here. Tricyclic antidepressants
have in common a tricyclic ring structure con-
sisting of a six-membered or, more commonly, (47) Pinoxepin
a seven-membered ring flanked, typically, by
two benzene rings. The exact composition and because doxepine lacks the N-hydroxyethyl
orientation of the central ring is relatively in- group of pinoxepin (a functionality known to
consequential (see Fig. 8.1). Tricyclic antipsy- enhance antipsychotic activity) and the elec-
chotics and tricyclic antidepressants appear to tron-withdrawing chloro group, it behaves
exist on a structural continuum. For example, more as an antidepressant than as an antipsy-
introduction of an electron-withdrawing group chotic agent.
to the aromatic ring typically enhances the an- Because the presence of a ring nitrogen
tipsychotic profile of the tricyclic agent. Re- atom or an sp2-hybridized carbon atom in the
placement of a ring nitrogen atom (as in the central ring of these tricyclic structures is not
phenothiazines) or an sp2-hybridized carbon a requirement for antidepressant activity,
atom (as with the thioxanthenes) to which the protriptyline (20) retains antidepressant ac-
aminopropyl substituent is attached, with an tion. Certain tricyclic antidepressants with a
sp3-hybrized carbon atom detracts from the six-membered central ring have been shown to
antipsychotic profile but can enhance the an- possess an antidepressant profile. If the cen-
tidepressant profde of an agent. That is, a ring tral ring is capable of aromatization, by oxida-
nitrogen atom or an sp2-hybridized carbon tion for example, to afford a completely planar
atom is not required at this position for anti- structure, the resulting compound is inactive.
depressant activity; for example, compare the If aromatization can be prevented, however,
structures of nortriptyline (17)and protripty- antidepressant activity is retained. Maproti-
line (20). line (13) is an example of a tricyclic agent
The tricyclic system is generally attached where aromatization is prevented by introduc-
to a basic terminal amine by a three-atom tion of an alkyl bridge. Aromatization is pre-
chain. The chain can be shortened to two at- vented according to Bredt's rule. Because it is
oms with retention of antidepressant activity a secondary amine, maprotiline is fairly selec-
and a decrease in antipsychotic character. The tive for inhibition of NE reuptake. Note that
terminal amine is typically a secondary or ter- maprotiline does not possess either a nitrogen
tiary amine, and the amine can be part of an atom or sp2-hybridized carbon atom in the
alicyclic ring. In general, tertiary amines are central ring. Although originally considered as
more nonselective with respect to inhibition of a member of a new class of antidepressants--
5 Structure-Activity Relationship and Metabolism

the "tetracyclic antidepressantsn-maproti-


line is now classified as a TCA.
Amoxepine is a structurally interesting
agent because of the introduction of an elec-
tron-withdrawing group. As already men-
tioned, the orientation of the tricyclic system
does not seem crucial to antidepressant (or an-
tipsychotic) activity. Loxapine (481, for exam-
(9) Fluoxetine X = -CF3, Y = -H
(49) Nisoxetine X = -H, Y = -OCH3

Newer norepinephrine-selective reuptake


inhibitors currently in clinical trials include
duloxetine (50) and milnacipran (51). An an-
alog of a bupropion metabolite, (52), has been
shown to act as a norepinephrine-selective re-
uptake inhibitor (204).

(48) Loxapine

ple, is an antipsychotic agent. Arnoxepine is


the N-desmethyl analog of loxapine. Because
secondary amines show a greater antidepres-
sant profile than that of tertiary amines,
amoxepine possesses greater antidepressant (50) Duloxetine
character than that of loxapine. However,
amoxepine also possesses some antipsychotic
character attributed to the -presence of the
electron-withdrawing chloro group.
The tricyclic antidepressants typically un-
dergo multiple routes of metabolism. The
most common, depending on the particular
ring system, are N-demethylation of the ter-
minal amine, aromatic hydroxylation, and
benzylic or "bridge" hydroxylation (see Table
8.7). In general, with the exception of the sec-
ondary amine metabolites of N,N-dimethyl-
amino TCAs, the metabolites are usually less (51) Milnacipran
active or inactive as antidepressants.
Remarkably little has been published on
the structure-activity relationships of re-
uptake inhibitors. Close inspection of these in-
hibitors reveals that manv " of them are related

in structure to ring-opened tricyclic antide-


pressants. Indeed, small structural changes
can result in shifts in selectivity. For example,
fluoxetine (9)is a serotonin-selective reuptake
inhibitor, whereas nisoxetine (49) is a norepi-
nephrine-selective reuptake inhibitor.
Antidepressants

Sertraline and fluoxetine undergo meta- tonin, and most other receptors, brofaromine,
bolic demethylation. Unlike the metabolites of interestingly, binds at the 5-HT and NE trans-
most other SSRIs, the desmethyl metabolite of porters with modest affinity (IC,, values of
fluoxetine, norfluoxetine (341, retains the abil- 150 and 500 nM) (207). For comparison, the
ity to inhibit serotonin reuptake (205). Hence, half-life for disappearance of MAO-A inhibi-
fluoxetine takes longer to achieve steady-state tion in brain is phenelzine (19), 11 days; tra-
levels, and it retains activity after metabolism. nylcypromine (23)' 2.5 days; brofaromine
The half-life of fluoxetine is approximately 1 (54), 12 h; and moclobemide (15)' 6 h (re-
day, but elimination of norfluoxetine is pro- viewed in ref. 207). Another advantage of RI-
longed (7-15 days) (205). In addition to its ac- MAS over the older MA0 inhibitors is that a
tions as an SSRI, norfluoxetine also binds at shorter washout time is required; whereas the
5-HT, receptors (127). older MA0 inhibitors typically require about 2
weeks for washout, the washout period for mo-
5.2 Monoamine Oxidase Inhibitors clobemide is about 48 h (208). This is an im-
portant consideration when switching antide-
Because of undesirable side effects associated
pressant therapies from a MA0 inhibitor to,
with monoamine oxidase inhibitor therapy
for example, a TCA or SSRI.
(see section 2.3.2), pharmaceutical companies
Moclobemide undergoes multiple routes of
nearly abandoned research on new analogs in
metabolism with formation of a lactam (55)
the 1960s. The early MA0 inhibitors were
nonselective and irreversible. Today, efforts
toward the development of monoamine oxi-
dase inhibitors are focused on selective
MAO-A or MAO-B inhibitors. Selective
MAO-B inhibitors are being examined in the
treatment of, for example, schizophrenia, Alz-
heimer's disease, and Parkinson's disease. (54) Brofaromine
MAO-B inhibitors might be effective in the
treatment of depression, but relatively little
work has been done in this area. Selegiline
(53) or (-)-deprenyl, a selective irreversible

(55) Moclobemide lactam

(53) Selegiline being a major metabolite. Other metabolites


include 3-hydroxymoclobemide, meclobemide
N-oxide, and compounds (56) and (57) (209).
MAO-B inhibitor, is one of the few agents that
Lactam (55) is devoid of activity as a MA0
has been examined in this regard and the clin-
inhibitor, whereas the primary amine (Ro 16-
ical results are mixed (reviewed in ref. 206).
Of greater application to the treatment of
depression are the reversible inhibitors of
monoamine oxidase-A or RIMAs. Brofaromine
(54) is a "tight-binding" but reversible inhib-
itor of MAO-A with approximately 100-fold se-
lectivity vs. MAO-B. Moclobemide (15) is a
RIMA with about five- to 10-fold selectivity for
MAO-A. Although both agents display micro-
molar (or lower) affinity for adrenergic, sero-
5 Structure-Activity Relationship and Metabolism

6491,57) and several other minor metabolites


are inhibitors of MAO-B (207). Analogs of the
latter compound have been developed, includ-
ingthe selective MAO-B inhibitor Ro 19-6327
(58)and the selective MAO-A inhibitor Ro 41-
1049 (59) (203).
Newer RIMASinclude the brofaromine an-
alog sercloramine (60) (which, incidentally, (61) Befloxatone
.

whereas duration of action decreases in the


order brofaromine > BW 1370U87 > be-
floxatone > moclobemide (207).

5.3 Serotonergic Agents


The two populations of 5-HT receptors that
have been definitely linked to depression are
the 5-HT, and the 5-HT,, receptors. Numer-
ous 5-HT, antagonists are available and be-
long to a multitude of chemical classes; struc-
ture-activity relationships are well beyond the
scope of this chapter and several reviews are
available (e.g., 151,210,211). 5-HT, receptors
consist of three families: 5-HT,,, 5-HT,,, and
5-HT,,. An important issue at this time is
which one (or more) of these subpopulations is
most involved in depression. This question re-
mains to be answered. Another issue is that
5-HT,, receptors have been linked to cardiac
valvulopathy (212). Hence, future develop-
ment of 5-HT, ligands might wish to avoid
agents with high affinity for 5-HT,, receptors.
5-HT,, receptor involvement is compli-
(60) Sercloramine cated by the issue of functional activity; what
is more important, agonist actions, partial ag-
also behaves as a 5-HT reuptake inhibitor), onist actions, or antagonist actions? Evidence
befloxatone (61), and BW 1370U87 (62) (168). suggests that presynaptic 5-HT,, antagonism
The latter two agents are somewhat more and postsynaptic 5-HT,, agonism might be
MOA-A selective than moclobemide and the the most desirable features for agents to tar-
relative order of potency is befloxatone > bro- get the treatment of depression. The struc-
farornine > moclobemide > BW 1370U87, ture-activity relationships of 5-HT,, agents
Region of
Figure 8.5. General struc- bulk
tural features of long-chain tolerance
arylpiperazines (LCAPs).
(Adopted from Refs. 135 and Aryl
214.) group

have been reviewed (120, 151,213). Of partic-


ular interest are the arylpiperazines and,
more specifically, the long-chain arylpipera-
zines (LCAPs) (Fig. 8.5). Simple arylpipera-
zines, those bearing only a small or no N,-
substituent, bind with modest affinity at
5-HT,,receptors and display little to no selec-
tivity, whereas the LCAPs, arylpiperazines
with elaborated N, substituents, bind with
higher affinity at 5-HT,, receptors and can
rl;onlo~r .nnn, 'derable selectivity (135, 151).
uluprcrJ Ibvuulu
The aryl pc~rtionof the LCAPs (Fig.8.5) can
be widely va~ried,and the unbranched or
branched spa(:er can be of two to five (or more,
depending on the nature of the terminus) at-
oms in length. The terminus is usually an ar-
omatic, heterc)aromatic, imide, or amide func-
tion, and is associated with a region of
considerable 1mlk tolerance (135). Given this
pharmacophore model, hundreds, if not thou-
sands, of possible analogs can be envisioned.
Many have been synthesized and evaluated
BMY-7378 (63) and NAN-190 (64) were tl
(e.g., reviewed in Ref. 151). Advantage has
been taken of the region of bulk tolerance to first examples of LCAPs with antagonist a
develop some very bulky analogs (214). In- tions (i.e., they are very low efficacy parti;
spection of the structures of buspirone (35), agonists); and WAY-100,635 (65) was the fir
gepirone (361, and ipsapirone (37) shows that example of a 5-HT,, "silent antagonist" (ri
they meet these criteria. Alteration of the viewed in Ref. 214).
substituents modifies functional activity, but Structural modification, particularly wit
this has not yet been investigated in a system- respect to the spacer and terminus group
atic manner. For example, buspirone, gepi- also influences selectivity; LCAPs show vay
rone, and ipsapirone are partial agonists; ing degrees of affinity toward several receptc
populations, notably, 5-HT,,, 5-HT,, dopi
mine D2, and a-adrenergic receptors (13!
151, 214). This has led to attempts to develo
agents selective for each of these receptor pol
ulations by the appropriate structural modif
cation. RK-153 (43) and adatanserin (44) ar
just two examples of such agents. Continue
exploration of LCAPs should prove bountif~
for the development of agents with the desire
mix of selectivity and functional activity.
5 Structure-Activity Relationship and Metabolism

5.4 Other Agents pound in plasma and cereobrospinal fluid at


steady state, and high levels of these metabo-
Several antidepressants work via mechanisms lites were suggested to be associated with poor
that are not yet fully understood. Perhaps the clinical outcome resulting from toxic effects -
best example of this is bupropion (3). Al- possibly involving the dopaminergic system
though the mechanism of action of bupropion (219). In contrast, bupropion metabolites
is most commonly attributed to inhibition of showed various degrees of activity in several
dopamine reuptake, its actions are diverse animal models of antidepressant activity
(215).In addition, one or more bupropion me- (220). However, the routes of metabolism in
tabolites also seem to be active. In humans, rodents and dogs are known to be somewhat
bupropion is metabolized to two amino alco- different from those in humans (221-222); in
hols, the racemic threo amino alcohol (R$- fact, routes of metabolism in mice differ from
threo; 66) and the racemic erythro amino al- those in rats (223). Nevertheless, at least hy-
cohol (R,S-erythro; 67), threohydroxybupro- droxybupropion is considered to be an active
pion and erythrohydroxybupropion, respec- metabolite of bupropion (223). Both threohy-
tively; and a morpholinol, hydroxybupropion droxybupropion (66) and hydroxybupropion
(68; BW 306U). The levels and half-lives of (68)inhibit norepinephrine reuptake with po-
tencies comparable to that of bupropion but
are 10 to 25 times less potent than bupropion
with respect to inhibition of dopamine re-
uptake (215).
Although there is evidence for dopaminer-
gic involvement in the antidepressant actions
of bupropion as determined by measuring, for
example, extracellular levels of dopamine in
the striatum and nucleus accumbens in rats
(224), or by examining the increase in dopa-
mine release in striatal synaptosomes upon
treatment with bupropion (2251, alternative
mechanisms have been proposed. Bupropion.
and its metabolites produced noradrenergic-
like effects on the firing rates of noradrenergic
neurons located in the locus coeruleus of rat
(226) and it has been suggested that bupro-
pion might work through some yet unidenti-
fied adrenergic mechanism (reviewed in ref.
215). More recently, it has been shown that
sustained administration of bupropion by the
use of minipumps decreases the firing rate of
norepinephrine neurons arising from in-
creased activation of somatodendritic a,-adre-
noceptors, suggesting that the actions of
bupropion are mainly attributable to enhance-
ment of norepinephrine release, not to re-
uptake inhibition (227). This latter study also
(68) Hydroxybupropion showed that bupropion can act on the seroto-
nergic system.
these metabolites have been quantitated in One of the latest theories to account for the
healthy volunteers (216-218). Hydroxybupro- action of bupropion is its influence on imidaz-
pion (68) is the major metabolite in depressed oline I, receptors. Agmatine (decarboxylated
patients (219). Interestingly, all three metab- arginine) may be an endogenous ligand for I,
olites predominated over the parent com- sites. Evidence indicates that plasma agma-
Antidepressants

tine levels are significantly elevated in de- (235,236) and Pierre Fabre [milnacipran (51)l
pressed patients relative to those in healthy (237,238). The Danish company NeuroSearch
controls and that treatment with bupropion has taken one step further and is developing a
normalized these levels (228, 229 and refer- triple inhibitor of norepinephrine/serotonin
ences therein). Peripheral norepinephrine and dopamine uptake with GSK (NS2389).
neurons possess nonadrenergic imidazoline Another idea is to separate the individual en-
binding sites that mediate inhibitory effects antiomers of existing racemic antidepressant
on the release of norepinephrine (230). Plate- drugs, in the hope that the individual isomers
let I, receptors are also downregulated after may show some improvement over the parent
antidepressant treatment; this has led to con- drug. A number of existing antidepressants
jecture that elevation in brain imidazoline re- are racemates, which include fluoxetine (9),
ceptors might lead to greater inhibition of nor- citalopram (41, mirtazepine (14), mianserin
epinephrine release (229). (27) and reboxetine (21). Lundbeck appears to
Another curious agent is tianeptine (69).In have been successful in developing the active
vitro, neither tianeptine nor any of its major (S)-enantiomer of citalopram (4), escitalo-
pram, which is reported to be slightly more
efficacious and to have fewer side effects and a
faster onset of action than that of the parent
compound (239, 240). This approach will not
always succeed, however. Lilly's attempt to
develop (R)-fluoxetinefailed because the com-
pound caused small increases in cardiac QT
intervals (241).
The ability of pindolol to accelerate the on-
set of action of antidepressant drugs has
(69) Tianeptine
prompted a search for more selective antago-
nists or partial agonists acting at the 5-HT,,
metabolites has any effect on monoamine re- receptor. The compound EMD 68843, from
uptake, release, or neurotransmitter binding; Merck KgaA, combines activity as an SSRI
the biochemical effects (acute or chronic) of with a partial agonist profile at the 5-HT,,
this agent in vivo indicate enhanced serotonin receptor, and is in development as an antide-
uptake in the cortex and hippocampus (230, pressant (242,243). The compound YM-35 992
231). (40) from Yamanouchi, which combines an
Tianeptine has now been evaluated in over SSRI profile with blockade of 5-HT,, recep-
3000 patients and has been found to be at least tors, represents another variant on this theme
as effective as the TCAs (e.g., amitriptyline, (244).
imipramine, maprotiline), SSRIs (e.g., fluox- In view of the good clinical safety profile of
etine, sertraline), and mianserin (231, 232). the reversible MAO-A-selective MA0 inhibi-
tor moclobemide (15), it is worth noting that a
6 RECENT DEVELOPMENTS A N D second reversible MA0 inhibitor befloxatone
THINGS TO COME (61)is in development (245). In animal studies
a combination of befloxatone with pindolol
greatly accelerated the action of the MA0 in-
6.1 Monoaminergic Drugs
hibitor in increasing serotonergic neuron dis-
All of the existing antidepressant drugs act charge in rat brain (246), suggesting that this
through monoaminergic mechanisms, and combination may be of clinical interest.
further refinements are still possible in this
6.2 N M D A Receptor Antagonists
arena. The concept of developing dual norepi-
nephrinelserotonin uptake inhibitors, claimed Since the early 1990s evidence has accumu-
for venlafaxine, has been adopted by other lated to show that a variety of drugs that block
companies. Compounds with this profile are the glutamate receptor of the NMDA subtype
being developed by Eli-Lilly [duloxetine (50)l have antidepressant-like profiles in behavioral
6 Recent Developments and Things to Come

tests thought to predict antidepressant activ-


ity (247, 248). Chronic treatment of animals
with NMDA antagonists causes a downregula-
tion of p-adrenergic receptors, as seen with
many antidepressant drugs (249). Skolnick
and colleagues further showed that treatment
of animals with clinically active antidepres-
sants almost invariably downregulated NMDA
receptor function, by reducing the affinity of
glycine for an important modulatory site on
the receptor (250,251). It is possible that this
reflects a change in the pattern of expression
of the various different subunits of which the
NMDA receptor is composed (252). The
changes in NMDA receptor function induced
by chronic treatment with antidepressants
may be regulated by the neurotrophic factor
BDNF, whose expression is known to be up- antidepressant drugs that are not directly re-
regulated in response to antidepressant expo- lated to monoaminergic function (257). Never-
sure (see Section 3.4) (247). Unfortunately, theless, there are intimate connections be-
the NMDA antagonist drugs that are cur- tween substance P-containing pathways in
rently available are not well tolerated in hu- the brain and the monoaminergic neurons, so
mans; they cause a range of serious adverse it is possible that alterations in monoamine
effects, including psychosis (253, 254). It is function may still represent a final common
possible, however, that novel drugs that tar- pathway for the actions of NK-1 antagonists
geted particular NMDA subunit combinations (255).
could prove more benign and potentially use-
ful as antidepressants (247). 6.3.2 CRF Antagonists. Corticotrophin re-
leasing factor (CRF, or CRH) is a peptide se-
6.3 Drugs Acting at Neuropeptide Receptors creted by hypothalamic neurons to control the
release of ACTH from the anterior pituitary,
6.3.1 Substance P-NK1 Receptor Antago- but in addition, is present in a variety of neu-
nists. Substance P is a neuropeptide that is ral pathways within the brain (258). A number
widely distributed in small sensory nerve fi- of animal experiments suggest that increased
bers and in a variety of neural pathways in the release of CRF within the brain and from the
brain. During the 1990s a range of potent non- hypothalamus may represent a final common
peptide drugs were developed that act as po- pathway in mediating the effects of stress on
tent and selective antagonists at the NK1 the brain and body (258-260). CRF elicits
receptor, which recognizes substance P. Al- behavioral signs of fear and anxiety when
though these drugs were targeted initially at administered into the brain, and CRF antago-
the treatment of pain, clinical trials in this nists conversely have anxiolyticlantidepres-
indication proved disappointing (255). A sant profiles in behavioral tests (257). The
breakthrough came when a team at Merck dis- chronic administration of antidepressant
covered that NK1 antagonists were active in drugs leads to a downregulation of CRF ex-
animal behavioral models predictive of antide- pression in rat brain (261). These findings
pressant action, and undertook a successful have led to an increased interest in the poten-
clinical trial (256). The results showed the tial use of CRF antagonist drugs as agents to
NK1 antagonist MK-869 (70) to be as effective combat stress, anxiety, and depression. A va-
as the SSRI paroxetine (IS), and to be associ- riety of small molecule nonpeptide antago-
ated with fewer sexual dysfunction side ef- nists have been discovered (71 and 72) and
fects. This result triggered a high level of in- shown to possess antidepressant activity in
terest in what is potentially the first series of animal behavioral tests (259,260,262).
Antidepressants

6. K. Parfitt,Ed., Martindale. The Complete Drug


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?

:
i

f Antianxiety Agents
KEVIN S. CURRIE .

Neurogen Corporation
Branford, Connecticut

Contents
1 Introduction, 526
1.1The Anxiety Disorders, 526
2 Clinical Applications, 527
2.1 Current Medications, 527
2.1.1 Monoamine Oxidase Inhibitors and
Tricyclic Antidepressants, 528
2.1.2 Benzodiazepines, 528
2.1.3 Buspirone, 531
2.1.4 Serotonin Reuptake Inhibitors, 531
2.2 Adverse Effects, 532
2.3 Drug Metabolism, 533
2.3.1 Benzodiazepines, 533
2.3.2 Buspirone, 536
3 Physiology and Pharmacology, 537
3.1 GABA, 537
3.1.1 The GABAA/BenzodiazepineReceptor
Complex, 538
3.2 Serotonin, 541
3.2.1 5HT-1 Receptors, 542
3.2.2 5HT-2 Receptors, 542
3.2.3 5HT-3 Receptors, 543
3.2.4 GABAISerotonin Interactions, 543
3.3 Norepinephrine, 543
3.4 Neuropeptides, 544
3.4.1 Cholecystokinin, 544
3.4.2 Corticotrophin-Releasing Factor (CRF),
544
3.4.3 Neuropeptide Y, 545
3.5 Glutamate Receptors, 546
4 History, 546
4.1 Discovery of the Benzodiazepines, 546
5 Structure-Activity Relationships, 548
5.1 Animal Models of Anxiety, 548
5.2 Benzodiazepines, 549
5.2.1 1,4-Benzodiazepine-2-Ones: General
Trends, 549
Burger's Medicinal Chemistry and Drug Discovery 5.2.2 1,2-Ring-Fused 1,4-Benzodiazepines,
Sixth Edition, Volume 6: Nervous System Agents 552
Edited by Donald J. Abraham 5.2.3 Heteroaryl[el[1,4]Diazepin-2-Ones,554
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 5.2.4 Bis-Heteroaryl[a,f][1,4]Diazepines,554
Antianxiety Agents 2

5.3 Non-Benzodiazepine Ligands at the BZR, 5.3.8 Imidazoquinoxalines, 564 j(


555 5.4 5HT-1A Ligands, 566 t
5.3.1 Partial Agonism and Subtype 5.4.1 Azapirones, 566 U
Selectivity, 555 5.5 5HT-2 Ligands, 570 0
5.3.2 P-Carbolines, 557 5.6 5HT-3 Ligands, 572
5.3.3 Cyclopyrrolones, 558 h
5.7 Neuropeptide Receptor Ligands, 573
5.3.4 F'yrazoloquinolines, 560 C
5.7.1 CCK-B Receptor Antagonists, 573
5.3.5 Imidazopyridines, 561 a
5.7.2 CRF-1 Fkceptor Antagonists, 575
5.3.6 F'yridobenzimidazoles,562 C
6 Current Developments and Things to Come, 578
5.3.7 Imidazobenzodiazepines, 563 0
- Cl
P
C1
1 INTRODUCTION (2) and 25% (3). The latter figure, reported in d
the U.S. National Comorbidity Survey (NCS),
Anxiety is a normal emotion that all people exceeds the 19.3% incidence rate for mood dis- (I
experience to some extent. Indeed, anxiety is orders such as depression (3). In any given P'
an essential part of the adaptive response to year, almost 1 in 5 people will suffer from an al
stressful or threatening stimuli. An appropri- anxiety disorder.
C
P
ate amount of anxiety heightens caution and Anxiety is not a single disorder but rather a si
awareness in potentially dangerous or stress- group of discrete conditions with their own CL
ful situations, and so constitutes part of the epidemiology and symptoms, the current diag- si
"fight or flight" response. The anxious state is nostic criteria for which are set forth in the 01
somewhat difficult to define, but may be de- Diagnostic and Statistical Manual of Mental lij
scribed as a sense of unpleasant anticipation Disorders, volume four (DSM-TV) (4). The ef- (3
and excessive mental tension. Most people ac- fectiveness of various treatments also varies a1
cept occasional anxiety as an integral part of from one disorder to another (51, so an accu-
normal life, but a significant number experi- rate diagnosis is important before therapy is vc
ence anxiety that is chronic, uncontrollable, commenced. In general, a diagnosis of an anx- wj
and completely out of proportion to the gener- iety disorder requires that the anxiety is not tr
ating stimulus. In such cases anxiety has attributable to a coexisting medical condition SU
ceased to serve an adaptive purpose: it has be- or an ingested substance (e.g., caffeine). PI
come pathological, and these individuals suf- st1
1 .I The Anxiety Disorders
fer from an anxiety disorder. The psychologi- Wi
cal symptoms include overwhelming worry Generalized anxiety disorder (GAD) (6) is de- sic
and apprehension, coupled with feelings of fined as excessive anxiety and worry occurring vic
helplessness and inability to cope. These are more days than not for a period of at least 6 co
frequently accompanied by somatic symptoms months. The anxiety is accompanied by at at1
such as tachycardia, palpitations, sweating, least three of the following symptoms: rest- cu
dizziness, nausea, insomnia, irritability, and lessness, fatigue, impaired concentration, irri- Prl
impaired concentration. The impact on the pa- tability, muscle tension, and sleep distur-
tient can be debilitating. The anxiety associ- bance. The anxiety is uncontrollable and (I!
ated with certain everyday activities can re- causes clinically significant distress. GAD has fol
sult in avoidance behaviors that cause a lifetime prevalence of 6-10% (7), and the ex1
extensive disruption of daily life and serious NCS study (3) indicates a high comorbidity SY'
impairment of productivity and social func- with other psychiatric disorders, especially de- re6
tioning. Indeed, recent epidemiological stud- pression and panic disorder. bat
ies show that anxiety is second only to depres- Social phobia (SP) or social anxiety disor- at1
sion in causing significant workplace der (SAD) (8-10) is characterized by a signifi- ew
absenteeism and reduced productivity (1). cant and persistent fear of social situations stii
Anxiety disorders, as a group, are among from which embarrassment may result (e.g., drl
the most common psychiatric conditions, with public speaking), or of situations where one is syr
lifetime incidence rates ranging between 16% being observed or scrutinized by others (e.g., tra
2 Clinical Applications

job interviews). Exposure to the feared situa- rates of 9-13% in the general population have
tion induces pronounced anxiety, and the sit- been reported (16), but this can increase to
uation is either totally avoided or is endured over 70% in high risk populations (e.g.,combat -
only with extreme distress. The avoidance be- veterans, serious accident victims) (17).
haviors and associated anxiety cause signifi- Specific phobias are perhaps the most fa-
cant disruption of the patient's normal social miliar of the anxiety disorders, and are char-
and occupational functioning. SP has been acterized by a disproportionate fear of an ob- '
classified into two subtypes: public speaking ject (e.g., spider, snake) or situation (e.g.,
only and generalized social phobia (11).Re- flying, receiving an injection). When the stim-
cent epidemiological studies reveal lifetime ulus is confronted it elicits an intense anxiety -
prevalence rates around 10% (12), making so- reaction, which the sufferer recognizes to be
cial phobia one of the most common anxiety excessive but is unable to moderate. Prophy-
disorders. lactic use of anxiolytics for predictably stress-
The essential feature of panic disorder ful situations is helpful, but in the long term,
(PD) (13) is the occurrence of repeated, unex- medication is less successful than behavioral
pected panic attacks. There is a marked worry therapy in the treatment of specific phobias.
about the consequences of the attack and the Anxiety disorders are chronic conditions
possibility of having a future attack. The per- and drug therapy may need to continue for
sistent anxiety evoked by the panic attacks months or even years, particularly for the
causes major behavioral changes and intru- more intractable disorders such as OCD and
sion into normal life. Around 50% of panic dis- PTSD. Response rates are often incomplete,
order patients also suffer from agoraphobia. A and relapse upon discontinuation of treat-
lifetime prevalence of 3.5% has been estimated ment is common. For disorders with multiple
(3), and a high comorbidity with depression symptoms (e.g., PTSD) only some of the symp-
and other anxiety disorders is observed. toms are relieved. Coexistence of anxiety with
Obsessive-compulsive disorder (OCD) in- other mental disorders, particularly depres-
volves recurrent obsessions and compulsions, sion (18,19),is very common and such comor-
which are severe enough to cause marked dis- bidity is predictive of a poorer treatment out-
tress and major functional impairment. The come.
sufferer is aware that the obsessions and com-
pulsions are unreasonable, but is powerless to 2 CLINICAL APPLICATIONS
stop them. Obsessions are recurrent, un-
wanted thoughts or images, whereas compul- 2.1 Current Medications
sions are repetitive acts or rituals. The indi-
vidual typically feels compelled to perform Throughout history, humankind has used a
compulsions to alleviate the anxiety associ- variety of different agents to relieve anxiety.
ated with an obsession, or to prevent the oc- The oldest one of these is probably alcohol,
currence of some dreaded event. The lifetime which has served as an anxiolytic for thou-
prevalence of OCD is estimated at 2.3% (14). sands of years and is still widely used for the
In posttraumatic stress disorder (PTSD) self-medication of anxiety today. In the past
(15),a characteristic set of symptoms develops century, a number of CNS-depressant medica-
following exposure to an event that induces tions have been introduced, beginning with
extreme-fe& or terror (e.g., war, rape). These ethanol surrogates such as chloral hydrate.
symptoms include a persistent and intrusive The barbiturates, carbarnates (e.g., mepro-
reexperiencing of the event through flash- bamate), and bromide salts were also used, al-
backs or nightmares, and an intense distress though these agents were associated with a
at exposure to cues that are reminiscent of the significant sedative effect, as well as more se-
event. The sufferer deliberately avoids such rious drawbacks such as the risk of depen-
stimuli and may become detached, with- dency, high toxicity in overdose, and a poten-
drawn, and emotionally numb. Additional tially fatal interaction with alcohol.
symptoms include insomnia, impaired concen- At present, a number of drugs with various
tration, and unprovoked anger. Prevalence mechanisms of action are available for the
Antianxiety Agents

pharmacotherapy of anxiety disorders (20-24). 2.1.2 Benzodiazepines. In light of the un-


Those with the most widespread current clin- favorable side-effect profiles of barbiturates,
ical use are listed in Table 9.1, and their chem- MAOIs, and TCAs, the discovery of the benzo-
ical structures are shown in Figure 9.1. diazepines (BZs) in the 1950s was to revolu-
tionize the treatment of anxiety. In 1960 the
2.1.1 Monoamine Oxidase Inhibitors and first member of this class to be marketed was
Tricyclic Antidepressants. In the 1960s, stud- Librium (chlordiazepoxide), and for the next
ies on the monoamine oxidase inhibitors 40 years benzodiazepines were the mainstay
(MAOIs) iproniazid and phenelzine (25) indi- of anxiety treatment. In addition to their an-
cated that this class of drugs might be useful xiolytic properties, benzodiazepines also pos-
in the treatment of anxiety disorders. It has sess sedative, hypnotic, anticonvulsant, and
since been shown that phenelzine is particu- muscle relaxant actions, and the sedative and
larly effective in social phobia (26-28), and muscle relaxant component of benzodiazepine
may be useful in panic disorder (29), PTSD activity may augment the anxiolytic effect.
(30, 311, or OCD that is refractory to other This overlap of pharmacodynamic activities
treatments. Another class of antidepressant blurs the distinction between sedatives and
medications to show anxiolytic activity is the true anxiolytics, and the classification of a
tricyclic antidepressants (TCAs) (32). Imipra- benzodiazepine as an anxiolytic is based
mine was the first member of this class pro- heavily on pharmacokinetic considerations,
posed to have anxiolytic activity (33). The with long-and short-lived benzodiazepines be-
TCAs were the first antidepressants widely ing used as anxiolytics and hypnotics, respec-
used for panic disorder, and their efficacy is tively. In the years since their discovery, over
well established (34,351. Clomipramine is the 30 benzodiazepines have entered into clinical
most effective agent, and was long considered practice for a variety of indications. Over the
to be the gold standard in the treatment of last 40 years the benzodiazepines have been
panic disorder. Clomipramine has also shown by far the most widely prescribed anxiolytic
significant efficacy in OCD (36-39), although agents and, although this dominance is now
at higher doses than those used for depression. being challenged by alternative medications,
Clomipramine was the first agent approved for they are still extremely popular (47).
OCD and its efficacy provided the earliest in- Although the BZs show a robust anxiolytic
dications that serotonergic dysfunction may effect, many of the clinical trials were con-
play a role in this disorder. Imipramine (40) ducted before the currently used divisions be-
and amitriptyline (41,42) have been shown to tween specific anxiety disorders became avail-
be effective at alleviating some, but not all, able (4). As a result, knowledge of their
PTSD symptoms, while desimipramine was efficacy in discrete anxiety disorders is incom-
ineffective (43). Imi~ramine
* has also demon- plete. In clinical practice (48) BZs are widely
strated efficacy approaching that of the benzo- used for GAD and as prophylactics in situa-
diazepines in GAD (44, 45), although with a tional anxiety, with diazepam (1)historically
slower onset of action. TCAs have not been being the most popular choice. Others in com-
widely studied in social phobia, but one study mon use are chlordiazepoxide (2), clorazepate
was unable to differentiate imipramine from (31,lorazepam (4), alprazolam (5),oxazepam
placebo (46). (61, bromazepam (7),and clonazepam (8).Re-
There is ample clinical evidence for the ef- sponse rates are high and the onset of thera-
ficacy- of the TCAs and MAOIs in almost all of peutic effect is immediate. This is an impor-
the anxiety disorders, and these medications tant contrast to the MAOIs, TCAs, and SSRIs,
are perhaps most useful when such anxiety is where an anxiolytic effect is not seen for sev-
comorbid with depression. In spite of this, pa- eral weeks. Although not specifically approved
tient acceptance
- and medical enthusiasm for for this disorder. BZs are also effective in so-
these agents is muted by their slow onset of cial phobia, with clonazepam (49) showing a
action and malignant side-effect profile (see superior response rate to that of alprazolam
below). Accordingly they are generally consid- (50). Alprazolam and clonazepam are the only
ered, at best, second-line medications. BZs approved for the treatment of panic disor-
Table 9.1 Antianxiety Agents i n Common Clinical Use
Generic Name Therapeutic Total Daily Dose
a
(structure) Trade Name Originator Mode of Action Indicationb (mg) Dosing Schedule
Diazepam (1) Valium Roche BZR agonist Anxiety" 5-40 2-10 mg, 2-4 times daily
Chordiazepoxide (2) Librium Roche BZR agonist Anxiety 15-100 5-25 mg, 3-4 times daily
Clorazepate (3) Tranxene Abbott BZR agonist Anxiety" 22.530 Once daily
Lorazepam (4) Ativan Wyeth-Ayerst BZR agonist Anxiety" 2-3 2-3 mg, 2-3 times daily
Alprazolam (5) Xanax Pharmacia & Upjohn BZR agonist GAD, PD 0.5-1.5 (GAD) 0.25-0.5 mg, 2-3 times daily
5-9 (PD)
Oxazepam (6) Serax Wyeth-Ayerst BZR agonist Anxiety 30-120 10-30 mg, 3-4 times daily
Bromazepamd (7) Lexotan Roche BZR agonist Anxiety 4.5-9 1.5-3 mg, 3 times daily
UI Clonazepam (8) Klonopin Roche BZR agonist PDc 0.5-1 0.25-0.5 mg, twice daily
N
r~ Buspirone (9) BuSpar Bristol-Myers Squibb 5HT-1A agonist GAD 20-30 7.5 mg, 2-3 times daily
Paroxetine (10) Paxil SmithKline Beecham SSRI GAD, OCD, PD, SADe 40 (OCD, PD) Once daily
20 (GAD, SAD)
Sertraline (11) Zoloft Pfizer SSRI OCD, PD, PTSDe 50 Once daily
Fluvoxamine (12) Luvox Solvay SSRI OCDe 100-300 1-2 times daily
Fluoxetine (13) Prozac Eli Lilly SSRI OCDe 20-60 1-2 times daily
Citalopram (14) Celexa Forest SSRI PD' 20-40 Once daily
Venlafaxine (15) Effexor Wyeth-Ayerst SNRI GAD" 75-225 Once daily
"BZR, benzodiazepine receptor; SSRI, selective serotonin reuptake inhibitor; SNRI, serotonin and norepinephrine reuptake inhibitor.
*GAD, generalized anxiety disorder; PD, panic disorder; OCD, obsessive-compulsive disorder; SAD, social anxiety disorder; PTSD, posttraumatic stress disorder.
'Also indicated as an anticonvulsant.
dNot available in the United States.
'First indication is depression.
Antianxiety Agents

8
(1) Diazepam (2) Chlordiazepoxide (3)Clorazepate

(4) Lorazepam
0
(5) Alprazolam (6)Oxazepam

v
(9) Buspirone
(7) Bromazepam (8)Clonazepam

CI CF3
(10) Paroxetine (11) Sertraline (12) Fluvoxamine

Figure 9.1. Anxiolytics in clinical use.

der, although other high potency benzodiaz- alprazolam requires higher doses than those
epines (e.g., lorazepam) have shown a similar for GAD, reflecting the greater resistance of
effect. Lower potency BZs (e.g., diazepam) re- panic disorder to pharmacotherapy. There is
quire higher doses for panic disorder, and even little evidence for the efficacy of benzodiaz-
2 Clinical Applications

-i
/
F
(13) Fluoxetine (14) Citalopram (15) Venlafaxine -

Figure 9.1. (Continued.)

epines in OCD or PTSD, and none has been in patients who have recently used benzodiaz-
approved specifically for these disorders. In epines (53). Buspirone is the only member of
addition to the most common anxiolytic ben- the azapirone class to be marketed in the
zodiazepines shown in Table 9.1, a number of United States, although tandospirone (16) is
others are available (51), including pinaz- registered in Japan.
epam, camazepam, 2'-chlorodesmethyldiaz-
epam, cloxazolam, ketazolam, and oxazolam.
The use of these agents is much less wide-
spread, however, and they are not available in
the United States. Benzodiazepines have the
potential to produce withdrawal symptoms
and dependency upon prolonged administra-
tion. As a result they are indicated primarily
for the short-term relief of anxiety and are
increasingly not recommended for chronic 2.1.4 Serotonin Reuptake Inhibitors. Although
dosing. The increasing awareness and nega- there have been no launches of novel first-indica-
tive reaction to the withdrawal, dependency, tion anxiolytics since buspirone in 1986, the last 10
and abuse liabilities of the benzodiazepines years have seen a @cant shift in the treatment
has led to a significant reduction in their use, of anxiety disorders. During this time it has be-
despite their proven efficacy. come increasingly clear that the selective sero-
tonin reuptake inhibitors (SSRIs), origmally
2.1.3 Buspirone. The dominance enjoyed launched as antidepressants, are effective in a
by the benzodiazepines is illustrated by the range of anxiety disorders (54-56). This finding
fact that no new anxiolytics were launched un- has coincided with the realization of the with-
til buspirone (9) reached the market in 1986. drawal and dependency liability of the benzodiaz-
Buspirone is a member of the azapirone class, epines, meaning that the SSRIs have comparable
and produces its therapeutic effects through efficacy with an improved safety protile. The net
partial agonism at 5HT-1A receptors. Buspi- result is that the SSRIs are now considered first-
rone is indicated and widely used for GAD, but line treatments for panic disorder, OCD (57), so-
has failed to show significant efficacy in other cial phobia (58),and PTSD, and are gaining popu-
anxiety disorders (52). Although perhaps less larity for GAD. Unlike the benzodiazepines or
consistently effective than the BZs, buspi- buspirone, the SSRIs have the added advantage of
rone's improved safety profile provides the effectively treating depression, which is frequently
main point of differentiation between the two comorbid with anxiety disorders (59).
therapies. Buspirone causes less sedation, mo- Paroxetine (10) (60), is the most widely
tor and cognitive impairment, and does not used SSRI in the treatment of anxiety. It is
appear to be associated with any withdrawal approved for the treatment of OCD and panic
syndrome. Drawbacks include a delayed onset disorder, and is currently the only SSRI indi-
of action (several weeks), and a reduced effect cated for use in social phobia and GAD. Parox-
Antianxiety Agents

etine has also shown efficacy in one small trial though they also act at muscarinic acetylcho-
for specific phobia (61).Fluvoxamine (12) (62) line receptors, histamine H1 receptors, and
is used in OCD, and was the first SSRI to gain al-adrenergic receptors. Common anticholin-
approval for this indication. Fluoxetine (13) ergic side effects include dry mouth, constipa-
(631, and sertraline (11)(64,65) are also indi- tion, urinary retention, and blurred vision.
cated for OCD. In addition, sertraline (66, 67) Blockade of adrenergic receptors can cause or-
is approved for treatment of panic disorder thostatic hypotension and dizziness, and ac-
and recently became the first and only medi- tions at histamine receptors lead to sedation
cation approved for PTSD. In the United and weight gain. The therapeutic effect of the
States, citalopram (14) (68) is indicated for TCAs does not appear until after 2-4 weeks of
use in OCD and has been used to prevent panic therapy, and during this period there can be
attacks for several years in Europe. Parox- an initial exacerbation of anxiety symptoms,
etine and sertraline are marketed as single en- which may lead to patient termination of ther-
antiomers, whereas citalopram and fluoxetine apy. The unfavorable side-effect profiles of the
are available as racemic mixtures, and fluvox- MAOIs and TCAs have largely relegated these
arnine is achiral. Venlafaxine (15) is a dual drugs to last resort cases where other medica-
serotonin and norepinephrine reuptake inhib- tions have failed.
itor (SNRI) that has recently been approved As a class, the benzodiazepines have dem-
for use in GAD (69, 70). The major drawback onstrated a remarkable safety profile and
of the SSRIs in comparison to the BZs is their their high tolerability has been a major factor
delayed onset of action. As with their antide- in their widespread acceptance and phenome-
pressant effect, it takes 2-4 weeks before an- nal success. The most commonly reported side
xiolytic efficacy is seen and this can cause pa- effects with benzodiazepine anxiolytics are
tients to discontinue the drug. In this daytime sedation ("hangover" effect), sleep
scenario, the benzodiazepines can be a useful disturbances, cognitive impairment, motor in-
adjunct to anxiolytic therapy with SSRIs. The coordination, and ataxia. The latter symptoms
immediate anxiolysis produced by the benzo- are of greater importance in the elderly, who
diazepine serves as a bridge until the efficacy constitute a significant population of BZ users,
of the SSRI appears after 3-4 weeks, and the in whom they are associated with an increased
BZ is then tapered off slowly to avoid with- incidence of falls and fractures (71). Many pa-
drawal, leaving the SSRI as a long-term mono- tients develop a tolerance to these side effects
therapy. over time, however, while rarely developing
tolerance to the anxiolytic effects. The great-
2.2 Adverse Effects
est problems with the benzodiazepines are
The monoamine oxidase inhibitors are associ- withdrawal symptoms, dependency liability,
ated with a number of undesirable side effects and abuse potential, the separation of which is
including weight gain, postural hypotension, not always obvious (72). Abrupt discontinua-
sexual dysfunction, and insomnia. The most tion of benzodiazepine therapy commonly
serious side effect is the risk of tyramine-re- leads to a "withdrawal syndrome" character-
lated hypertensive crisis, often referred to as ized by insomnia, anxiety, fatigue, irritability,
the "cheese effect," which can be fatal. To light-headedness, headache, and gastrointes-
avoid this situation patients taking MAOIs tinal upset. These symptoms must be differen-
must limit their tyramine intake, and the re- tiated from rebound phenomena (i.e., recur-
strictive diet required to accomplish this leads rence of the original anxiety), which may also
to low patient compliance. A similar interac- occur upon termination of therapy. Short-act-
tion occurs when switching patients from ing benzodiazepines (e.g., lorazepam) tend to
MA01 to SSRI therapy, and a minimum have more severe withdrawal symptoms than
2-week washout period before commencement those of long-acting ones (e.g., diazepam) be-
of SSRI therapy is essential to allow MA0 lev- cause of the more pronounced fluctuations in
els to return to normal. The therapeutic ef- blood levels.
fects of the TCAs derive from their inhibition To minimize the risk of withdrawal effects.
of serotonin and norepinephrine uptake, al- benzodiazepine therapy is usually discontin-
2 Clinical Applications

ued by a gradual tapering of the dose. Never- however, and the symptoms typically resolve
theless, an estimated 25% of patients find after a few days. Like buspirone, the SSRII
withdrawal difficult and fail to discontinue SNRI class has a delayed therapeutic effect
therapy (73, 741, and such patients may be and a potentially serious drug interaction with
considered to have a low dose dependency on MAOIs.
benzodiazepines. On the other hand, high 2.3 Drug Metabolism
dose dependency, and abuse, is characterized P
by drug-seeking behaviors and the consump- The metabolic profile of anxiolytic agents has
tion of elevated, nontherapeutic doses. The important ramifications for their clinical use.
risk of withdrawal and dependency increases This section discusses the metabolism of the -
with dose and length of treatment, but clinical benzodiazepines and buspirone in some detail.
experience shows that anxious patients have The metabolism of the SSRIs, TCAs, and
little tendency to escalate the dose of benzodi- MAOIs is covered in the chapter on antide-
azepines, and such abuse is typically found in pressants.
patients who have a history of alcohol and/or
substance abuse (75, 76). It is noteworthy, 2.3.1 Benzodiazepines. To varying de-
however, that substance abuse is often comor- grees, all benzodiazepines produce five clinical
bid with anxiety disorders. The increasing effects: anxiolysis, sedation, muscle relax-
public and medical concern over the depen- ation, seizure protection, and memory impair-
dency and abuse liabilities of benzodiazepines ment. In terms of the pharmacology underly-
has considerably reduced their use, and many ing these effects there is little to choose
countries now have restrictions on their dis- between the benzodiazepines, in that they all
pensation. This may be an overreaction, how- act as nonselective agonists at the benzodiaz-
ever, which in many cases has likely led to the epine receptor (BZR). The classification of
substitution of benzodiazepines by less effec- benzodiazepines into therapeutic indications
tive medications. Recently, it has been argued is therefore based largely on their pharmaco-
that the risk-to-benefit ratio of benzodiaz- kinetic profile. Thus, benzodiazepines with
epines be reassessed and their clinical utility long half-lives and/or long-lived active metab-
reevaluated (77, 78). olites are used as anxiolytics, whereas those
Buspirone is a well-tolerated drug, the with short half-lives are more appropriately
most commonly reported side effects being used as sedative-hypnotics. Elimination of the
transient dizziness, light-headedness, head- benzodiazepines is by hepatic metabolism and
ache, and gastrointestinal disturbances. excretion of conjugated metabolites in the
Other limitations of buspirone are its delayed urine (80-83). During metabolism, many ben-
onset of action (few days to a few weeks) and a zodiazepines give rise to metabolites that of-
significant drug interaction with MAOIs. ten have comparable pharmacological activity
The SSRIs (paroxetine, fluoxetine, sertra- to, but a longer half-life than, the parent com-
line, fluvoxamine, citalopram) and SNRI (ven- pound. The metabolic profile is therefore an
lafaxine) have an impressive side-effect pro- important determinant of the ultimate in vivo
file, and this has contributed to their biological activity.
widespread use. Possible adverse effects in- In general the first, and most rapid, step in
clude nausea, insomnia, and agitation, but 1,Cbenzodiazepine metabolism (Fig. 9.2) is
these are generally manageable and diminish the oxidative removal of the N-1 alkyl sub-
over time. More significant is the association stituent, if present (82).Benzodiazepines with
-
of the SSRIs with sexual dysfunction. in both a methyl group at N-1 are the most stable and
men and women. These effects are longer last- the rate of dealkylation increases with the size
ing, and can occur in up to 40% of patients of the N-1 alkyl group. For example, the deal-
(79). A withdrawal syndrome has also been kylation half-life for diazepam is 20 -30 h, but
observed with the SSRIs, characterized by " diz- for prazepam, which bears a cyclopropyl-
ziness, headache, and irritability upon abrupt methyl group at N-1, this half-life is approxi-
discontinuation. This is much less serious mately 1 h (82).Substituents elsewhere in the
than that observed with benzodiazepines, molecule have little impact on the rate of deal-
Antianxiety Agents

Chlordiazepoxide Diazepam --

I Dealkylation I
+
NP-desmethyl
chlordiezepoxide

demoxepam*
\
45h #
1-2 h
Clorazepate ----+ desmethyl diazepam*, Alprazolam Bromazepam

I Hydroxylation I
1-hydroxymethyl 3-hydroxy Lorazepa,,,
Oxazepam* Temazepam* alprozolam bromazepam
5-15 h I 10-20 hl 1-2 h l Short 1 10-20 hl
1 Glucuronidation I

Inactive glucuronides, excreted in urine


Figure 9.2. Metabolic pathways for common anxiolytic benzodiazepines. Capitalized names are
marketed drugs. *Active metabolite.

kylation. Following dealkylation, the next step disease, making these drugs more suitable for
is hydroxylation at the 3-position. The hy- use in elderly patients and those with liver
droxylation half-lives (typically approaching dysfunction. The limited structural diversity
or exceeding 100 h) are longer than the deal- of the benzodiazepines means that the same
kylation half-lives, resulting in an accumula- active metabolites can be generated from sev-
tion of the pharmacologically active N-1 deal- eral different drugs. For example, oxazepam,
kylated metabolites, so these compounds which is marketed as an anxiolytic in its own
contribute significantly to the overall biologi- right, is generated in uivo from diazepam, clo-
cal activity. The rates of hy droxylation are rel- razepate, prazepam, and chlordiazepoxide. In
atively independent of the substituent in the the case of the triazolo- (e.g., alplrazolam) and
C-ring, with the exception of bromazepam. imidazo- (e.g., midazolam) benzodiazepines,
The 3-hydroxy metabolites are then glucu- hydroxylation of the C-1 methyl group is the
ronidated and excreted in the urine. The glu- principal metabolic pathway.
curonides are pharmacologically inactive, and Alprazolam (5) is rapidly absorbed after
this fact has been exploited in drugs such as oral dosing, reaching peak plasma levels in
oxazepam, lorazepam, and temazepam. As less than 1 h with an oral bioavailability ex-
3-hydroxybenzodiazepines, these agents are ceeding 90% (86). Alprazolam has a lower pro-
glucuronidated directly and their clinical use tein binding (68%)than that of most benzodi-
is not complicated by the formation or accu- azepines (87), reflecting the increased polarity
mulation of active metabolites. Further, the imparted by the triazole ring. Although the
rate of glucuronidation (84, 85) appears to be principal metabolite l-hydroxymethylalprazo-
much less impacted than the rate of dealkyla- lam is a potent BZR ligand (Ki = 4.2 nM) (881,
tion or hydroxylation (82) by aging or by liver it does not contribute significantly to the clin-
2 Clinical Applications

ical effect because it is rapidly conjugated and pared to other benzodiazepines, has a rela-
plasma levels never exceed 10% of the parent tively high free fraction (30%).Bromazepam is
drug (89). The elimination half-lives of alpra- metabolized principally by hydroxylation at.
zolam and 1-hydroxymethylalprazolamare 9 the 3-position. The pyridyl ring at position 5
to 12 h and 1 to 2 h, respectively. facilitates this reaction, the hydroxylation'
Chlordiazepoxide (2) is completely ab- half-life for bromazepam being considerably
sorbed upon oral administration and reaches shorter (t,,, = 8-19 h) than that for other benr
peak plasma concentrations in 1-2 h (90).As a zodiazepines (94).A second pathway opens the
highly lipophilic molecule it is 94% bound to diazepine ring to give the pharmacologically
plasma proteins (91) and readily penetrates inactive 2-(2-amino-5-bromobenzoy1)pyridine-
the brain, with CSF levels paralleling un- (95). Bromazepam metabolism does not pro-
bound plasma levels (92). Chlordiazepoxide duce any metabolites with a longer half-life
has a mean half-life of 15 h. It is metabolized than that of the parent compound.
first by oxidative removal of the N-2 methyl Clonazepam (8) is almost completely ab-
group (to give N-desmethylchlordiazepoxide), sorbed after oral dosing (96) with an average
followed by hydrolysis to the lactam (demox- T,, of 2-4 h. As with other 7-nitro benzodi-
epam), and reduction of the N-5 oxide to give azepines, the major metabolic pathway for
desrnethyldiazepam. All of these metabolites clonazepam is reduction of the nitro group,
are pharmacologically active. acetylation of the resulting amine, and elimi-
Clorazepate (3)is readily decarboxylated in nation of the acetamide. Hydroxylation of
the stomach to generate desrnethyldiazepam, clonazepam or of 7-amino clonazepam to give
which is then rapidly absorbed with peak the 3-hydroxy derivatives represents minor
plasma levels occurring 0.5 to 2 h postdose. metabolic pathways. The elimination half-life
Clorazepate itself is poorly absorbed (93) and of clonazepam is 20-30 h (97), and no active
acts only as a prodrug of desmethyldiazeparn. metabolites are produced.
Diazepam (1)is completely and rapidly ab- Lorazepam (4) is well absorbed, with oral
sorbed following oral administration, reach- bioavailabilty close to 100% after a typical 2
ing peak plasma levels after 30-90 min. As a mg dose, and peak levels are obtained within
result of its lipophilic character it is highly 2 h of administration. Lorazepam is conju-
protein bound (98-99%)and is widely distrib- gated at the 3-hydroxy group and the resulting
uted, readily crossing the blood-brain barrier inactive glucuronide is excreted in the urine
and placenta, and also passing into breast with a mean elimination half-life of approxi-
milk. Metabolism of diazepam gives rise to mately 14 h (82).
three active metabolites. N-1 demethylation Oxazepam (6)is formed during the metab-
produces desmethyldiazepam, which has a olism of many other benzodiazepines, but its
longer half-life than that of diazepam own metabolic profile is relatively simple. Like
(40-200 h compared to 20-30 h) (82).On mul- lorazepam, the major metabolic pathway is
tiple dosing, plasma desrnethyldiazepam lev- glucuronidation at the 3-hydroxy group fol-
els exceed diazepam levels. Hydroxylation of lowed by urinary excretion. Up to 80% of the
desrnethyldiazepam then produces oxazepam dose is recovered from the urine as the gluc-
(6), which is conjugated and eliminated as the uronide. The mean half-life of oxazepam is ap-
glucuronide. Direct hydroxylation at the 3-po- proximately 9 h (98).
sition of diazepam yields temazepam, which is As previously mentioned, the choice of ben-
also directly conjugated and excreted. Of these zodiazepine for a given indication is governed
metabolites, desmethyldiazepam contributes in large part by its plasma half-life. This half-
more to the overall pharmacodynamic effect life, however, does not always predict the du-
because of its longer half-life and resultant ration of the pharmacological effect. Using se-
accumulation. dation (99) or psychomotor impairment (100)
After oral dosing bromazepam (7) is well as endpoints, lorazepam was shown to have a
absorbed, with a bioavailability of 84-98% and longer lasting effect than that of diazepam,
a rather variable T,, of 0.5 to 8 h (94). It has even though its plasma half-life is about half
an elimination half-life of 8-19 h and, com- as long. For diazepam, the rate of elimination
Antianxiety Agents

from the CSF is equivalent to the rate of elim- 5'-hydroxybuspirone plasma levels (both free
ination from plasma (101), but lorazepam has and conjugated) are up to six times greater
a longer half-life in CSF than in plasma. than buspirone levels, indicating the impor-
Lorazepam has a greater affinity for the BZR tance of this metabolic pathway. Plasma levels
than does diazepam (lorazeparn, Ki = 1 nM; of 1-PP are approximately fourfold greater
diazepam, Ki = 27 nM) and dissociates from than those of buspirone (105). 5-Hydroxybus-
the receptor more slowly (102). Thus the re- pirone shows no biological activity, in keeping
lease of lorazepam from the receptor has been with the structure-activity relationship (SAR)
suggested as the rate-limiting step in its elim- for this series of compounds as it relates to
ination from CSF, resulting in a longer phar- affinity for the 5HT-1A receptor (see section
macodynamic effect than would be expected 5.4.1); however, 1-PP has up to 20% of the
based on the plasma half-life. potency of buspirone in the Vogel anticonflict
model (105). It also has some affinity (IC,, =
2.3.2 Buspirone. Buspirone is completely 95 nM) for the adrenergic a2 receptor, al-
absorbed after oral dosing, but exhaustive though it has no activity at the 5HT-1A recep-
fist-pass metabolism limits the absolute bio- tor. Given its significantly higher plasma and
availability to only 4% (103). The pharmacoki- brain levels relative to those of buspirone,
netics are linear and metabolism is not satu- 1-PP may contribute to the overall anxiolytic
rated in the therapeutic dose range (10-40 effect.
mg) (104). First-pass metabolism is decreased Until recently,- . it was believed that 1-PP
when buspirone is taken after a meal but ab- was the only buspirone metabolite to possess
sorption is not, leading to increased drug ex- any biological activity. Under the assumption
posure (105). This effect is also seen with that buspirone was the active agent, dosing
other drugs that undergo extensive first-pass schedules were designed to optimize buspi-
metabolism (106).Age has little impact on bu- rone exposure at the expense of metabolites.
spirone pharmacokinetics, but hepatic cirrho- Bristol-Myers Squibb, the manufacturer of
sis extends the elimination half-life by 50% buspirone, recently carried out clinical studies
(105). The mean half-life of buspirone in nor- on a buspirone transdermal patch (108) with
mal subjects ranges from 2 to 11 h, averaging the aim of increasing buspirone levels, and
at around 4 h, and this short half-life accounts hence the anxiolytic effect, by circumventing
for one of buspirone's drawbacks, that is, the first-pass metabolism. Surprisingly, no signif-
need for three times daily dosing. Buspirone is icant activity was seen with this delivery sys-
a lipophilic compound and is highly bound to tem, prompting a reevaluation of buspirone
plasma proteins (>95%), predominantly albu- and its metabolites. Remarkably, almost 15
min (105). years after the launch of buspirone, it was dis-
The extensive oxidative metabolism of bu- covered that 6-hydroxybuspirone (18) not
spirone, mediated by CYP450 3A4, produces a only possessed anxiolytic activity, but is ap-
number of hydroxylated metabolites including parently responsible for most, if not all, of bus-
1-(2-pyrimidiny1)piperazine (1-PP), 5'-hy- pirone's clinical effects (109). (18)has signifi-
droxybuspirone (17) and 6-hydroxybuspirone cant affinity for the 5HT-1A receptor (Ki = 57
(18) (107). After a 20-mg dose of buspirone, nM), approaching that of buspirone (Ki = 31
nM). Furthermore, (18) is the second most
abundant human metabolite of buspirone,
having blood levels 40 times greater than that
of buspirone and severalfold greater than that
of 1-PP after oral dosing. The initial preclini-
cal work on buspirone revealed no in vivo an-
xiolytic activity for (18)in animal models, but
more recently, using the rat pup ultrasonic
vocalization model, (18) was found to have
(17) Rl = OH, R2 = H comparable activity to that of buspirone (ID,,
(18) Rl = H,R2 = OH = 0.13 and 0.10 mgbg, respectively) (109).
3 Physiology and Pharmacology

Subsequent human pharmacokinetic studies such a group of complex emotional disorders


have demonstrated that plasma levels of bus- can be reduced to the dysregulation of a single
pirone after oral dosing are minimal in com- neurotransmitter system. In reality, all of the
parison to those of (lg), leading to the conclu- aforementioned systems are intertwined with
sion that (18)mediates the clinical anxiolytic complex and dynamic interactions existing be-
effect of buspirone. These surprising discover- tween them, and the exact role and relative
ies were disclosed by Bristol-Myers in a U.S. contribution of each one in the pathology OT
patent (109) (the so-called 365 patent), the anxiety remains unknown (115, 116). The
timing of which was remarkable. The "365" function of a given neurotransmitter receptor
patent was granted on November 21, 2000, may vary between receptor subtype and anar
only one day before the expiration of buspi- tomical region, and responses to acute and
rone's patent protection, and was subse- chronic therapy may differ. The multitude of
quently listed by the FDA in the Approved overlapping pathways that contribute to the
Drug Products with Therapeutic Equivalence regulation of anxiety makes it difficult to elu-
Evaluations list (the "Orange Book"). This cidate the pathology of the various disorders,
move effectively granted Bristol-Myers a fur- but also offers numerous opportunities for
ther 20 years exclusivity for buspirone, a drug pharmacological intervention. The following
that generated $700 million in sales in 2000. section discusses the roles of the aforemen-
Several generic companies, who were already tioned neurotransmitter systems in the patho-
in production of buspirone in anticipation of physiology of anxiety.
the November 22 deadline, filed suit against
the FDA, charging that the "365" patent had
3.1 GABA
been improperly listed. At the time of writing,
the courts have ruled against the FDA (110), GABA (y-aminobutyric acid) is the major in-
the "365" patent has been removed from the hibitory neurotransmitter in the brain and is
Orange Book, and generic forms of buspirone estimated to be present at 30-50% of all CNS
are now available. The future development of synapses. Consequently, many important
6-hydroxybuspirone, if any, is unknown. neurotransmitter systems are under the in-
hibitory influence of GABA, including the se-
rotonin, norepinephrine, CCK, and dopamine
3 PHYSIOLOGY A N D PHARMACOLOGY systems. Three types of GABA receptors have
been identified (117): GABA,, GAB&, and
It is evident from section 2.1 and Table 9.1 GAB&. GABA, receptors belong to the su-
that the clinically effective anxiolytics have perfamily of ligand-gated ion channels, and
several distinct modes of action and interact mediate fast synaptic inhibition. GABA, re-
with a number of important neurotransmitter ceptors are G-protein-coupled receptors that
systems (111-114). The efficacy of the benzo- can mediate inhibition or excitation, and
diazepines clearly implicates GABA in anxi- GABA, receptors appear to be similar to
ety, whereas the clinical utility of buspirone GABA, receptors but are localized predomi-
and the SSRIs point to an important role for nantly in the retina. GABA exerts its inhibi-
serotonin. The TCAs exert their therapeutic tory effects in the central nervous system by
effects through inhibition of serotonin and binding to the GABAA receptor and opening
norepinephrine reuptake, and their efficacy the chloride channel at the center of the recep-
suggests the involvement of both systems in tor. The resulting influx of chloride ions hy-
anxiety disorders. Although there are no clin- perpolarizes the neuron and reduces its sensi-
ically available drugs that modulate the chole- tivity to incoming stimuli. Within the GABAA
cystokinin (CCK) and corticotrophin-releas- receptor complex, and in close proximity to the
ing factor (CRF) systems, increasing evidence GABA binding site, there is an allosteric site,
argues for their participation in the regulation the benzodiazepine receptor (BZR), through
of anxiety. which the benzodiazepines produce their ef-
Anxiety is actually a cluster of several dif- fects. Up to 10 additional modulatory sites on
ferent conditions, and it is highly unlikely that the GABA, receptor have been proposed, in-
Antianxiety Agents

Figure 9.3. Fkpresentations of GABA-ac-


tivated ion channels. a: general structure
of one of the five protein subunits showing
four membrane spanning regions; b: pen-
tameric arrangement of the protein sub-
units showing the second membrane span-
ning region lining the pore of the ion
channel; c: heteromeric makeup of the
GABAa receptor with two cul, two P2, and
one y2 subunit. (Reprinted with permis-
sion from J. Med. Chem., 43, 1427-1447,
2000. Copyright 2000 American Chemical
Society.)

cluding those for barbiturates, neurosteroids, ranged round a central chloride channel (Fig.
picrotoxinin, inhalation anesthetics, and eth- 9.3). To date, 21 receptor subunits have been
anol (118). cloned (six a, four P, four y, one 6, one E , one T ,
Studies have shown a reduced density of one 8, and three p), although the E and p sub-
lymphocyte BZ receptor sites (119) and plate- units appear to be associated with GABA,
let BZ sites in GAD patients, which was in- rather than GABA, receptors. Immunohisto-
creased following diazepam treatment (120). chemical studies indicate that the a,P2/3, and
These peripheral receptors are pharmacologi- y2 subunits are most frequently coassembled
cally distinct from the central GABA, recep- to form GABA, receptors in uiuo, with a stoi-
tors, so the relevance of these studies to anxi- chiometry of 2 ~ ~ 2 P : l (129).
-y Even with this
ety is unclear. More relevant may be the study restriction, the differential combination of
of central BZR activity in anxiety patients. Re- these subunits could potentially lead to thou-
duced BZR sensitivity has been shown in GAD sands of receptor subtypes. Fortunately, the
patients by measuring saccadic eye move- GABA, receptor population appears to be
ments (121, 122). This effect was even more dominated by only a handful of receptor sub-
pronounced in patients with panic disorder types, differentiated mainly by the identity of
(123), but was absent in OCD (124). These the a subunit. These subtypes have been
studies suggest that there may be a reduced shown to possess a distinct but regionally
BZ receptor function in some anxiety disor- overlapping distribution within the brain
ders. (128, 130). a1-containing subunits are the
most abundant, accounting for over 50% of
3.1 .I The GABAJBenzodiazepine Receptor all GABA, receptors, and are distributed
Complex. The GABAAreceptor (125-127) is a throughout the brain (131-133). a2 and a3
transmembrane protein belonging to the su- subtypes together constitute a further 30-
perfamily of ligand gated ion channels (128). 35% of GABA, receptors, with a2 isoforms lo-
The receptor consists of five subunits ar- cated in limbic structures and a 3 receptors
i
:I
3 Physiology and Pharmacology
!
found mainly in the cortex (134). a5 subtypes (Ambien) has implicated the a1 subtype in se-
represent only 5% of the total GABA, receptor dation, whereas the localization of the a 5 sub-
population and are localized in the hippocam- unit in the hippocampus suggests its involve-.
pus (135). ment in memory processes. The presence of (112.
As shown in Fig. 9.3 the GABA, receptor and a 3 subtypes in limbic structures points to
has a topology characteristic of the nicotinoid a role for these subtypes in anxiety and emo-
superfamily of receptors. Each subunit spans tional behavior. Recent work with transgeniiz
the membrane four times, and the second animals is confirming, for the first time, some
transmembrane domain of each subunit forms of these theories (142). Mutation of the critical
the wall of the ion channel. The GABA binding His-102 of the a subunit to an arginine abol-
sites, of which there are two per receptor, are
ishes the binding affinity of benzodiazepines
located at the two homologous alp interfaces.
(143) at the mutated subtype, but does not
Point mutation studies have identified several
key amino acid residues on both subunits that affect the response to GABA. Mice expressing
contribute to GABA binding (1361, and both al, a2, or a 3 receptors containing this knock-in
GABA sites must be occupied to induce open- mutation develop normally and show no overt
ing of the chloride channel. The benzodiaz- anxious phenotype, arguing against the long-
epine receptor site (BZR) (137) is located at held notion that there are endogenous ligands
the interface of the a- and y-subunits, and for the BZR that regulate anxiety.
there is one BZR per GABA receptor (129). Evaluation of these animals in behavioral
Point mutation and photoaffinity labeling ex- paradigms shows that the sedative and amnes-
periments have revealed at least 11amino acid tic effects of diazepam are mediated through
residues in the a- and y-subunits that contrib- the a1 subtype (144-146). Although the a1
ute to ligand binding and efficacy at the BZR subtype appears to mediate sedation, the sleep
(138),the most significant of which is the his- latency and sleep pattern were unchanged in
tidine at position 102 (101 in rat) of the a-sub- the mutant mice, indicating that different
unit. The a1-, a2-, a3-, and a5-containing re- subtypes mediate the sedative and hypnotic
ceptors carry a histidine at position 102 and effects of diazepam (147). Conditional knock-in
are benzodiazepine sensitive, but the a4 and mice wherein the a2 and a 3 subtypes are ren-
a6 subtypes, which bear arginine at this posi- dered benzodiazepine insensitive have also
tion, are benzodiazepine insensitive (139). been generated. In the elevated plus maze and
The y2 subunit is more abundant in the brain lightldark choice models, a loss of diazepam
than y l or y3 subunits and is important for anxiolytic activity is observed in the a2
ligand binding, given that the GABA, recep- knock-in animals, but not with the a 3 knock-
tors of mice lacking the gene for y2 subunits ins, implicating the a2 subtype in the media-
are insensitive to benzodiazepines (140). The tion of benzodiazepine anxiolytic effects (148).
nature of the P-subunit has a lesser influence Given this evidence, it is tempting to speculate
on BZR pharmacology (141). This fact, cou- that the ideal anxiolytic, one that is clinically
pled with the consistent expression of y2 sub- effective but free from sedation, amnesia, de-
units in various subtypes, means that the pendency, and withdrawal effects, will be real-
identity of the a -subunit is the major deter- ized in a compound possessing the appropriate
minant of BZR pharmacology (128, 135). Ac- subtype selectivity. It is probable, however,
cordingly, the dominant benzodiazepine-sen- that a given subtype is associated with more
sitive GABA, subtypes in the brain are often than one clinical effect. Indeed the a2 subtype,
referred to simply as the al, a2, a3, and a5 although clearly associated with the anxiolytic
GABAAreceptors. actions of diazepam, has also been shown, us-
Along with an increased understanding of ing a2 and a 3 knock-in mice, to contribute to
the molecular diversity and anatomical local- the myorelaxant actions of diazepam (149).
ization of different GABAAreceptor subtypes Thus, simple subtype selectivity alone may
has come the notion that specific clinical ef- not be enough to yield a true side effect-free
fects may reside in specific subtypes. The se- anxiolytic. More fruitful may be the combina-
lective affinity of the hypnotic agent zolpidem tion of subtype selectivity and partial ago-
Antianxiety Agents

+ve Amnesia, dependence


7 Full agOnist
Sedation Seizure protection
Partial agonist
Anxiolysisj
Potentiation
of GABA 100% - Receptor
induced occupancy
CI- current
Partial inverse
Proconvulsant agonist
............................................................ .........................................................
-ve Full inverse
Convulsant agonist
Figure 9.4. Anxiolysis via partial agonism.

nism, and this hypothesis underlies the most response is modulated by a given ligand is de-
promising area of current anxiolytic research. r~endenton the GABA concentration used in
A

Ligands at the BZR are allosteric modula- the assay. When this variability is superim-
tors of GABA function, and they have no effect posed on the subunit heterogeneity and differ-
in the absence of GABA. This allosteric mod- ential anatomical distributions of GABA, re-
ulation can be positive (enhancement of ceptors a complex picture emerges, but it is
GABA function, increased neuronal inhibi- one that offers numerous possibilities for im-
tion) or negative (inhibition of GABA func- proved therapeutic modulation of central
tion, reduction in neuronal inhibition). Li- GABA function.
gands effecting maximum positive modulation Based on SAR data for a variety " of struc-
are known as full agonists, or as compounds t u r d classes of ligands, several models of the
with high intrinsic efficacy; that is, they pro- benzodiazepine binding site have been ad-
duce the maximal response at low receptor oc- vanced (151-162). These models, although
cupancy. This profile is characteristic of the sharing many common features, have gener-
classical benzodiazepines. Ligands that induce ally been slightly different for inverse ago-
maximum negative modulation are full in- nists, antagonists, and agonists, as well as for
verse agonists, whereas antagonists have no diazepam-sensitive and diazepam-insensitive
effect on GABA function. In between these ex- subtypes. The pharmacophoric descriptors for
tremes, on a continuum of intermediate effi- all these models have now been incorporated
cacy, lie partial agonists and partial inverse into an inclusive pharmacophore model for
agonists. Partial agonists can be defined as li- the BZR (163) that rationalizes ligand-recep-
gands that induce a smaller response than tor interactions at the molecular level for in-
that of a full agonist, at the same receptor oc- verse agonists, antagonists, and agonists and
cupancy (Fig. 9.4). In principle, a partial ago- for all major subtypes (d-a6) (Fig. 9.5). This
nist might never produce the maximum poten- model identifies three important interactions
tiation of a full agonist, even at 100% receptor that anchor the ligand through hydrogen bond
occupancy. Because anxiolysis requires less donor (HI, H2) and hydrogen bond acceptor
receptor occupancy than sedation and other (Al) points on the receptor. L1, 2, 3, and Di
side effects (150),a number of partial agonists represent lipophilic regions, the occupation of
have been investigated as potential nonsedat- which influences the affinity, efficacy, and se-
ing anxiolytics. The modulation of GABA re- lectivity of the ligand. S1, S2, and S3 are re-
sponse can span a tremendous range, from gions of steric intolerance that restrict the size
increases in GABA-induced C1- current ap- of BZR ligands. Region LDi appears to be
proaching 800% to inhibition of 60%. It should larger in a1 subtypes than in the others, and
be noted that the degree to which the GABA occupation of this region may thus confer a1
3 Physiology and Pharmacology

LP

-- , . H I , H2 = hydrogen bond donor sites.

.: A = hydrogen bond acceptor site.


-\
I
'> - - L1, L2, L3, LDi = lipophilic binding pockets.

n
I
I
LDi , S1, S2, 53 = regions of steric repulsion.
,, I

L--4
0 I

I
' \ I

Figure 9.5. Diazepam (1)(heavy line) and CGS9896 (67) (dotted line) fitted to a schematic repre-
sentation of the inclusive pharmacophorelreceptor model for the BZR. Adapted from Ref. 163, copy-
right Overseas Publications Association, NV, with permission from Taylor and Francis Ltd.

selectivity (161, 162). Occupation of region L3 originate in the raphe nucleus (168). They in-
(e.g., by the C-5 phenyl ring of the benzodiaz- nervate a number of brain regions including
epines) is commonly associated with agonist the limbic system, and in particular the septo-
activity. Recently, the inclusive pharmaco- hippocampal system and the amygdala. It has
phore model has been integrated with data been proposed (169) that anxiety is a result of
from point mutation and photoaffinity-label- excessive serotonin activity in these specific
ing experiments to provide an enhanced pic- brain regions. The serotonergic neurons aris-
ture of the benzodiazepine binding site (164). ing from the dorsal raphe nucleus innervate
Another study has used behavioral endpoints the periacqueductal gray (PAG)and the arnyg-
for different ligands to construct a model of dala, and these may regulate adaptive responses
ligand-BZR interactions that contribute to an to acute stress (166). On the other hand, 5HT
anxiolytic effect (165). neurons originating in the median raphe nu-
cleus, which innervate the hippocampus, me-
3.2 Serotonin
diate resistance to chronic stress and failure of
Both depression and anxiety appear to be as- this pathway may contribute to depression.
sociated with a dysregulation of serotonergic Through their widespread blockade of the
function at some level, a hypothesis supported serotonin transporter, the SSRIs are known to
by the clinical efficacy of the SSRIs in both increase serotonin levels at virtually every
disorders. On the other hand, the benzodiaz- synapse in the CNS, yet the exact neuronal
epines have no clinical utility as antidepres- pathways and receptors through which their
sants. It has therefore been suggested that, anxiolytic effect is ultimately produced re-
although serotonin has a role in both disor- main unclear (166). To date, 15 different 5HT
ders, different serotonergic pathways and re- receptor subtypes have been identified (170).
ceptor subtypes are responsible for the modu- Of these, seven subtypes have been implicated
lation of anxiety and depression (166, 167). to a greater or lesser degree in anxiety: the
Some of the major 5HT neuronal pathways 5HT-lA, 5HT-lB/D, 5HT-2A/B/C, and 5HT-3
Antianxiety Agents

receptors (171, 172). A survey of preclinical lytic effect in the mouse lightldark box model,
research into serotonergic agents as potential and this effect was attenuated by a 5HT-1B
anxiolytics (173) shows that 50% of studies agonist and also by the benzodiazepine antag-
over the past two decades involve 5HT-1A li- onist flumazenil (185). The latter phenome-
gands, whereas 5HT-2 and 5HT-3 compounds non suggests a functional interaction between
account for 15 and 13% of studies, respec- 5HT-1BP receptors and the GABA system in
tively, giving a rough guide to the presumed the modulation of anxiety. Indeed, the 5HT-
importance of each receptor in anxiety. 1 B P heteroreceptor is known to exert an in-
hibitory influence on the release of a number
3.2.1 5HT-1 Receptors. Of all the seroto- of neurotransmitters, including GABA (186).
nin receptors implicated in anxiety, the Thus, antagonists at the 5HT-1B/D receptors
5HT-1A receptor (174) has been the subject of may produce an anxiolytic effect, at least in
the most study. The only marketed anxiolytic part, through a secondary enhancement of
acting directly on a serotonin receptor is bu- GABA function. 5HT-1B knockout mice (187)
spirone (91, a 5HT-1A partial agonist. The exhibit behaviors consistent with reduced
5HT-1A receptor is a member of the G-pro- anxiety in some animal models but not in oth-
tein-coupled receptor family, and is found in ers (188-190). 5HT-moduline is an endoge-
brain structures known to be involved with nous tetrapeptide that influences serotonergic
emotional behavior, such as the hippocampus, activity through antagonism at 5HT-1Brecep-
amygdala, raphe nuclei, and hypothalamus. In tors (191, 192). Centrally administered 5HT-
the raphe nucleus, 5HT-1A receptors are pre- moduline desensitizes 5HT-1B receptors, re-
synaptic autoreceptors, whereas in the other sulting in increased serotonin release (193).
brain regions they are postsynaptic. Activa- Consistent with this observation, specific
tion of the postsynaptic receptors leads to neu- 5HT-moduline antibodies have shown anti-
ronal inhibition in some limbic structures. anxiety effects in animal models (194), sug-
Activation of presynaptic autoreceptors sup- gesting the involvement of this peptide in the
presses the firing rate of serotonin raphe neu- regulation of anxiety. Clearly, further study is
rons, thereby reducing serotonin turnover in needed to fully characterize the role of 5HT-
the terminal fields (175, 176). Both modes of 1BD receptors in anxiety and to ascertain the
action are presumed to contribute to the ther- potential, if any, of 5HT-1BP antagonists as
apeutic effects of buspirone (177). Mice lack- anxiolytic drugs.
ing the 5HT-1A receptor have been generated
by homologous recombination (178, 179), and 3.2.2 5HT-2 Receptors. It has been sug-
these animals show an overt anxious pheno- gested that the pathology of anxiety disorders
type in several anxiety models, supporting a may involve a hypersensitivity of central
role for the 5HT-1A receptor in the regulation 5HT-2 receptors (171). This is supported by
of anxiety. the anxiogenic effect of the nonselective
5HT-1BP receptors, best known as the site 5HT-2 agonist m-chlorophenylpiperazine (m-
of action of popular antimigraine drugs such CPP) in animal models of anxiety (195). Fur-
as sumatriptan, have also been associated ther, administration of m-CPP, which is the
with anxiety (180), although the evidence for principal metabolite of the antidepressant ne-
their involvement is less compelling than that fazodone, elicited anxiety in panic disorder pa-
for the 1A subtype. The 5HT-1/BP receptors tients (196) and induced a transient exacerba-
are found in the basal ganglia, hippocampus, tion of symptoms in OCD patients (197).
and cortex (1811, where they exist as autore- Together, these data raise the possibility of
ceptors on serotonergic neurons and as het- 5HT-2 receptor antagonists as anxiolytics. All
eroreceptors on nonserotonergic neurons. three of the 5HT-2 subtypes (2A, 2B, 2C) have
5HT-1Breceptor agonists show an anxiogenic been associated with anxiety to some degree,
effect in various animal models (1821, includ- the 2A and 2C isoforms being the most fre-
ing the elevated plus maze (183) and social quently linked.
interaction (184)tests. Furthermore, selective In the CNS, 5HT-2A and 2C receptors are
5HT-1BP antagonists have shown an anxio- found postsynaptically on nonserotonergic
3 Physiology and Pharmacology

neurons (198). 5HT-2C receptors are found in ing norepinephrine, dopamine, and CCK
the choroid plexus, cerebral cortex, hippocam- (211). Overall, 5HT-3 antagonists display er-
pus, and amygdala (199), and this localization ratic efficacy in animal models of anxiety and -
is supportive of a role in affective disorders. As have failed to demonstrate a significant anxi- :
well as in anxiety, 5HT-2C receptors have olytic effect in the clinic (173,208).
been implicated in depression (200) and in the
-v
modulation of feeding behavior (201). 5HT-2A 3.2.4 GABAISerotonin Interactions. The un-
receptors are more widespread, with higher certainty surrounding the relative roles of
levels in cortical regions (198), and antago- GABAergic and serotonergic pathways in the .
nists at this subtype may also possess antipsy- regulation of anxiety is compounded by the
chotic activity. In behavioral studies there is interactions of the GABA system with the se-
i considerable inconsistency, in that 5HT-2 an-
tagonists have been shown to produce anxio-
rotonergic system. The inhibitory influence of
benzodiazepines on serotonin turnover in the
a lytic effects, no effects, or even anxiogenic ef- brain was first noted over 30 years ago (212)
I
fects in various animal models (202). and led to the theory that the therapeutic ef-
Administration of a nonselective 5HT-2 an- fects of the BZs may be mediated, in part, by
tagonist (mianserin) or a selective 5HT-2BlC their potentiation of GABAergic inhibition of
antagonist, but not a selective 5HT-2A antag- 5HT neuronal firing and subsequent reduc-
onist, produced anxiolytic effects in animal tion in serotonin release.
models, implicating the 2B/C subtypes in anx- Genetically modified mice lacking the
iety modulation (203). The available evidence 5HT-1A receptor are inherently anxious, and
paints a confusing picture of 5HT-2 receptors are insensitive to the anxiolytic effect of diaz-
in anxiety, and knowledge of the exact func- epam (213)in the elevated plus maze and open
tion and potential clinical applications of the field tests. In addition, there is altered GABA,
various 5HT-2 subtypes remains incomplete. receptor expression in the brains of these
Further behavioral studies with subtype-se- 5HT-1A knockout mice. Expression of the a2
lective ligands would help delineate the prop- subunit was reduced to 59% of wild type levels
erties of the 5HT-2 subtypes, but the high de- in the amygdala, and to 47% of wild-type levels
gree of homology among the 5HT2 receptors in the cortex, whereas no reduction in a 3 ex-
(204, 205) has made this approach difficult. pression was found. In addition, no subunit.
The pharmacology of this class of receptors is. reduction of any kind was found in the hip-
further complicated by the unusual down- pocampus and raphe nucleus. Given that the
regulation of 2A and 2C receptors upon expo- knockout mice lack both pre- and postsynaptic
sure to antagonists (206). 5HT-1A receptors, the relative influence of
each on GABA, receptor expression remains
3.2.3 5HT-3 Receptors. 5HT-3 receptors unclear. These results, and the fact that ben-
are best known as the site of action of clinically zodiazepines are known to mediate fast inhib-
useful antiemetics, such as ondansetron (Zof- itory transmission in the amygdala by interac-
ran). Although 5HT-3 receptors are found pre- tion with GABA, receptors (214), point to an
dominantly in the medulla oblongata (2071, intimate relationship between the 5HT-1A re-
their presence, albeit at lower levels, in the ceptor and GABA* a2 receptors. This is par-
amygdala and hippocampus raises the possi- ticularly interesting in light of recent work
bility of some role in emotional behaviors such with genetically altered mice containing mu-
as anxiety (208, 209). In rats, 5HT-3 antago- tations in GABA, receptor subtypes (148),
nists have shown anxiolytic effects when in- which suggests that the anxiolytic effect of di-
jected into the amygdala but not when injected azepam is mediated specifically by the a2 sub-
into the dorsal raphe nucleus (210). A similar unit.
anatomical pattern was observed for the anx-
3.3 Norepinephrine
iogenic effects of 2-methyl-5-hydroxytrypta-
mine, a 5HT-3 receptor agonist. Central The majority of noradrenergic neurons in the
5HT-3 receptors may influence the release of brain are located in the locus ceruleus (LC),
other neurotransmitters in the brain, includ- and electrical stimulation of this region in an-
Antianxiety Agents

imals leads to behaviors typical of an anxiety tapeptide) are important neurotransmitters


state. Increased norepinephrine (NE) levels in the central CCK system, and may have a
are also associated with the somatic symptoms role in the mediation of anxiety responses in
of anxiety, such as dry mouth, rapid heart animals and humans (220). Administration of
rate, and elevated blood pressure. CCK-4, a CCK-B agonist, promotes arousal
In the resting state, no differences in epi- and fear responses in a variety of animal mod-
nephrine and norepinephrine levels were els (221,222), and this agonist-induced anxio-
found between GAD patients and normal con- genic response can be blocked by pretreat-
trols (215). A different picture emerges using ment with CCK-B antagonists such as
challenge paradigms, which explore the dy- L-365,260 and CI-988 (222). Furthermore, ad-
namic properties of the adrenergic system in ministration of CCK-4 or pentagastrin in-
its response to stress. A blunted growth hor- duced panic attacks at a much higher rate in
mone response to the adrenergic a2 partial panic disorder (223), OCD (224) and GAD
agonist clonidine in GAD patients suggests a (225) patients than that in normal controls.
reduced sensitivity of a2 adrenergic receptors These studies are indicative of a role for CCK
(216). Furthermore, a decrease in platelet a2 in anxiety (226).
receptor sites has been reported in GAD pa- In addition, the CCK system interacts with
tients (217).Stressful events are known to in- other neurotransmitter systems that have es-
crease NE release in brain regions intimately tablished roles in anxiety. CCK is found in
involved with emotional behavior including GABA neurons in the cortex, hippocampus,
the hypothalamus, amygdala, and LC, and this and amygdala, and discontinuation of long-
increase is attenuated by diazepam (218). term diazepam therapy produces an upregula-
Moreover, the attenuating effect of diazepam tion of CCK-8 binding in rat cortex (219). Ad-
was blocked by the benzodiazepine antagonist ditionally, clinically relevant concentrations
flumazenil, whereas benzodiazepine inverse of benzodiazepines have been shown to inhibit
agonists (p-carbolines)facilitate NE release in CCK-&induced activation of rat hippocampal
these brain areas. Thus, inhibition of NE re- cells (227). A CCWGABA relationship has yet
lease in specific brain regions subsequent to to be demonstrated in human studies, how-
GABA, receptor activation may contribute to ever. In one study, the benzodiazepine recep-
the clinical action of the benzodiazepines. The tor antagonist flumazenil failed to reduce the
present data leave the exact role of norepi- panicogenic effect of CCK-4 in healthy volun-
nephrine in the neurobiology of anxiety unre- teers (228). In rats, the inhibition of explor-
solved. It appears that in resting situations atory behavior induced by CCK agonists can
the noradrenegic system functions normally, be blocked by pretreatment with the 5HT-3
but under challenge GAD patients may exhibit antagonist ondansetron (229). A CCWnorepi-
signs of reduced adrenergic receptor sensitiv- nephrine interaction has also been proposed.
ity. Selective neurotoxin destruction of noradren-
ergic nerve terminals in projections from the
3.4 Neuropeptides LC results in increased CCK receptor binding
density in brain regions that receive noradren-
3.4.1 Cholecystokinin. Cholecystokinin ergic input from the LC (219). CCK may also
(CCK) is one of the most abundant neuro- have a modulatory role in the HPA axis, in
transmitters in the central nervous system. that CCK-B agonists have been shown to in-
Two CCK receptor subtypes have been cloned crease ACTH and cortisol secretion (230). In
to date, that is, CCK-A (Alimentary), which addition, CCK-8 administration stimulates
are primarily located in the periphery, and the release of ACTH and of hypothalamic CRF
CCK-B (Brain) (219). CCK-B receptors are (231).
widely distributed throughout the brain, but
have particularly high densities in the hypo- 3.4.2 Corticotrophin-Releasing Factor (CRF).
thalamus, limbic system, basal ganglia, hip- CRF, a 41 amino acid peptide, mediates ACTH
pocampus, and brain stem (219). CCK-4 release from the hypothalamus and is inti-
(a tetrapeptide) and CCK-8S (a sulfated oc- mately involved in the stress response. CRF is
1
i
3 Physiology and Pharmacology

also located in brain regions associated with equate evidence that excessive CRF secretion
anxiety, including the LC and the amygdala. or activity is associated with at least some of
The modulatory effects of CRF are mediated the anxiety disorders (233,234,2581,and CRF -
through CRF-1 and CRF-2 receptors, both receptor antagonists are therefore valid anxi- :
members of the GPCR superfamily. CRF-1 re- olytic targets.
ceptors are the dominant form in the CNS
and hence the most frequently associated 3.4.3 Neuropeptide Y. Of the neuropep-'
with neuropsychiatric disorders such as anxi- tide Y (NPY)receptors identified to date, Y-1is
ety, depression, and stress disorders (226, the most strongly linked to the regulation of
232-234). CRF also interacts with the soluble anxiety. This receptor is found in high densi- - -
CRF-binding protein, which influences CRF ties in the brain, particularly in the cortex,
neurotransmission as well as the ability of thalamus, and amygdala, and Y-1 receptors in
CRF to activate the HPA axis (235). the latter structure are believed to mediate
Application of CRF directly into the LC the anxiolytic effect of NPY (226,259,260). In
stimulates neuronal firing, enhances NE re- rats, administration of antisense oligonucleo-
lease (236, 237), and produces anxiogenic ef- tides corresponding to the Y-1 receptor signif-
fects in behavior models (238, 239). Alprazo- icantly increased anxiety in behavioral models
lam reduces CRF concentrations in both the compared to normal controls (261). Postmor-
LC and the amygdala (2401, suggesting that tem examination of the brains of the treated
suppression of CRF stimulation of noradren- animals revealed a 60% decrease in Y-1 recep-
ergic neurons in the LC may contribute to the tors and no change in Y-2 receptors.
anxiolytic effect of the benzodiazepines. In NPY has shown an anxiolytic effect in sev-
various rodent models, including the elevated eral animal models (262, 263), although the
plus maze (2411, social interaction (242), and mechanism through which this anxiolysis is
Geller-Seifter conflict (243) paradigms, ad- produced is unclear. In rats, the anxiolytic ef-
ministration of CRF elicits behaviors consis- fect of NPY could be blocked by treatment
tent with an anxiogenic effect (244,245). CRF with an adrenergic a2 antagonist (idazoxan),
also potentiates the acoustic startle reflex, and but not by an a1 antagonist (prazosin) or a
this potentiation can be blocked by treatment benzodiazepine receptor antagonist (flumaze-
with chlordiazepoxide (246). Genetically al- nil) (262, 264). These results might suggest a
tered mice that overproduce CRF have been selective interaction between NPY and norad-
described and these animals exhibit a height- renergic transmission, and indeed NPY is ex-
ened state of anxiety in animal models (247, tensively colocalized with norepinephrine in
248). Conversely, mice lacking the CRF-1 re- the CNS (265). Yohimbine, an adrenergic a2
ceptor display reduced anxiety in many behav- antagonist known to increase anxiety, signifi-
ioral models (249, 250). The behavioral re- cantly increases circulating NPY levels in hu-
sponses to CRF in animals are therefore man subjects, again suggesting that the anxi-
suggestive of a role for CRF in human anxiety ety-modulating effects of NPY are, in part,
disorders. This proposal is supported by the related to noradrenergic transmission (266).
elevated cerebrospinal fluid levels of CRF Other clinical data regarding this proposal are
found in OCD (251) and PTSD (252,253) pa- inconclusive, however. Low CSF levels of NPY
tients, although this was not the case in panic have been correlated with higher anxiety
disorder (254) or GAD (255) patients. Simi- scores among depressed patients (267), yet
larly, urinary free cortisol levels were no dif- higher levels of NPY were found in panic dis-
ferent in social phobia patients compared to order patients than those in normal controls
those of normal controls (256), suggesting (268). Another study failed to find any differ-
normal function of the HPA axis in this ences in plasma NPY levels between normal
disorder. volunteers and patients with panic disorder or
The fact that CRF enhances the behavioral social phobia (269). Although current evi-
responses to stressful situations in animals in- dence suggests a linkage to the noradrenergic
dicates that it may play a role in the develop- system, NPY is an abundant transmitter in
ment of anxiety in humans (257). There is ad- the CNS and interactions with a variety of sys-
Antianxiety Agents

tems are likely. For example, NPY is also fre- vated plus maze test (279,280). Furthermore,
quently colocalized with GABA and soma- NMDA was able to substitute as a discrimina-
tostatin, offering further pathways through tive stimulus in pigeons trained to recognize
which NPY may modulate anxiety. In mice, the anxiogenic benzodiazepine receptor in-
chronic treatment with benzodiazepine recep- verse agonist P-CCE (281). The BZR antago-
tor agonists has been shown to increase Y-1 nist flumazenil blocked the ability of P-CCE,
receptor expression in the amygdala (270). Ad- but not NMDA, to act as a cue, suggesting that
ditionally, it has been suggested that NPY anxiety is the common stimulus produced by
could reduce anxiety by counteracting the both compounds.
anxiogenic effects of stress-induced CRF re- The foregoing evidence suggests that the
lease from the amygdala (271). excitatory glutamate system could have a com-
plementary role to that of the inhibitory
3.5 Glutamate Receptors
GABA system in anxiety. Thus activation of
The glutamate system is responsible for most glutamate receptors or inhibition of GABA re-
of the brain's excitatory neurotransmission. ceptors is anxiogenic, whereas inhibition of
Glutamate interacts with a number of recep- glutamate receptors or activation of GABA re-
tors, including the NMDA, AMPA, kainate, ceptors is anxiolytic.
and metabotropic glutamate receptors. The
latter receptor is coupled to G-proteins,
4 HISTORY
whereas the others are directly linked to ion
channels. In addition to the ion channel, the
The anxiolytic agents currently on the market
NMDA receptor contains a number of modu-
owe much to serendipity as well as rational
latory sites, including sites for glycine and glu-
design in their genesis. With the exception of
tamate. Just as enhancement of GABA's in-
buspirone, all first indication anxiolytics were
hibitory action decreases anxiety, it might be
introduced before 1975, before many of the
expected that inhibition of glutamate's excita-
modern techniques of medicinal chemistry
tory functions would produce the same effect.
such as radioligand binding assays, molecular
Indeed, the direct injection of NMDA antago-
modeling, and pharmacokinetic screening
nists into discrete brain regions has provided
were introduced into common practice.
evidence that functional antagonism of spe-
cific populations of these receptors produces
4.1 Discovery of the Benzodiazepines
an anxiolytic effect. Competitive antagonists
(272), as well as glycine site antagonists and The benzodiazepines represent the single
partial agonists (273, 2741, are active in the most important advance in the treatment of
elevated plus maze when microinjected into anxiety, and the story of their discovery is a
the dorsal periaqueductal gray matter truly remarkable one (282,283). In the 1950s,
(DPAG). In addition, intrahippocampal ad- a major research effort was the search for new
ministration of competitive and uncompeti- tranquilizers that would overcome the short-
tive NMDA antagonists and glycine partial comings of the medications in use at the time,
agonists was reported to significantly increase such as the barbiturates and the phenothia-
punished responding (275, 276). Complemen- zines. In the chemistry laboratories at Hoff-
tary to these results indicating that blockade man-La Roche in New Jersey, Dr. Leo Stern-
of glutamate receptors is anxiolytic, other bach approached this task by turning to a
studies shave shown activation of NMDA re- series of compounds, the "benzoheptoxdia-
ceptors to be anxiogenic. Thus NMDA in- zines" (191, which he had previously investi-
creases distress calls in the rat pup isolation gated as dyestuffs during his research at the
model (2771, decreases social interaction in Jagiellonian University in Krak6w, Poland.
rats, and decreases the time spent on the open Sternbach considered, then rejected, the pos-
arms of the elevated plus maze (2781, behav- sibility of making modifications to known nat-
iors characteristic of increased anxiety. Addi- ural or synthetic tranquilizers and, having no
tionally, injection of glycine into the DPAG knowledge of any discrete receptor target, he
produced an anxiogenic response in the ele- decided to pursue the benzoheptoxdiazines
4 History

compound was duly submitted, with everyone


involved unaware that this decision was the
first step of a revolution in the treatment of-
anxiety disorders. A few days later, Sternbach -
and his colleagues were amazed to hear that
this compound possessed an impressive biop
logical activity profile, including sedative,
muscle relaxant, anxiolytic, and anticonvul-
sant properties, that were comparable to, or- -
greater than, the prevailing reference com-
pounds of the time. Excitement grew when
simply out of his interest and familiarity with subsequent studies revealed the low toxicity of
their chemistry. In today's world of directed the compound, which was a real advantage
and target-based medicinal chemistry, it over the current medications. The intensive
would surely be difficult to justify basing one's chemistry effort inspired by this discovery was
research strategy on such a personal prefer- to provide yet another twist in the tale. It was
ence. Then, as now, there was an appreciation found that just like the starting materials, the
that a significant number of CNS agents were structure of this exciting compound had been
organic bases, and the essence of the research incorrectly assigned! Instead of the expected
strategy was to introduce basic groups into the substitution product (25), an unusual ring-ex-
molecule by reaction of the chloride (20) with pansion reaction had produced the 1,4-benzo-
secondary mines. The synthesis of numerous
diazepine (2). This compound, named chlordi-
compounds of type (21) followed, none of
azepoxide, progressed quickly through clinical
which showed any interesting biological activ-
ity. studies with outstanding results and was sub-
Then, studies on the chemistry of these sequently approved by the FDA. In what
compounds revealed that the structures of the seems an impossibly short timeframe to the
presumed benzoheptoxdiazines (20) had been scientist in modern drug discovery, chlordiaz-
erroneously assigned, and that they were in epoxide was launched as Librium in 1960, a
fact quinazoline N-oxides (22). The reaction mere 2%years after pharmacological studies
products were then reassigned structure (23), on the compound had begun. Further SAR
rather than structure (21). studies of this new class of compounds im-
proved upon the potency of chlordiazepoxide
and 3 years later, in 1963, Valium (diazepam)
was launched and went on to become one of
the most popular drugs in history. These suc-
cesses created an intense and widespread in-
terest in the benzodiazepines, and during the
next two decades over 30 members of this class
reached the marketplace as anxiolytics, seda-
At this point the demands of other projects tive-hypnotics, and anticonvulsants.
forced the abandonment of this synthetic Even in today's more rational drug discov-
work, and that would have been the end of the ery environment, it may be said that serendip-
story but for a remarkable stroke of good for- ity is one of the medicinal chemist's best
tune almost 2 years later. Duringa lab cleanup friends. Of course, serendipity alone cannot
in 1957 Sternbach's assistant, Earl Reeder, provide a drug; it requires someone to recog-
came across a small quantity of a crystalline nize the opportunity and capitalize on it. As
compound that had been formed from the re- demonstrated by Sternbach and his col-
action of the quinazoline N-oxide (24) with leagues, when chance discoveries fall into the
methylamine in 1955, but had not been sent hands of open-minded and persistent scien-
for biological testing. To tie up loose ends the tists, the results can be remarkable.
Antianxiety Agents

(2) Chlordiazepoxide

5 STRUCTURE-ACTIVITY RELATIONSHIPS benzodiazepines and serotonergic agents dis-


play very different behavioral profiles when
5.1 Animal Models of Anxiety examined in a range of anxiety models (208).
Regardless of the biological target with which As already noted, anxiety is a complex disor-
it interacts, any potential anxiolytic agent der with a multitude of contributory and pos-
must demonstrate efficacy in animal models to sibly overlapping mechanistic pathways, and
justify further development. Historically, the differences in behavioral effects may reflect
benzodiazepines have exerted a strong influ- the extent to which the model in question ac-
ence on the development of such models. The tually represents the anxiety pathway being
majority of in uiuo anxiety models have been targeted (284). Accordingly, it is now well ac-
designed to detect benzodiazepine-like effects, cepted that all models are not equivalent in
and have been optimized and validated using their sensitivity, and novel anxiolytic agents
benzodiazepines and benzodiazepine receptor must be subjected to a battery of behavioral
ligands. With the evolution of non-benzodiaz- tests for their activity to be determined with
epine anxiolytics such as those acting on the any confidence.
serotonin or neuropeptide systems, the gener- There are over 30 animal tests reported to
ality and predictive validity of many of these model anxiety and anxiolysis (202), and those
models is coming into question. For example, most commonly used are shown in Table 9.2.

Table 9.2 Animal Models of Anxiety


Unconditioned Models Conditioned Models
Exploratory Behavior Social Behavior Other Conflict Other
Elevated plus maze Social interaction Marble burying Geller-Seifter Activelpassive
Lightldark box Ultrasonic Cork gnawing Vogel Avoidance
Open field test Vocalization Pigeon conflict Fear potentiated
startle
Zero maze Human threat Monkey conflict Acoustic startle
Social competition
5 Structure-Activity Relationships 549

These models are classified into two major stable in acid solution, hydrolyzing to the lac-
groups: those based on unconditioned behav- tam (261, which possessed superior anxiolytic
ior and those based on conditioned behavior.
The former tests employ responses controlled
by operant conditioning procedures, and are
typified by the traditional Geller-Seifter and
Vogel conflict tests, whereas the latter models
rely on the natural aversive reactions of ani-
mals to novel stimuli, such as an unfamiliar
environment (elevated plus maze) or another
animal (social interaction). Although it is im-
perative to use a variety of animal models,
tests that do not involve unnatural responses
or punishment are increasingly favored. potency. In general, a carbonyl group is the
optimum substituent at the 2 position, the
5.2 Benzodiazepines
analogous 2-amino derivatives being some-
what weaker. Thus the basic side chain, the
In the study of compounds acting at the BZR, introduction of which formed the basis of the
modern researchers have at their disposal an original research strategy, turned out to be
array of powerful in vitro assays that provide a unnecessary, indeed detrimental, to the de-
detailed pharmacological profile of any new li- sired activity. An exception to this generaliza-
gand prior to in vivo behavioral testing. This tion is medazepam (27), which lacks any sub-
environment is in sharp contrast to that which
produced most of the classical 1,Cbenzodiaz-
epines. The clinical success and structural
novelty of chlordiazepoxide and diazepam
sparked a massive chemical investigation of
this class of compounds, but in the 1960s and
1970s no in vitro assays existed for the phar-
macological profiling of these new compounds.
Indeed their mode of action was a mystery, the
benzodiazepine receptor had yet to be discov-
ered, and the concepts of intrinsic activity and
subtype selectivity were many years away. stituent at position 2. In humans, medazepam
Nevertheless, the productivity of this period is metabolized to give a number of pharmaco-
was remarkable, with thousands of analogs logically active benzodiazepines, however, in-
being prepared and examined for tranquiliz- cluding diazepam, desmethyldiazepam, and
ing activity. Consequently, many of the key oxazepam (287,288),all of which contribute to
SAR observations on the benzodiazepines are the anxiolytic effect. Quazepam (Doral, 28) ex-
to be found in the older chemical literature
(for reviews, see 285, 286.) These SAR obser-
vations were initially built around i n vivo test-
ing for tranquilizing and anticonvulsant activ-
ity rather than pharmacological properties
such as affinity and intrinsic efficacy.

5.2.1 1,4-Benzodiazepine-2-Ones: General


Trends. The large number of compounds syn-
thesized in the few years following the launch
of chlordiazepoxide quickly identified some
general SAR trends in the benzodiazepine se-
ries. Chlordiazepoxide (2) was found to be un-
Antianxiety Agents

emplifies another variation at the 2 position, tution with fluorine or chlorine is allowed.
where the benzodiazepin-2-one has been con- These substituents strongly potentiate the an-
verted to the thiolactam. The reverse lactam xiolytic effects, however, giving compounds
of diazepam (29)shows comparable activity in significantly more potent than the unsubsti-
anticonvulsant tests (289). tuted analogs (282,290). Although much less
common than the C-5 phenyl benzodiaz-
epines, some heteroaryl derivatives, of which
bromazepam (7) is an example, have shown
significant biological activity. Bromazepam is
available as an anxiolytic and a sedative and is
reported to have a similar in vivo activity pro-
file to that of diazepam (291). Other heterocy-
cles at C-5 (e.g., pyrimidine, pyrazine) show
less activity than that of the 2-pyridyl group
(290). Within the 1,4-benzodiazepine tem-
plate, the effects of favorable substituents in
different parts of the molecule appear to be
Some of the fundamental structure-activ- synergistic. Flunitrazepam (31),which com-
ity relationships established in the early years
of benzodiazepine research have held true for
virtually all benzodiazepines prepared since
then. It was quickly found that methylation of
chlordiazepoxide at N-1 enhanced the potency
severalfold (282). N-Methyl benzodiazepines
are typically more potent than the N-H ana-
logs, and substituents larger than methyl
generally diminish activity. In the A-ring,
electronegative substituents such as halogen
(especially chlorine and bromine), nitro, or tri-
fluoromethyl at position 7 are required for sig-
nificant biological activity (290). Electron-re-
leasing groups (e.g., methyl, methoxy) at this
position decrease activity, as does substitution bines the optimal pharmacophoric groups at
of any kind at position 6, 8, or 9. An aromatic N-1, C-2, C-7, and C-5 (2921,is among the most
substituent at C-5 is usually required for use- active of all the benzodiazepines. Flunitraz-
ful biological activity, although tetrazepam epam (Rohypnol) is a powerful sedative-hyp-
(30) provides a rare example where this is not notic with significant memory-impairing and
the case. The C-5 phenyl ring is not tolerant of muscle-relaxant effects, all of which are
structural modification, and only ortho substi- strongly potentiated by alcohol. In recent
times, these effects have earned Rohypnol no-
toriety as a "date-rape" drug, and have re-
sulted in its removal from the market in many
countries.
3-Hydroxybenzodiazepines represent ac-
tive metabolites of many clinically useful ben-
zodiazepines (e.g., diazepam), and conse-
quently a large number of s-substituted
derivatives have been prepared and evaluated
as anxiolytics in their own right. These com-
pounds often show comparable potency to that
of the parent benzodiazepines, but have a dra-
matically different metabolic profile. In hu-
mans, diazepam gives rise to several active 3-oxazepam hemisuccinyl ester produced po-
metabolites that contribute to buildup of ac- tentiations of GABA induced chloride flux al-
tive agent in the blood over time. One of these most twofold greater than that of the 3-(R).
metabolites, oxazepam, is itself a marketed enantiomer (299). Likewise the 3-(S) enantio--
anxiolytic (293). Oxazepam is directly conju- mer of 3-methyldesmethyldiazepam is twice
gated at the 3-hydroxy group and is excreted as potent as, and is a stronger agonist (GABA
in the urine as the pharmacologically inactive shift = 2.7) than, the 34R) isomer GAB^
glucoronide (294,295). By virtue of this small shift = 1.5) (300). This stereochemical bias is
structural change, the clinical use of oxaze- believed to arise from a preferential stabiliza-
pam is not complicated by the buildup of active tion of conformation (33) by the 345) antip-
metabolites, a factor known to contribute to
the "hangover" effect seen with some benzo-
diazepines. Other 3-hydroxybenzodiazepines
in clinical use include lorazepam Ativan (4),
and the hypnotics temazepam (Restoril) and
lormetazepam (Loramet).
The &position, by way of the hydroxy
group, has been modified in an attempt to in-
crease the water solubility of benzodiazepines,
which are generally highly lipophilic com-
pounds. For example, the amino ester deriva- odes, in which the substituent occupies a
tive (32) of lorazepam had excellent water sol- quasiequatorial orientation (301). This con-
formation is believed to be preferred by the
receptor (3021, and is disfavored for the 3-(R)
enantiomers. The commercially available
3-hydroxybenzodiazepines are marketed as
racemic mixtures because their rapid race-
mization in uiuo renders a chiral formulation
impractical and unnecessary.
The N-4 atom may be replaced with a car-
bony1 group, as in clobazam (Frisium, 34),

ubility (as the methanesulfonate salt), and


showed anxiolytic efficacy comparable to that
of the parent compound (296). The carboxylic
acid at the 3-position of clorazepate (3) im-
parts high water solubility (297). Adminis- which has clinical anxiolytic and anticonvul-
tered as its dipotassium salt, the anxiolytic ac- sant properties. The carbonyl group presum-
tivity of chlorazapate derives from its rapid ably participates in a hydrogen bond interac-
decarboxylation in uiuo to give desmethyldiaz- tion with the receptor in a similar fashion to
epam (298). The stereochemistry of the &sub- that of the imine nitrogen in the typical 1,4-
stituent impacts on both the affinity and in- benzodiazepines. Other modifications in this
trinsic efficacy at the BZR, the 3 4 s ) isomers region include the fusion of heterocyclic rings
generally having greater affinity and higher across the 4,5 bond. Oxazolam, cloxazolam,
intrinsic efficacy than those of the 34R) iso- and ketazolam (35)are examples of this vari-
mers. For example, the 3 4 s ) enantiomer of ation that are in limited clinical use outside
Antianxiety Agents

(5) R1 = CH3, Rz = H (alprazolam)


the United States as sedative anxiolytics (51). (36) Rl = CH3, Rz = C1 (triazolam)
The fused heterocyclic ring is removed during (37) R1, R2 = H (estazolam)
metabolism to generate the parent benzodiaz- (38) Rl = CH20H, R2 = H
epine (303, 3041, which contributes signifi- (39) Rl = CH2N(CH3)2,Rz = H
cantly to the activity. Ketazolam (35),for ex-
ample, is converted into the active metabolites do show appreciable activity, however (310,
desmethylketazolam and desmethydiazepam, 311). The related C-1 aminoalkyl derivatives,
both of which have longer half-lives than that typified by adinazolam (Deracyn, 39), have
of the parent compound. Ultimately, 80% of a been reported to show anxiolytic or antide-
single oral dose (30 mg) of ketazolam is recov- pressant activity in animal models, depending
ered as oxazepam or oxazepam-glucoronide in on the length of the chain linking the amino
the urine (305). group to C-1 (312). With a single methylene
linker, activity was seen in anxiolytic and an-
5.2.2 1,2-Ring-Fused 1,4-Benzodiazepines. tidepressant endpoints, and lengthening this
In the early 1970s it was found that the fusion chain abolished anxiolytic but maintained an-
of a triazole ring (306, 307) across the 1,2 po- tidepressant activity. Increasing the size of
sitions of the benzodiazepine ring significantly the dimethylamino group was detrimental to
enhanced the in vivo potency (up to 10-fold) both activities. For adinazolam, the pharma-
compared to that of the corresponding lactam cological effects are largely mediated by the
(308). Subsequently, a range of five- and six- N-desmethyl metabolite. Repeated adminis-
membered heterocycles has been annelated at tration of (39) downregulates 5HT-2 recep-
this position (285),the most interesting being tors, and this may underlie its antidepressant
the triazole and imidazole variants. properties (313). An NDA was filed for adina-
Of the three possible triazole isomers that zolam following demonstration of anxiolytic
maintain a nitrogen at position 1 of the benzo- efficacy in clinical trials (314, 315), but was
diazepine ring, only the 4H-[1,2,4]-tria- subsequently withdrawn.
zolo[4,3-a]-1,4-benzodiazepine analogs, exem- In keeping with the SAR of the 1,Cbenzo-
plified by alprazolam (51, appear to have diazepine-2-ones, the biological activity of the
useful activity (285). Aiprazolam is clinically triazolobenzodiazepines is enhanced with
effective in GAD and is approved for use in electron-withdrawing groups (Cl, Br, NO,,
panic disorder. Other members of this class in CF,), and decreased with electron-donating
clinical use include the hypnotics estazolam groups (e.g., NH,, SMe), at the C-8 position
(36)and triazolam (37).A methyl group at the (285). Activity is potentiated by an ortho
C-1 position is optimal, and replacement with chloro or fluoro substituent in the C-6 phenyl
hydrogen, larger alkyl groups, or aromatic ring. The N-5 oxides (316) and the 4-hydroxy
rings reduces activity in animal models predic- derivatives (317) exhibit less anxiolytic activ-
tive of anxiolysis (285, 308, 309). The C-1 hy- ity than that of the parent compounds. This is
droxymethyl compounds (381, which are sig- in contrast to the benzodiazepin-2-one series,
nificant metabolic products of this chemotype, where the analogous 3-hydroxy derivatives
Structure-Activity Relationships

show comparable activity to that of the parent midazolam (41). Midazolam is a highly potent
compounds. In general, ksubstitution in the compound possessing strong hypnotic, anxio-
triazolobenzodiazepine series is detrimental
to activity (285, 318).
Imidazo[l,2-al[1,4lbenzodiazepines gener-
ally show inferior biological activity to that of
the analogous triazolo [1,2,4][4,3-a] deriva-
tives, but some success has been achieved with
a related series of amino-substituted imida-
zolone derivatives. This series is exemplified
by loprazolam (40), which possesses potent

lytic, and memory-impairing effects. This ac-


tivity profile has made midazolam (Versed) a
popular choice as a premedication for surgical
anesthesia.
Under acidic conditions many of the 1,2-
heteroaryl fused benzodiazepines, including
alprazolam (321) and triazolam (322),exist in
the ring-opened form (e.g., 42, for alprazo-
lam). Above pH 7 the reaction reverses to gen-
erate the benzodiazepine ring, meaning that
this is the active form under physiological
conditions.
hypnotic activity (3191, and is available under The majority of 1,2-ring fused benzodiaz-'
the trade name Dormonoct in Europe. The epines maintain a nitrogen atom at position 1
most active compounds of type (40) contain a of the benzodiazepine ring This nitrogen has
methyl, ethyl, or propyl group at the N-4 posi- been removed altogether to give a large num-
tion of the piperazine ring. The activity is fur- ber of 2-benzazepine derivatives, of which the
ther enhanced with a chlorine or fluorine at 5H-pyrimido[5,4-d][2]benzazepine class
the 2-position of the C-6 phenyl ring, but is shows the most interesting activity. Ro22-
generally insensitive to the nature of the elec- 3245 (43) has a comparable BZR affinity to
tronegative substituent at C-8 (320). More ro- that of diazepam, but is up to eightfold more
bust activity is observed with the isomeric imi- potent in animal anticonflict tests (323). The
dazo[l,5-a][1,4]benzodiazepines, typified by 9-chloro substituent is necessary for signifi-
Antianxiety Agents

epam (49) (330), both of which showed anti-


anxiety effects in human studies. Lopiraz-

(43) R1, R2 = H (R022-3245)


(44) R1 = OH, Rz = H
(45) Rl = H, Rz = OH

cant antianxiety activity, and the activity was


potentiated by a chlorine or fluorine at the
ortho position of the C-7 phenyl ring. Two of
the metabolites of Ro22-3245 are the 5-hy-
droxy (44) and the 4'-hydroxy (45) com-
pounds. In keeping with established benzodi-
azepine SAR, (44) shows comparable activity
to that of the parent compound and (45) is
inactive (324).

5.2.3 Heteroaryl[el[l,4lDiazepin-2-Ones.A
number of chemical classes with anxiolytic ac-
tivity have been produced by replacement of
the fused phenyl ring of the 1,4-benzodiaz-
epines with heterocycles. Ripazepam (46)

epam (50)appears to be the most interesting


member of the pyridodiazepin-2-one family,
and is said to have potentially useful antianx-
iety activity (331).
(32'5, 326) and zolazepam (47) (327) are
among the most active members of a series of 5.2.4 Bis-Heteroaryl[a,fl [I ,4]Diazepines.
6,8-dihydropyrazolo[3,4-el[1,4lbenzodiaze- Not surprisingly, the A-ring modifications of
pin-2-ones. Of the three possible isomeric the benzodiazepin-&ones (Section 5.2.3) have
thieno[l,4ldiazepine-2-ones(3281, only the been extended to many of the more potent 1,2-
[2,3-el derivatives are reported to possess sig- ring fused benzodiazepines described in Sec-
nificant anxiolytic activity. This chemotype is tion 5.2.2 to give a large number of bis-het-
typified by bentazepam (48) (329) and clotiaz- eroaryl derivatives (285). Of the many variants
5 Structure-Activity Relationships

appropriate. The major driving force behind


the investigation of new ligands at the BZR .
has been the development of compounds that -
retain the therapeutic effects of the benzodi-
azepines, but are devoid of their unwanted
side effects. This objective has been ap- r
proached in two ways, through partial ago-
nism and subtype selectivity.
-
5.3.1 Partial Agonism and Subtype Selectiv-
ity. The benzodiazepines act as full agonists
(positive allosteric modulators) at the BZR,
F
and they are able to induce maximal receptor
investigated, the thieno[3,2-fl[1,2,4ltriazolo- response with low receptor occupancy. It has
[4,3-a][1,4]diazepines, of which brotizolam been suggested that anxiolysis requires less
"
L
(51)and Y7131 (52) are prominent examples, receptor occupancy than sedation (150) and
have the greatest biological activity. At least other benzodiazepine side effects. In addition,
one substituent, usually alkyl, on the thio- a downregulation of receptors has been dem-
onstrated upon prolonged treatment with full
BZR agonists, a phenomenon that may under-
lie the development of tolerance and depen-
dency. Based on this theory that different lev-
els of receptor activation produce different
clinical effects, compounds that act as partial
agonists (i.e., compounds that produce less re-
ceptor activation than a full agonist at a com-
parable receptor occupancy) have become the
focus of much attention (335). It is important
to note that high affinity must be maintained
in a partial agonist; only the functional activ-
ity is moderated. The intrinsic activity of BZR
ligands may be determined in a number of
ways. tert-Butylbicyclophosphorothionate
(TBPS) is a ligand at the picrotoxinin side of
the GABAAreceptor whose binding affinity is
modified in the presence of BZR ligands, and
phene ring is required for significant anxio-
the TBPS shift (ratio of TBPS binding for the
lytic activity, and any activity observed is en-
test drug to that of a known standard, such as
hanced with an ortho chloro or fluoro diazepam) is used to estimate the intrinsic ac-
substituent on the C-6 phenyl ring (332). Bro- tivity (336). This is a relative measurement:
tizolam has been introduced as a hypnotic, full agonists have a TBPS shift of 1; antago-
andY7131 (etizolam)is reported to have inter-
nists, 0; and inverse agonists have negative
esting anxiolytic activity (333, 334).
shifts. Partial agonists have values intermedi-
ate between 0 a i d 1 (337).
5.3 Non-Benzodiazepine Ligands at the BZR
A second method describes intrinsic activ-
Initially it was believed that the 1,kbenzodi- ity in terms of the GABA shift (338). This
azepine structure was an essential require- method relies on the bidirectional nature of
ment for high affinity binding to the BZR, but the allosteric coupling between the BZR and
a wide range of non-benzodiazepine chemo- the GABA site. Just as the activity of GABA at
types have since been shown to bind to the its receptor site is enhanced by ligands at the
BZR with high potency, rendering the term BZR, the affinity of BZR ligands for the benzo-
"benzodiazepine receptor" no longer strictly diazepine site is enhanced in the presence of
556 Antianxiety Agents

Table 9.3 Preferred Profiles of Partial Agonists and Profiles of Reference Drugs
a1 a2 a3 a5 Reference
Preferred profile <20% >30% >30% <20% 344
Preferred profile <10% nd 40->60% nda 345
Alprazolam (5) 326% 355% 787% 264% 127
Diazepam (1) 186% 290% 568% 157% 127
Lorazepam (4) 328% 233% 421% 181% 127
Bretazenil (83) 40% 37% 76% 64% 127
"nd. not disclosed,

GABA. This coupling, and hence affinity en- been an intensive effort to identify "anxio-
hancement, is stronger for full agonists than selective" compounds that selectively modu-
for partial agonists, and is nonexistent for an- late GABA function at specific receptor sub-
tagonists. Thus the GABA shift (ratio of IC,, types. Although they are attractive proposals,
without GABAK!,, with GABA) is loosely partial agonism or subtype selectivity on their
predictive of the relative degree of intrinsic own may not be enough to produce the desired
efficacy. This estimate is based on comparison clinical profile. A given subtype (e.g., a2) may
with known full agonists such as diazepam, be associated with more than one clinical ef-
which has a GABA shift of 2.2-2.9. Accord- fect, depending on receptor activation, and so
ingly, inverse agonists have values less than 1,
a full agonist selective for this subtype would
full agonists have values of 2 or more, and par-
be of little value. Similarly, a nonselective par-
tial agonists lie between 1 and 1.5 (339,340). A
tial agonist may be unable to differentiate be-
more accurate and meaningful assay is the di-
rect measurement of the potentiation of tween effects requiring low activation of only
GABA-induced chloride currents by a BZR li- one subtype. In recent times both these ap-
gand. This is determined in single oocytes ex- proaches have coalesced into the search for
pressing the desired recombinant receptor subtype-selective partial agonists, and this ef-
subtype, using a two-electrode voltage-clamp fort dominates the current medicinal chemis-
technique (341-343). A fixed concentration of try and preclinical work in the area. With in-
GABA is applied (typically enough to produce creasing knowledge of the physiological roles
10-20% of the maximal current), and the po- of GABA, subtypes guiding the subtype selec-
tentiation of this current by the drug is mea- tivity profile, the next challenge in this ap-
sured over a full dose-response range. The proach is the determination of the "right
maximal potentiation (%) and the EC,, value amount" of partial agonism. Based on preclin-
describe the efficacy and the potency, respec- ical animal models, some companies have re-
tively. This assay directly measures the recep- vealed their preferred partial agonist profile
tor activation by the ligand, unlike the TBPS for anxiolytics (344,345) (Table 9.3). It is clear
and GABA shift assays that provide only rela- from Table 9.3 that these profiles are dramat-
tive efficacies. ically different from those of the classical ben-
A second approach to improve the side-ef- zodiazepines, and are more selective than the
fect profile has grown from the increasing prototypical partial agonist bretazenil.
knowledge of the diversity of GABA, receptor An exhaustive review of the non-benzodi-
subtypes. Each of the four major diazepam- azepine ligands at the BZR is beyond the scope
sensitive subtypes exhibits a distinct, al- of this chapter, and the following section fo-
though perhaps overlapping, pharmacology, cuses only on those templates that have pro-
anatomical distribution, and physiological duced advanced anxiolytic candidates. In addi-
hnction. Recent work with conditional tion to the compounds described below, a wide
knock-in animals strongly implicates the a1 range of small molecules bind with high affin-
and a2 subtypes in the mediation of the seda- ity to the BZR. The reader is invited to consult
tive and anxiolytic actions of diazepam, re- recent reviews on this topic for more extensive
spectively (144-149). Accordingly, there has coverage (346-351).
5 Structure-Activity Relationships

5.3.2 p-Carbolines. The isolation of the po- a to the oxygen, but not P or y to the oxygen,
' tent BZR ligand p-CCE (53) from human suggesting a well-defined and limited li- .
pophilic pocket in the receptor (354). In the
C-6substituted p-carbolines this change -
causes a greater loss in affinity, possibly be-
cause of a steric interaction between the C-3 ?.
and C-4 groups and consequent disruption of
hydrogen bonding at N-2 (356). A 3-amino
substituent abolishes binding affinity (356) -
because of insufficient lipophilic interaction
(53) X = COzEt (P-CCE) with the receptor and the existence of the
(54) X = C02CH3(P-CCM) amino group in the imino tautomer, which
(55) X = C02-n-Pr would prevent hydrogen bond formation with
(56) X = alkoxy N-2.
The size of the substituent at position 6
urine in 1980 (352) prompted a great deal of also has a major impact on the intrinsic effi-
interest in p-carbolines as possible endoge- cacy, but less so on receptor affinity. Thus
nous ligands for the BZR. Although the pres- compound (57) has an IC,, value of 0.5 nM for
ence of p-CCE in urine was subsequently
shown to be an artifact of the extraction pro-
cedure (3531, interest in this series continued
because of their high potency and unusual
pharmacology. p-CCE and p-CCM (54) were
the first compounds to exhibit inverse ago-
nism at the BZR, and p-carbolines have be-
come the most widely studied class of BZR li-
gands after the benzodiazepines themselves.
The pyridyl nitrogen atom is essential for
affmity and is presumed to participate in a
critical hydrogen bonding interaction with the
receptor (354,355). A free NH at position 9 is
also required, as affinity is drastically reduced
in the N-methyl analogs (356). Computer the BZR, antagonized the anticonvulsant ef-
modeling suggests that this loss of affinity re- fects of diazepam, and showed no anticonvul-
sults from a negative steric interaction be- sant effects of its own, consistent with an an-
tween the N-methyl group and the receptor tagonistic profile (359). The corresponding
rather than the removal of a hydrogen bond n-propyl compound (58)has an IC,, value of 8
donor site. Most of the early p-carbolines were nM, and at 20 mgkg showed comparable effi-
inverse agonists but, through appropriate cacy to that of diazepam (2.5 mg/kg) in the
modification of substituents, compounds span- elevated plus maze. Further, (58) showed no
ning the entire continuum of intrinsic activity myorelaxation activity and antagonized diaz-
up to full agonist can be obtained. Increasing epam-induced myorelaxayion, indicating par-
the size of the 3-substituent increases the in- tial agonist properties. Increasing the size of
trinsic activity. Thus extending the ester alkyl the 6-substituent further gives ZK93423 (59),
group from methyl (54) to n-propyl (55) which behaves as a full agonist. Modeling
changes the profile from inverse agonist to an- studies suggest that the influence of the 6-sub-
tagonist (357). The p-carboline ester group is stituent on intrinsic efficacy derives from its
hydrolytically labile and it can be replaced full occupation of a lipophilic pocket (L3) of
with alkoxy groups (56) to enhance stability the receptor. The partial agonist (58)only par-
and water solubility" (358). The rank order of tially occupies this region compared to the full
potency is methoxy < n-butyloxy < ethoxy < agonist (59). Moving the 6-benzyloxy group
n-propyloxy (356,357). Branching is tolerated from the 6- to the 5-position lowers the activ-
Antianxiety Agents

ity to that of a partial agonist (360, 361), fur- symptoms of withdrawal, tolerance, and de-
ther underlining the importance of this inter- pendency (364-367), although the latter
action in the agonist response. The C-5 phenyl symptoms have been observed in other studies
ring of the benzodiazepines is also believed to (368). In clinical trials, abecarnil was found to
confer agonist activity by interacting with the be well tolerated (369) and effective in GAD at
L3 region (see Fig. 9.5). Agonist and inverse doses of 3-9 mg per day with minimal side
agonist p-carbolines probably bind at the effects or discontinuation symptoms (370),al-
same site, but have slightly different interac- though the therapeutic effect diminished after
tions with various receptor regions. The pres- 6 weeks of dosing (371). At higher doses, how-
ence of a methoxyrnethyl substituent at C-4 is ever, side effects typical of a full agonist were
proposed to favor the "agonist" alignment of observed including sedation, amnesia, and un-
the ligand through formation of a hydrogen steady gait. Subsequent studies have shown
bond with the receptor. This substituent does that abercarnil potentiates GABA-induced
indeed confer agonist properties, as evidenced chloride currents at the a 3 subtype to the
by the anxiolytic, anticonvulsant, and myore- same degree as the full agonist flunitrazepam
laxant activities of (59). The corresponding (372), and to the same degree as diazepam in
4-ethyl analog, which lacks this hydrogen rat cerebellar slices (373). These results sug-
bonding capability, is five- to 10-fold weaker at gest that abercarnil possesses neither the op-
the BZR and is devoid of any such agonist ac- timal subtype selectivity nor the optimal par-
tivity (356). The affinities of numerous p-car- tial agonist properties for a side effect-free
boline derivatives at recombinant receptor anxiolytic, and its clinical development has
subtypes reveal nonselective binding to a l , been terminated.
a2, a3, and a5 subtypes (356). In the absence
of efficacy measurements at these subtypes, 5.3.3 Cyclopyrrolones. The cyclopyrrolones
the clinical relevance of even the best selectiv- were among the earliest non-benzodiaz-
ity (~20-fold) remains questionable. epine structures shown to have high affinity
The conversion of the ethyl ester of (59)to for the BZR. The best-known member of this
an isopropyl ester gives abercarnil (60) the series is zopiclone (611, which is available as a

most clinically advanced P-carboline to date.


Abecarnil is a potent BZR ligand (IC,, = 0.8
nM) and binds with equal affinity to all diaze-
pam-sensitive subtypes (362). Abercarnil has
a GABA shift of 1.2-1.4, compared to 2.8 for hypnotic (Imovane, Rhone-Poulenc Rorer) in
diazepam, indicating partial agonist charac- Europe and Canada. Several members of the
ter. In preclinical models, abercarnil showed cyclopyrrolone family have progressed into
anxiolytic (362) and anticonvulsant (363) ac- clinical trials as anxiolytics, including suri-
tivity, and appeared to be devoid of significant clone (62), pazinoclone (63), and pagoclone
sedative and myorelaxant properties (362, (64). Cyclopyrrolones are highly potent BZR
364). In addition, abercarnil exhibited little al- ligands with affinities often in the subnano-
cohol interaction (362) or tendency to induce molar range. The pyrrolone moiety is common
E
b
k
5 Structure-Activity Relationships

doses of 0.3-1.2 mg, but was withdrawn from


development before approval. Pazinaclone
(DN-2327, Takeda Industries, (63)) has an
IC,, value of 0.4 nMfor the BZR and exhibits -
a number of properties that indicate partial
agonist character. It is active in a range of,
conflict and nonconflict anxiety models with
med's ranging from 2.5 to 10 mg/kg, po (3751,
and these anxiolytic effects could be blocked .
by flumazenil. (63) showed little propensity to
cause sedation or muscle relaxation (375,376)
and did not affect sleep structure in cats at
doses up to 20 m a g (377). Although (63)
showed less memory impairment than that of
diazepam (378), the two drugs were able to
substitute for each other in drug discrimina-
tion tests (379). In Phase I trials, however,
pazinaclone (single doses of 2-32 mg) pro-
duced similar deficits in psychomotor perfor-
mance and short-term memory to alprazolam
(0.25-2 mg) (380-382). It appears that pazina-
clone may not possess the necessary selective
partial-agonist profile to improve significantly
on the benzodiazepines, and its development
has been discontinued.
Pagoclone (64) is the most clinically ad-
vanced of the anxiolytic cyclopyrrolones, and
has reached late-stage clinical trials for GAD
and panic disorder. (64) has an IC,, of 0.4 nM
at the BZR and shows no selectivity among'
the benzodiazepine-sensitive subtypes (383).
Pagoclone shows in vivo anxiolytic activity at
low oral doses (NO. 1 mg/kg). In animal studies,
(64) is 30 times more potent than diazepam in
anxiety models but 10 times less potent in sed-
ative paradigms (384). Although intrinsic effi-
cacy data are not available, pagoclone's behav-
ioral profile is that of a partial agonist, and
accordingly it is claimed to have a greater sep-
aration of anxiolytic effects and side effects
than those of standard anxiolytics (385).
Phase I studies showed pagoclone to be well
tolerated and revealed no significant effects on
sleep, psychometric, or withdrawal measures
(384, 386, 387). Drowsiness, a characteristic
benzodiazepine action, was one of the most
commonly reported side effects, however, es-
to all these structures, and modifications of pecially at doses exceeding 1 mglday. Clinical
the N-2 and C-3 substituents give rise to dif- studies to date confirm pagoclone's effective-
ferences in intrinsic efficacy. ness in panic disorder. At daily doses of 0.3
Suriclone (62) has shown positive anxio- mg/kg (0.1 mg/kg, tid), (64) reduced panic at-
lytic efficacy in human trials (374) at daily tacks by 40-73% (387-389).
Antianxiety Agents

5.3.4 Pyrazoloquinolines. The pyrazoloquino- increasing size (H, methyl, ethyl, n-propyl, n-
line series, originally developed at Ciba-Geigy, butyl) in the thiophene ring leads to a shift in
provides highly potent BZR ligands that span efficacy from inverse agonist, through partial
the entire continuum of intrinsic efficacy from agonist, to agonist (394). Incorporation of un-
full inverse agonist to full agonist. The freely substituted heterocycles at N-2 (pyrazine,
rotating phenyl ring at N-2 plays a critical role pyridine) maintains affinity and gives inverse
in determining the intrinsic efficacy of the agonist compounds (395). The influence of the
molecule, and minor changes in this ring in- N-2 aromatic ring on the intrinsic activity is in
duce dramatic shifts in efficacy. In anticonvul- keeping with molecular modeling studies,
sant and anticonflict tests CGS8216 (65) behaves which place this ring in a lipophilic binding
pocket (L2) responsible for agonist activity
(396) (see Fig. 9.5) and identify N-1 and the
C-3 carbonyl group as the key hydrogen bond
acceptors. Differential occupation of the L2 re-
gion by various substituents is proposed to
produce varying degrees of agonism.
In the A-ring, small substituents (e.g., OH,
OCH,, C1, ethynyl) are tolerated at all four
positions (395, 396), and have less impact on
intrinsic activity than that of substituents in
the N-2 phenyl ring. Large substituents are
tolerated only at the 8-position, as indicated
by the high affinity of the benzyloxy derivative
(68) (396). The other three positional isomers

as an inverse agonist, and the 6methoxy ana-


log (66) as a weak partial agonistlantagonist.
Replacing the methoxy group with chlorine
gives CGS9896 (671, a more potent partial ag-
onist (390) that displays robust anxiolytic and
anticonvulsant activity in animal models
(391). The relative intrinsic activities of these
compounds are also indicated by their GABA
shifts (392). Moving the methoxy- or chloro-
substituent from thepara to the meta position are inactive. The large benzyloxy group also
of the phenyl ring has little effect on affinity confers agonist character on the molecule,
but increases the degree of agonism, as indi- which has a GABA shift of 1.3 (compared to
cated by the change in the GABA shifts (from the unsubstituted analog 65, a full inverse
1.07 and 0.94 to 1.7 and 1.1, respectively). The agonist).
ortho-substituted derivatives are weak or in- Pyrazoloquinolines frequently possess sub-
active, possibly because of disruption of the nanomolar affinity for the BZR, but show no
coplanar arrangement between the phenyl subtype selectivity in their binding (396). Un-
ring and the pyrazoloquinoline nucleus. The like the benzodiazepines, some pyrazoloquino-
N-2 phenyl ring may be replaced by thiophene lines also bind to the diazepam-insensitive re-
(393). These compounds are potent BZR li- ceptor subtypes (a4 and a6). Although several
gands (Ki <. 3 nM),and different thiophene compounds show partial agonist and anxio-
isomers possess different levels of intrinsic ef- selective profiles (e.g., CGS9896) in preclinical
ficacy. Also, the introduction of substituents of models, there is no evidence to suggest any
subtype selectivity in these compounds. Poor efficacious anxiolytic, but was withdrawn
solubility is another drawback that has hin- from development because of the emergence
dered their development. of liver toxicity.
-
Selectivity for the CBZR over the PBZR is
E
"
5.3.5 Imidazopyridines. The best known
member of the imidazopyridine class is zolpi-
highly sensitive to small structural changes in
the imidazopyridine nucleus and zolpidem, de-
F dem (Ambien, 69), the world's most popular spite its similarity to alpidem, has no affinity
1 for the PBZR. At the 6-position of imidazopy-
ridines, chlorine is the optimal substituent .

and is fivefold more potent (IC,, = 86 nM)


than the unsubstituted analog at the CBZR
(405). The order of CBZR potency for 6-sub-
stituents is C1> Br > CH, > I > H %- OCH, %-
NO,, but PBZR affinity is largely unaffected
by the nature of this substituent. Incorpora-
tion of substituents at the 8-position of the
imidazopyridine nucleus eliminates affinity
for the CBZR but maintains, and may en-
hance, affinity for the PBZR (405, 406). A
4-chloro substituent in the C-2 phenyl ring po-
tentiates the affinity of imidazopyridines for
hypnotic drug. The close analog alpidem (70) both the CBZR and PBZR (406). In the acet-
is the most prominent anxiolytic of this class. amide side chain, the optimum N-alkyl groups
Alpidem is active in a number of anxiolytic are methyl, ethyl, and propyl(399). Increasing
models but is reported to be less effective than the length of the alkyl chain, or the introduc-
classical benzodiazepines such as diazepam tion of branching, reduces affinity. Secondary
and alprazolam (397, 398). This difference amides are generally more potent than ter-
may be a consequence of the subtype selectiv- tiary amides, and replacement of the amide
ity of the imidazopyridines. Both alpidem and moiety of zolpidem and alpidem with esters of
zolpidem are selective for the a1 subtype of similar size virtually eliminates affinity for '

the BZR, having intermediate affinity at a2 both BZRs (405). Removal of the methylene
and a 3 sites and low affinity for a5 sites. The linker between the carbonyl group and the
original anxiolytic imidazopyridine research imidazo ring, or extension of this linker to two
strategy was based on al-selective ligands carbons, dramatically reduces affinity at both
(399), but it is now believed that the a2 sub- BZRs (405). This suggests that there is a crit-
type mediates the anxiolytic effects of BZR li- ical spatial relationship between the two hy-
gands and so a1 selectivity is clearly a nonop- drogen bond acceptor sites (the imidazole ni-
timal profile for an anxiolytic. The picture is trogen and the carbonyl oxygen) that cannot
further complicated by the fact that alpidem be disrupted. Indeed, most BZR receptor mod-
has an affinity for the peripheral benzodiaz- els demand the formation of two hydrogen
epine receptor (PBZR) comparable to that for bonds at specific locations.
the central BZR (Ki = 1-28 and 0.5-7 nM,re- Molecular modeling studies have suggested
spectively) (400). Further, the BZR antagonist that the acetamide side chain of alpidem is
flumazenil completely blocks the anxiolytic more important for PBZR binding than for
and anticonvulsant effects of benzodiaz- CBZR binding, whereas the hydrogen bonding
epines, but only partially blocks the same ac- capability of the imidazole nitrogen is more
tions of alpidem (401). Thus it is possible that important for CBZR than for PBZR affinity
the anxiolytic actions of alpidem may result (407). The a1 selectivity of imidazopyridines
from a combination of direct action at the cen- has also been rationalized through conforma-
tral BZR and an indirect action at the periph- tional analysis and molecular calculations
eral BZR (402-404). Alpidem progressed into (408). Zolpidem is selective for BZl(a1) sites,
clinical trials, where it was shown to be a n whereas saripidem (71) has equal affinity for
Antianxiety Agents

showed poor affinity (IC,, = 990 nM),the


2-chloro derivative (74) was comparable (12
nM)to the unsubstituted anilide (75), and the
2-fluoro derivative (76) was the most active
(1.7 nM). (76) also possessed partial agonist
character, as evidenced by its GABA shift of
1.2, and was active in conflict models (1m a g ,
ip), The benzylamide (77) was also active (IC,,
= 12 nM), but with a GABA shift of 4.6 (com-
pared to 2.2 for diazepam, a full agonist) it is
clearly a full agonist itself. Methylation of the
BZ1 and BZ2 (a2, a 3, and a5) sites. A two- imidazole nitrogen in the 2-fluoro compound
dimensional NMR analysis (409) found that (761, to give (781, enhances the affinity (0.47
zolpidem possessed only one family of confor-
mations, in which the acetamide moiety was
positioned 2 A above the plane of the imidazo-
pyridine ring. This is consistent with the crys-
tal structure of alpidem (399). Saripidem also
exists in this conformation, which is presumed
to impart BZ1 affinity. However, saripidem
may exist in a second conformation in which
the acetamide group is in the plane of the imi-
dazopyridine system, and this conformation
may confer BZ2 affinity. nM), raises the intrinsic efficacy (GABA shift
= 1.61, and greatly enhances the in uiuo po-
5.3.6 Pyridobenzimidazoles. The pyrido- tency (conflict med = 0.03 m a g , ip) (340). In
benzimidazoles (72) (for a review, see Ref. both the NH and N-methyl cases, the intro-
duction of the ortho fluoro substituent de-
creased the GABA shift relative to that of the
unsubstituted anilide. Efforts to improve the
poor oral bioavailability of this series led to
RWJ-38293 (791, but only at the expense of in
uitro (IC,, = 160 nM)and in vivo (conflict med
= 3 mgkg, ip and 10 mgkg, pol potency (411).
On the other hand the A-ring pyridyl deriv-
atives (e.g., 80) have substantial water solubil-

410), developed at the R.W. Johnson Research


Institute, are a relatively new class of benzo-
diazepine receptor ligands that range in effi-
cacy from antagonist to full agonist. SAR stud-
ies on the amide portion of the molecule ity and promising oral anxiolytic activity (con-
showed that only the secondary amides are flict med = 3 m a g , po) (412). Substitution of
active, and that substituents in the 4-position the phenyl A-ring at the 6 and/or 7 positions
of the phenyl ring generally lower the BZR with chlorine or fluorine provided the most
afflnity (340). The effect of &substitution is active compounds in the conflict model. The
variable: the 2-methoxy compound (73) sum of these SAR investigations has led to the
i

5 Structure-Activity Relationships

identification of RWJ-51204 (81), which com-


bines favorable substitutions in the A-ring,
the anilide, and at N-5, and is currently in

EtO
F
4T N

\
C02Et Y

CH3
0
-
(82)

clinical development as an anxiolytic (410).


(81) is an extremely potent partial agonist
(IC,, = 0.3 nM, GABA shift = 1.171, with a
preferential affinity for a1 and a2 subtypes.
Because the reported GABA shift data are
based on a heterogeneous population of native
GABA, receptors it gives no information on
subtype selectivity in terms of efficacy, and the
clinical relevance of the binding selectivity re-
mains unclear. (81) is reported to be highly assays. Bretazenil is the most significant anxi-
active in animal models of anxiety with little olytic candidate to emerge from this series.
tendency to induce sedation, motor incoordi- (83) is a potent BZR ligand (Ki = 2 nM) and
nation, or withdrawal symptoms. In a monkey has a GABA shift of 1.4, compared to 2.9 for
conflict model, RWJ-51204 was 10 times less diazepam, indicating partial agonist character
potent (ED,, = 0.4 mg/kg, po) than loraz- (414). This has also been demonstrated by in
epam, alprazolam, and clonazepam, and was vitro experiments relating BZR receptor occu- '
equipotent with diazepam. When side effects pancy to the potentiation of GABA-stimulated
are considered, however, RWJ-51204 has a chloride flux (415). Bretazenil was found to
significantly wider therapeutic window than induce a maximal potentiation of C1- current
these reference benzodiazepines. Phase I stud- of only 20%, compared to a 50% potentiation
ies in healthy volunteers revealed no adverse for diazepam. Diazepam produced 25% poten-
effects and clinical development is continuing. tiation at 35% receptor occupancy, but breta-
A safe and cost-effective large-scale synthesis zenil did not reach 25% ~otentiationeven
of this compound has been reported (413). at receptor saturation. Electrophysiological
measurements further confirm bretazenil's
5.3.7 lmidazobenzodiazepines. The imida- partial agonist character (Table 9.3) (127), al-
zobenzodiazepines constitute a large and im- though these data also reveal a lack of subtype
portant series of high affinity BZR ligands that selectivity. Comparison of in uivo receptor oc-
are structurally distinct from the classical cupancy and behavioral effects shows that
benzodiazepines, and have produced inverse bretazenil requires higher occupancy than
agonists, antagonists, and partial agonists. that of diazepam to produce comparable anxi-
This family is exemplified by flumazenil (82) olysis (416). Because sedation and myorelax-
and bretazenil (83). Flumazenil is a potent ation require even higher receptor occupancy,
BZR antagonist that is used clinically (Roma- it might be expected that these effects would
-
zicon) to reverse benzodiaze~ine-induced se- be minimized with bretazenil. Indeed. in ani-
dation and for the management of benzodiaz- mal models bretazenil is an effective anxio-
epine overdose. Tritiated flumazenil is also lytic that induces less sedation than that of
widely used as the radioligand in BZR binding classical benzodiazepines (4161, and can an-
Antianxiety Agents

tagonize the sedative and myorelaxant effects heterocycles have been investigated as poten-
of benzodiazepines. Clinical trials showed tial replacements for the metabolically labile
bretazenil to be an effective anxiolytic, but ester group, of which the 3- and 5-alkyl-1,2,4-
also revealed side effects including sedation, oxadiazole derivatives appear to possess the
amnesia, and performance impairment. The best affinity (420). As a general rule, the ox-
development of bretazenil was discontinued in adiazole derivatives have a higher intrinsic ef-
1997, and the results with this compound sug- ficacy than that of the corresponding ester an-
gest that nonselective partial agonism alone alogs. The SAR of the 3-substituent closely
may not be sufficient to provide a side effect- parallels that of the 3-substitent in the p-car-
free anxiolytic. bolines, suggesting that this region of both
Many members of the imidazobenzodiaz- templates occupies the same binding pocket
epine class display potent affinity for diaze- (420). The substitution pattern in the phenyl
pam-insensitive (DI) subtypes (a4, a6) as well ring also has implications for DSDI affinity
as the diazepam-sensitive (DS) subtypes ( a l , and selectivity. Substitution with electron-
a2, a3, a5) of the BZR, and numerous SAR withdrawing groups (e.g., halogens) at posi-
studies have examined the requirements for tion 7 enhances affinity for the DS subtype
DSDI selectivity. Overall, these studies sug- more than for the DI subtype, whereas 8-sub-
gest that the binding sites for DS and DI sub- stitution preferentially enhances affinity for
types are similar and that selectivity is gov- the DI subtype (421-423). The net result of
erned by structural modifications at positions 7-substitution is therefore an enhancement of
3,7,and 8 of the imidazobenzodiazepine struc- DS selectivity. Substitution at C-8 and C-9 of
ture (84). DS subtypes are responsible for the the phenyl ring dramatically reduces affinity
typical benzodiazepine actions (anxiolysis, se- for DS and DI isoforms (422). Among the four
dation, etc.), and DI subtypes have been impli- DS subtypes, a lipophilic substituent at C-8
cated in mediating some of the behavioral ef- has been found to confer selectivity (4251, but
fects of ethanol (417-419). no selectivity for subtypes implicated in anxi-
olysis (a21 has been reported.

5.3.8 Imidazoquinoxalines. Panadiplon


(85)is the most advanced member of this se-

At the N-5 position, a methyl group appears


to be optimal for DS binding, given that the
NH, N-propyl, and N-aryl analogs are inactive
(420). The N-benzyl derivatives do show com-
parable affinity (2-14 nM) to that of the N- ries, having reached phase I trials as an anxi-
methyl derivatives, however. Cyclization of olytic. (85)behaves as a partial agonist in vitro
the N-5 substituent onto the 4-position [as in and in vivo (337), is active in numerous anxi-
bretazenil (8311 is tolerated and tends to in- ety models, and appears to possess fewer side
crease intrinsic activity relative to that of the effects than those of typical benzodiazepines,
N-methyl analogs. The presence of an ester at at least in animal models. However, the drug
the 3-position is essential for potent DS and DI was withdrawn from the clinic because of evi-
binding (421), and the DI subtypes are much dence of dose-dependent hepatotoxicity, pre-
more sensitive to the size of this group than venting a full assessment of its efficacy and
are the DS subtypes (422-424). A variety of side-effect profile in humans. This toxicity is
5 Structure-Activity Relationships

mediated by cyclopropane carboxylic acid, series showed desirable anxiolytic efficacy


which is formed by metabolism of the oxadia- (Geller-Cook conflict and Vogel punished licking
zole moiety (337). models) with minimal ethanol potentiation, al--
Given the toxicity associated with the oxadia- though early tests showed physical dependency.
zole at the 3-position of panadiplon, a number of to be a common liability (337).
alternative substituents were investigated at A curious finding among certain imidazo-
this site of the imidazoquinoxalin-4-ones. Esters quinoxalines is a discrepancy in the efficag
have similar potency to, and lower intrinsic effi- results from the TBPS shift assay and direct
cacy than, the oxadiazoles, but are less stable measurement of chloride currents, the latter
toward hydrolysis. Aryl groups at position 3 re- method consistently giving higher intrinsic ef--
duce affinity by up to 24-fold, and this deleteri- ficacy (426). Further investigation revealed
ous effect is exacerbated by substitution of the that some compounds have a biphasic dose-
aromatic ring (426). In this series there was lit- response curve in the chloride current assay.
tle, if any, afKnity or efficacy selectivity between For example, (89)potentiates chloride current
a1 and a3 and any selectivity observed was in
favor of a1 (426,427).In a closely related series
of imidazoquinoxalinesthe carbonyl group now
resides on the N-5 nitrogen, giving urea (861,

(86) Y = NR2
(87) Y = alkoxy
(88) Y = alkyl, aryl at concentrations up to 1 and reduces it
thereafter, returning to baseline at around 10
carbamate (87),and arnide (88)derivatives. In (429).Given that the TBPS assay was run
this series the 3-oxadiazole and 3-aryl deriva- at 5 and the chloride current assay at 0.5
tives were equipotent. The 3-phenyl derivatives pM, the latter method gives a higher, but
were active in physical-dependency models, more relevant, result. This phenomenon is
whereas the oxadiazoles generally were not, irn- limited specifically to the piperazine ureas and
plicating the 3-phenyl group in the mediation of thus appears to be intimately related to the
this side effect (426). The nature of the N-5 sub- presence of a basic nitrogen in the urea moi-
stituent has little impact on affkity (generally ety. Other ureas, amides, carbamates, and the
4 5 nM) but strongly influences intrinsic effi- imidazoquinoxalin-4-ones show no biphasic
cacy. The amide and carbamate derivatives properties. This phenomenon may result from
tended to be full agonists, the degree of agonism the interaction of ligands such as (89) with
increasing with the size and lipophilicity of the two binding sites at the BZR, one high affinity
carbamate group (337, 428), whereas the urea and one low affinity (426). Such behavior led
analogs usually gave partial agonist profiles. In to the hypothesis that ureas such as (89)
addition, the urea derivatives showed more con- would antagonize their own agonistic effects
sistent in vivo activity (anticonvulsant) than at high concentrations and so limit their abuse
that of the others. As with the quinoxalin-4-one liability, although acute dependency studies
series, no useful subtype selectivity was ob- have failed to support this theory.
served in terms of affinity or efficacy (TBPS Molecular modeling studies show that the
shift). Nevertheless, several compounds in this imidazoquinoxalin-4-ones, despite their obvi-
Antianxiety Agents

ous structural similarity to the imidazobenzo- among simple phenyl piperazines and azapi-
diazepines (e.g., 831, adopt quite different rone derivatives. 1-Pyrimidinylpiperazine,the
three-dimensional conformations (428). For parent piperazine of buspirone, has negligible
the imidazoquinoxalines (e.g., 86) the N-5 affinity for 5HT-1A receptors and l-phe-
substituent lies out of the plane of the rigid nylpiperazine has only weak affinity (-500
tricyclic nucleus, and may occupy the same ag- nM)(433, 4341, but appropriate substitution
onistic receptor pocket as the C-5 phenyl of the of the phenyl ring produces phenylpiperazines
benzodiazepines and the piperazine side chain with potent 5HT-1A activity. Substitution at
of zopiclone (61). Such a n orientation ac- the 2- or 3-position is generally favorable for
counts for the strong influence of this group on 5HT-1A affinity, but 4-substitution is not, and
the intrinsic efficacy. a C1 or CF, substituent at the 3-position en-
hances affinity twofold over that of 1-PP (434).
5.4 5HT-1A Ligands
2-Methowhenyl is consistently one of the
A number of chemical classes are known to most active substitution patterns among sim-
provide potent 5HT-1A ligands (174, 430) in- ple aryl piperazines. A methoxy group at the 2-
cluding the aminotetralins (e.g., 8-OH or 3-position increases affinity by three- and
DPAT), indolealkylamines (serotonin mim- 1.5-fold, respectively, relative to that of l-phe-
ics), ergolines (e.g., LSD), and arylpiperazines. nylpiperazine, and the 4-methoxy derivative is
In terms of potential antianxiety agents, by far inactive (433). The 2,3-dimethoxy compound
the most important of these chemotypes are is weaker (1pik0 than either of the monome-
the arylpiperazines, also referred to as the thoxy derivatives, but constraining the me-
azapirones. In 1986 buspirone (9) became the thoxy groups into a ring system such as ben-
first azapirone to be approved for the treat- zodioxan increases affinity dramatically (40
ment of GAD, and tandospirone (16) has re- nM). The 2-methylbenzodioxene derivative
cently been launched for the same indication, (90) is more potent still, with an affinity (5
although only in Japan. Other azapirones to
reach late-stage clinical trials (431) for anxiety
are gepirone, flesinoxan, and ipsapirone, al-
though development of the latter two com-
pounds has been discontinued. Buspirone it-
self has potent affinity (IC,, = 31 nM) for the
5HT-1A receptor, but also has significant do-
pamine D2 receptor binding (IC,, = 250 nM)
(432).Indeed, buspirone was originally inves-
tigated as an antipsychotic and the dopami-
nergic properties were initially believed to un-
derlie its unexpected anxiolytic effects. Many nM)comparable to that of &OH-DPAT. 2,3-
azapirone compounds possess significant D2 Fusion of other rings such as furan, thio-
and adrenergic a1 activity in addition to the phene, and phenyl gave similarly active com-
desired 5HT-1A affinity, and much of the me- pounds. These results indicate that the
dicinal chemistry work has been directed to- azapirone N-4 substituent is not required for
ward improving the selectivity for the 5HT-1A potent 5HT-1A affinity. The phenylpiperazine
receptor. Modifications of the azapirone struc- SAR also applies to N-4 substituted azapi-
ture can be broken down into three regions of rones, with 2- and &substitution favored and
the molecule: the N-1 aromatic ring, the linker 4-substitution being detrimental to receptor
between N-4 and the imide, and the imide sub- affinity (435, 436). In a bicyclohydantoin se-
structure. ries, the 3-trifluoromethyl derivative (91) was
the only compound to show any selectivity (27-
5.4.1 Azapirones. Numerous SAR studies fold) over that of a1 receptors (435). A positive
have shown that the N-1 aryl substituent relationship between the van der Wads vol-
plays a key role in determining affinity and ume of the meta substituent and the 5HT-
selectivity for the 5HT-1A receptor, both 1Na1 selectivity has been noted (437). In
5 Structure-Activity Relationships 567

(440). The development of flesinoxan was re-


cently terminated.
Mazapertine (94) is a highly potent, nonse- -
lective 5HT-1A ligand that also possesses high -

agreement with this observation, computa-


tional analysis of a series of arylpiperazines
predicts that the 5HT-1A active site is able to
accommodate bulky groups at this position,
whereas the a1 receptor is not (438).
affinity for D,, D,, D,, and a1 receptors (Ki
In a series of flesinoxan analogs, the 5HT-
values of 3 nM). In accord with other studies,
1A/D2 selectivity was found to be predomi-
2-alkoxyphenyl derivatives were found to be
nantly modulated by the N-1 aryl substituent
the most potent 5HT-1A ligands in the maza-
rather than by the N-4 substituent (439). The
pertine series (436). Increasing the size of this
2-methoxy derivative (92) exhibited high af-
substituent from OCH, to OEt, to 0-iPr had
little effect on the 5HT-1A or a1 affinity, but
enhanced D, affinity, thus leading to dimin-
ished 5HT-1A/D2 selectivity. Electron-with-
drawing groups (CF,, C1, F, CN) at the 2-posi-
tion also showed high 5HT-1A and a1 affinity
(Ki < 20 nM), but with some selectivity over
D, receptors (K, > 60 nM). At the 3-position,
the same substituents showed greater selec-
tivity over D, (>300-fold) and a1 (>200-fold)
sites. Molecular modeling suggests that a fa-
vorable conformation for phenyl piperazines,
including those with single ortho substituents,
places the phenyl and piperazine rings in a
near coplanar arrangement (plane angle
~ 3 0 " )with
, the nitrogen lone pair almost per-
pendicular to this plane, as in (95) (433,441-

finity at both receptors (<5 nM) and was only


fivefold selective for 5HT-1A. Constraining
the methoxy group into a fused ring such as
furan or benzodioxan enhanced 5HT-1A affin-
ity and reduced D, affinity, thus enhancing
the 5HT-1A/D2selectivity. The selectivity was
improved further by substitution of the dioxan 443). This is in agreement with the X-ray crys-
ring at the 2-position with a hydroxymethyl tal structure of mazapertine, which shows the
group to give flesinoxan itself (931, which has isopropoxyphenyl ring to be 35" out of plane
excellent affinity for 5HT-1A receptors (1.7 with the piperazine ring (436). The notion
nM)and is 82-fold selective for 5HT-1A over that this represents the active conformation of
D2 sites. Flesinoxan reached Phase 111trials azapirones is supported by the potent affinity
having shown efficacy in GAD and depression, (12 nM) of the tricyclic mazapertine analog
but studies in panic disorder revealed a lack of (96) (444),in which the phenyl and piperazine
efficacy and a possible panicogenic effect rings are constrained in a near coplanar ar-
Antianxiety Agents

I1 trials as an anxiolytic. SAR studies showed


that the 5-methoxy group, a tertiary amine,
and a four carbon linker provide the optimum
compromise between 5HT-1A affinity and se-
lectivity vs. adrenergic and dopaminergic sites
(447). The aminobenzopyran moiety, which is
derived from the prototypical 5HT-1A ligand
8-OH-DPAT, contributes more to the 5HT-1A
rangement by the -CH,O-bridge. In contrast affinity, whereas the carbon linker has a
to mazapertine, (96) showed minimal affinity greater impact on selectivity than on affinity.
for al, D2, D3, or other 5-HT receptors, sug- The (+) enantiomers are consistently more
gesting that the multireceptor activity of potent and selective than the (-1 antipodes.
arylpiperazines results from their ability to Alnespirone binds with higher affinity (0.3
adopt a variety of active conformations, and nM)and selectivity than that of either buspi-
that selectivity for the 5HT-1A receptor can be rone or ipsapirone (447, 4481, is a full agonist
achieved by forcing the arylpiperazine into a at pre- and postsynaptic 5HT-1A sites, and is
coplanar conformation. active in animal models at low doses (<4 mg/
Replacement of the pyrimidine ring of bu- kg, ip) with no sedative effects.
spirone with other heterocycles, such as pyr- Overall, the SAR data for the linker be-
azine, pyridazine, or tetrazole, results in a loss tween N-4 and the imide group show that this
of affinity (445).The N-1 position need not be region does not provide any interactions with
directly attached to an aromatic ring, as the receptor and merely acts as a spacer. Some
shown by the benzocycloalkyl piperazines (97) studies point to a role for this region in the
modulation of the intrinsic activity of the
arylpiperazines and of their selectivity for the
5HT-1A receptor. The general observation is
that potency is optimized with a four carbon
linker and drops off significantly as the chain
is shortened, as exemplified by the phthaloyl
derivatives (99) (434). This preference is fur-

(446). Optimum affinity was obtained when


the cycloalkyl ring was six membered. The (-)
enantiomers were 10-50 times more potent
than their (+) counterparts, and exhibited su-
perior selectivity (>loo-fold) over a1 and D,
receptors. Elements of the tetralin and azipi-
rone pharmacophores are combined in al-
nespirone (981, which has advanced to phase

ther underlined by the tetralin derivatives


(97), in which the benzamidoethyl derivatives
were the only ones to be active (446). In the
bicyclohydantoin series, the chain length was
an important factor in determining the 5HT-
1AIal selectivity (435,449).
In the flesinoxan series (loo),replacement
of the amide NH with a methylene to give the
butyrophenone derivative (101) had no effect
I
i
5 Structure-Activity Relationships
Ii
shown by the high affmity of mazapertine
(94), which incorporates a phenyl ring (4361,
and sunepitron (1041, which contains a bicy-

(100) X = NH, Y = (C = 0)
(101) X = CH2,Y = (C = 0)
(102) X = CH2, Y = CHOH
(103) X = CH2,Y = CH2

on 5HT-1A or D, affinity, indicating that the clic piperazine linker. Sunepitron is an agonist
NH does not contribute a hydrogen bond in- at 5HT-1A autoreceptors and also has appre-
teraction (439). Likewise, reduction of the car- ciable affinity (35 nM) for a2 adrenergic recep-
bony1group in (100)to the alcohol (102) or the tors, where it acts as an antagonist (451).
methylene (103) had only minor effects on the (104) was effective in the Vogel conflict test
affinitiesfor both receptors. In contrast to its with an med of 1.78 mg/kg, ip, and a maximal
minimal effects on receptor affinity, the na- effect greater than that of gepirone and com-
ture of the linker has a significant impact on parable to that of diazepam (452). The combi-
agonist/antagonist character (450). The amide nation of 5HT-1A agonist and a2 antagonist
(100) is a full agonist, whereas the buytrophe- activities may account for the enhanced effi-
none analog (101)is a partial agonist, and the cacy relative to gepirone. Sunepitron is cur-
n-butyl compound (103) has a predominantly rently in phase I1 clinical studies for anxiety.
antagonistic profile. These studies maintained The substituent at the terminus of the
the length of the spacer at 4 atoms and showed linker chain is tolerant of a number of changes
that changes in the electrostatic or conforma- without a loss in potency. Indeed, the nature
tional nature of this chain had no effect on of this moiety provides the only point of differ-
5HT-1A or D2 affinity, but did modulate the entiation between buspirone (91, tandospi-
functional characteristics of the compounds. rone (16), gepirone (105), ipsapirone (1061,
The linker need not be a linear chain, as and zalospirone (107), five of the most clini-
Antianxiety Agents

cally advanced azapirones. In a series of buspi- from buspirone, (110) has negligible activity
rone analogs, a gradual enhancement of affin- at adrenergic and dopaminergic sites. In ani-
ity was seen as the log P of the molecule was mal models of anxiety, such as the mouse
increased through variation of the imide lightldark box and the rat social interaction
(4451, indicating a positive relationship be- test, (110) was effective at low doses (c0.5
tween the lipophilicity of this group and mgfkg, ip) and produced no sedative effects
5HT-1A receptor affinity. The imide of buspi- (453).Drug metabolism studies in rats suggest
rone may be replaced by hydantoin deriva- that, like buspirone, lesopitron may be subject
tives, as in (99) (435, 449), diketopiperazines to extensive first-pass metabolism (455).
(4371,phthaloyl groups, amides, or even a sim- Phase I studies showed lesopitron to be well
ple phenyl ring (434, 439) without disruption tolerated in human subjects up to 50 mg/day
of affinity. In the amide series, a preference for (456). In a lorazepam controlled phase I1 trial
a lipophilic group was suggested by the fact in patients with GAD, lesopitron (4-80 mg/
that the acetamide analog (108) was 25 times day), showed signs of efficacy, although a clear
endpoint was not achieved.
In the field of 5HT-1A receptor ligands ago-
nists and partial agonists abound, but pure
antagonists remain scarce. The first such com-
pound to become available was WAY-100135
(111) (4571, which incorporates a lipophilic

(108) R = CH3, Ki = 800 nM


(109) R = Ph, Ki = 1.3 n M

less potent at the 5HT-1A receptor than was


the benzamide (109). Replacement of the phe-
nyl ring in this series with thiophene main-
tains 5HT-1Aand D, affinity, but substitution
for more polar rings, such as furan, pyrrole,
pyridine, or pyrimidine, reduces affinity 10- tert-butyl amide in the position normally occu-
100 times at both receptors. Evidently the pied by the imide. The affinity resides primar-
5HT-1Aand D, receptors both favor nonpolar, ily in the ( S ) isomer, which is 30 times more
lipophilic groups at this position, and conse- potent than its enantiomer. This compound is
quently little 5HT-1A selectivity is observed. highly selective for 1A receptors, with negligi-
This conclusion was supported by an excellent ble afEnity for various dopamine, adrenergic,
correlation of the measured log P of the com- or 5HT sites, and is an antagonist at pre- and
pounds with their 5HT-1A and D, affinity postsynaptic 5HT-1A receptors.
(correlation coefficients of 0.96 and 0.93, re-
spectively) (439). 5.5 5HT-2 Ligands
Lesopitron (110),a buspirone analog with
a chloropyrazole as the terminal moiety, has Activity at the 5HT-2 receptor is an important
moderate affinity for the 1A receptor (101 feature of many atypical antipsychotic drugs
nM),where it acts as a pre- and postsynaptic (e.g., risperidone, olanzapine, sertindole), but
agonist (453,454).In an important distinction the body of knowledge on 5HT-2 ligands in
anxiety is more limited (173). Nonselective
5HT-2 antagonists, such as ritanserin (112),
mianserin (1131, and ketanserin (114), have
been shown to produce anxiolytic effects in
less than half of the preclinical studies con-
ducted (202). The clinical data for ritanserin
in human subjects are likewise inconclusive
(458, 459). The mixed results obtained with
5 Structure-Activity Relationships

(113) candidates to exhibit some preference be-


tween 5HT-2 subtypes, having 20-fold selec-
tivity for the 5HT-2A (IC,, = 5.8 nM) over the
5HT-2C receptor (464). Eplivanserin showed
anxiolytic activity in the elevated plus maze in
rats (465) as well as in phase I human trials
(167). Clinical anxiety studies with this com-
pound appear to have been terminated, how-
ever. SB-242084 (117) (466) is the most selec-
H

these nonselective compounds may reflect the


fact that the various 5HT-2 receptor subtypes
(2A, 2B, 2C) play different, perhaps even op-
posing, roles in the modulation of anxiety. De-
ramciclane (115)has high affinity for 5HT-2A
(Ki = 18 nM)and 2C (Ki = 30 nM) receptors
with antagonistic properties at both sites (460,
461). It is reported to elicit anxiolytic effects in
animal models and to possess minimal seda- tive 5HT-2C antagonist known, having 160-
tive or muscle relaxant side effects (462). Al- and 100-fold selectivity over 5HT-2A and
though the preclinical behavioral data are 5HT-2B receptors, respectively (467-470). Li-
promising, a true assessment of deramci- gand-receptor modeling studies suggest that
clane's anxiolytic potential awaits the comple- steric differences among the receptor sub-
tion of ongoing clinical trials (463). Eplivan- types may underlie this selectivity (469). (117)
serin (116) is one of the few anxiolytic shows anxiolytic activity in several animal
Antianxiety Agents

models including the Geller-Seifter and social iety is clearly desirable, but the 5HT-2 recep-
interaction paradigms (470). tors form a very closely related group (475)
In addition to the 5HT-2 antagonists de- and this objective has been hampered by the
scribed above, some agonists have also shown lack of subtype selective ligands.
anxiolytic effects. Org-12962 (118) is a pyri- A number of compounds with mixed
5HT-1A agonist and 5HT-2 antagonist prop-
erties have been investigated, seeking to com-
bine the anxiolytic effects of both mechanisms
(476). Molecular modeling studies have been
used to study the receptor interactions that
may contribute to 1A and 2A affinity among a
series of buspirone analogs (477). Adatanserin
(120) is a modified azapirone derivative with
dylpiperazine derivative with agonist activity
at 5HT-2A and 2C receptors that is undergo-
ing clinical investigation for anxiety and de-
pression. In a DPAG stimulation model of
panic in rats, (118)was reported to have anti-
panic efficacy intermediate between that of
clonazepam and fluoxetine (471). The 5HT-2B
agonist BW-723C86 (119), whose structure is affinity for 5HT-1A sites (Ki= 1 nM), where it
acts as a partial agonist, and 5HT-2 sites (Ki =
66 nM)where it acts as an antagonist (478-
480). It is an effective anxiolytic in a range of
anxiety models (481,482) predictive of clinical
anxiolysis. In a pigeon conflict model adatan-
serin was the only mixed 5HT-1A agonistl
5HT-2 antagonist to show significant effects,
and elicited larger anxiolytic-like effects than
those of either a 5HT-1A agonist or a 5HT-2
antagonist alone (481). HT-SOB (121) is an-

based on that of serotonin, showed anxiolytic


activity in conflict models as well as in the rat
social interaction test, with the magnitude of
effect in the latter test approaching that of
chlordiazepoxide (472,473). The observed an-
xiolytic effect was blocked by a 5HT-2B12Can-
tagonist, but not by a selective 5HT-2C antag-
onist, implicating the 5HT-2B subtype in the
production of anxiolysis. other mixed 5HT-1A agonist15HT-2 antago-
Overall, the utility of 5HT-2 antagonists in nist that shows anxiolytic, as well as antide-
the treatment of anxiety remains in question, pressant, activity in preclinical models (483).
given the mixed history of these compounds in The development of adatanserin and HT-SOB
animal and human studies. The fact that has been discontinued.
5HT-2 agonists and antagonist have both been
5.6 5HT-3 Ligands
reported to show anxiolytic effects leaves the
relative roles of the 5HT-2 subtypes in anxiety The main clinical action of 5HT-3 antagonists
unclear. A fuller understanding of the contri- (484) is antiemesis, and several compounds
butions of the 2A, 2B, and 2C receptors to anx- have achieved considerable commercial suc-
5 Structure-Activity Relationships

cess in this indication. It has also been sug- The discovery of the first nonpetide CCK an-
gested that 5HT-3 antagonists may have use- tagonist, the natural product asperlicin, in
ful antianxiety properties (209,485). The vast 1985 (495) shifted the medicinal chemistry fo- -
majority of clinical data in this respect con- cus from peptides to small molecule antago- .
cerns ondansetron (122) (4861, a widely pre- nists (496,497).CCK-B receptors are the dom-
inant isoform in the brain, and antagonists at
this subtype are potential anxiolytics. Many
CCK-B antagonists also modulate gastric acid
secretion through peripheral CCK-B (gastrin)
receptors.
The most significant structural class de-
rived from the asperlicin structure is the 1,4-
benzodiazepines, exemplified by L-365,260
(123). The most striking aspect of the SAR in

scribed antiemetic. In one placebo controlled


trial (487,488) comparing ondansetron (1or 4
mg, tid) with diazepam (2 mg, tid), a statisti-
cally significant effect was observed, with the
low dose being slightly more effective than the
higher dose. Other studies (489,490) failed to
demonstrate any significant effect in patients
with GAD, and a study in panic disorder pa-
tients was inconclusive (491). In preclinical
models the anxiolytic activity of 5HT-3 antag-
onists is highly variable (208), and consistent this series is the profound influence of the ste-
activity is seen only in a limited range of un- reochemistry at C-3 on the binding profile: the
conditioned models such as the lightldark ex- (R) configuration is essential for potent and
ploration test. Ondansetron showed anxiolyt- selective CCK-B affinity, the ( S )configuration
ic-like effects in only 63% of the reported provides potent ligands selective for the
preclinical studies (2021, mainly in those CCK-A receptor. In healthy volunteers
based on exploration. The antianxiety activity L365,260 was shown to relieve anxiety in-
of ondansetron, and of 5HT-3 antagonists in duced by the CCK agonists CCK-4 (498) and
general, is marginal at best and this group ap- pentagastrin (499), although other studies
pears unlikely to provide an advance in the failed to show efficacy on chronic dosing (500).
treatment of anxiety. The inconclusive evidence for the anxiolytic
efficacy of (123) may be ascribed to its ex-
5.7 Neuropeptide Receptor Ligands tremely low aqueous solubility and resultant
formulation issues (501). Consequently, a ma-
5.7.1 CCK-B Receptor Antagonists. Chole- jor objective in this area became the enhance-
cystokinin (CCK), a 33 amino acid peptide, ment of physical properties, by incorporation
was isolated in 1968 (492), and since that time of acidic or basic solubilizing groups. Incorpo-
there has been great interest in developing li- ration of acidic functions (e.g., carboxylic acid,
gands that interact with this important neu- tetrazole) in place of the methyl group at the
ropeptide. The early CCK ligands were them- 3-position of the ureido phenyl ring (502)
selves peptide derivatives (493,494) and were maintained, or enhanced, CCK-B affinity
thus of little value as drug candidates, partic- (IC,, = 0.1-6 nM) and selectivity (500- to
ularly for CNS applications such as anxiety. 10,000-fold), and increased aqueous solubility
Antianxiety Agents

by three orders of magnitude. However, in


contrast to L-365,260, these and other acidic
derivatives had very low brain penetration
(503,504),which precluded their development
as anxiolytics. Replacement of the C-5 phenyl
ring in (123) with cyclohexyl improves the
CCK-B potency (30-fold) and selectivity (70-
fold) (505).This modification also offered the
possibility of improving solubility through the
corresponding cyclic amine analogs, exempli-
fied by L740,093 (124). These amidine deriva-
tives have excellent CCK-B affinity and selec-
tivity (IC,, = 0.1 nM, CCK-AICCK-B = 16,000 (126) R = Ph, Cyclohexyl: X = NH, 0
for 124) along with improved water solubility (127) R = Ph, X-= NH -
and physical properties (506). n
The N-1 methyl group may be replaced by
aroylmethyl or methylene ester substituents,
as in (125). High aMinity is maintained and
The most promising anxiolytic candidate from
this series is GW-150013 (127) (504), cur- I

rently in Phase I1 trials. In preclinical studies, I

(127) was active in anxiety models at excep- 1


tionally low doses, with an oral ED50 value of I
0.05 pglkg in the mouse lightldark box model. 1
Furthermore, a 0.3 pgkg oral dose of (127) 2
produced a longer-lasting anxiolytic effect
than a 1 mglkg oral dose of diazepam (515). E
(127) has also shown significant anxiolytic ef- I
ficacy in rats (social interaction test) and mar-
mosets (human threat model) (516). The aque-
ous solubility of GW150013 is improved by
replacement of the C-5 phenyl with a morpho-
linoethyl substituent, giving GW191869 (128)
(506, 517). (128) exhibits anxiolytic efficacy
I
CCK-B selectivity is improved over that of over a wide dose range in several models, and
L-365,260 (507, 508). The pyridyl group in surpasses the activity of (127) in the mouse
(125) provides a significant enhancement in lighttdark box model (ED,, = 0.002 pglkg, po).
oral bioavailability relative to the phenyl ana- The issue of the absolute stereochemistry at
log. Replacement of the 3-methyl group in C-3 is circumvented in a series of symmetrical
(125) with basic moieties (NHMe, NMe,) like- 1,5-benzodiazepinediones (518) that have (I
wise maintains the receptor binding profile identical substituents at N-1 and N-5. These cl
and enhances oral bioavailability (509). compounds contain a plane of symmetry and t€
In a related series of 1,5-benzodiazepinedi- are thus achiral. Excellent affinity and selec- al
one compounds (e.g., 126) a large alkyl group tivity are seen in the N-1,5-bis-carbonyl- sf
at N-1is important for high affinity, the 1-ada- methyl derivatives, but the corresponding bis- te
mantylmethyl group being optimal (510). At alkyl derivatives are generally less potent e\
the 3-position, ureido (511) and carbamate (519). ak
(512, 513) substituents are tolerated, the CP-212,454 (129) (520) is representative of ici
former class having superior affinity and se- a series of benzazepin-2-ones that possess of
lectivity. As with the 1,4-benzodiazepine se- high affinity and CCK-B selectivity. (129) was nil
ries, the absolute configuration at C-3 is a crit- selected for clinical study as an anxiolytic but, tec
ical determinant of CCK-A/Bselectivity (514). not uncommonly among CCK-B antagonists, e fl
5 Structure-Activity Relationships

(527) patients. The SAR work in the dipeptoid


family reveals that the Tre and Phe residues
are the essential components of the CCK-4
structure required for binding (528). Accord- .
ingly, the indole moiety is essential for the re-
ceptor affinity of CI-988 (529). Bulky substitu-
ents are preferred at the N-terminus, the '
2-adamantyl group being optimal. Modifica-
tions at the C-terminus have resulted in en-
hanced affinity and have produced orally
available anxiolytics with improved brain pen-
! (129) R = Ph, X = C1 etration, such as CI-1015 (514).
(130) R = cyclohexyl, X = COzH Other CCK-B antagonist series to show
!
i. some anxiolytic activity include the quinazo-
t solubility, bioavailability, and formulation is- lines, also derived from asperlicin, developed
sues terminated its development (521). The at Eli Lilly (530), and "hybrids" (531-534),
related carboxylic acid derivative CP-310,713 which combine important components of the
(130) (522) displayed enhanced potency (IC,, 1,4-benzodiazepine series (the phenylurea)
= 0.1 nM) and selectivity (14,000-fold) for the and the quinazolines.
CCK-B receptor, as well as dramatically in-
creased (24,000-fold) water solubility relative 5.7.2 CRF-1 Receptor Antagonists. Antianxi-
to that of (129). In monkeys, however, unex- ety activity has been demonstrated with pep-
pectedly large doses of (130) were required to tide CRF-1 receptor antagonists, such as a-he-
block CCK-4 induced panic attacks, presum- lical CRF,-,,, D-P~~-CRF,,_,,, and astressin,
ably because of low brain penetration (521). but this activity is evident only after central
A series of dipeptoids based on the CCK-4 administration as the peptidic nature of these
structure have been developed at Parke- compounds prohibits brain penetration. The
Davis, culminating in CI-988 (131) (523). first patent for a nonpeptidic CRF antagonist
was issued in 1991 and covered a series of ox-
opyrazolines that had only micromolar affm-
ity for the CRF receptor (535).Since that time
great strides have been made in the medicinal
chemistry of CRF antagonists, and a number
of potent and selective CRF-1 antagonists
with oral efficacy are now available (258,
536-540).
The anilinopyrimidines and triazines, gen-
eralized in (132), constitute the first major
class of small molecule CRF-1 antagonists
(131)is active in various anxiety models in- (541, 542). On the heterocyclic ring, a methyl
cluding the elevated plus maze and social in- group is optimal at the 6-position, whereas the
teraction tests. In keeping with other CCK-B 4-position tolerates a range of substituents in-
antagonist anxiolytics, exquisite potency is ob- cluding dialkylamino, cyclic amino, phenyl,
served: the med in the mouse lightldark box and tetrahydropyridyl (543-545). Compound
test is 100 nglkg, sc (524). Once again, how- (133)has an IC,, of 12.7 nM for the rat CRF-1
ever, poor brain penetration and low bioavail- receptor (rCRF1)and an oral med of 0.3 mglkg
ability limited the clinical efficacy (499). Clin- for reduction of CRF-induced anxiety in the
ical studies found that high doses (100 mg, po) elevated plus maze (546). The nitrogen at po-
of CI-988 were required to antagonize the pa- sition l of the heterocycle is essential for bind-
nicogenic effects of CCK-4 in healthy volun- ing affinity, and small alkyl groups (methyl,
teers (4991, and other studies failed to find any ethyl) are preferable on the central (aniline)
efficacy in GAD (525, 526) or panic disorder nitrogen. On the phenyl ring, ortho substitu-
Antianxiety Agents

potent CRF-1 antagonists. Conformational


studies of the anilinopyrimidines and tria-
zines (547) by the use of variable temperature
NMR showed that there is restricted rotation
about the two bonds connecting the central
nitrogen to the aromatic rings, and that the
phenyl ring is nearly orthogonal to the plane
of the heterocyclic ring. This is in agreement
with the positive effects of substituents on the
central nitrogen and at the ortho position of
the phenyl ring on receptor affinity, in that
these modifications should reinforce the pre-
ferred conformation.
X=CH, N
Y = substituted amino, phenyl, tetrahydropyridyl
Given the conformational insights just de-
Z = small alkyl scribed, it is not surprising that conformation-
A, B = medium size lipophilic groups ally restricted analogs have been intensively
C = H or medium size lipohilic groups investigated. Cyclization of the anilino nitro-
gen in (132) onto the heterocyclic ring leads to
an extensive series of bicyclic CRF antago-
nists, many of which have improved potency
and pharmacokinetics relative to the monocy-
clic derivatives such as (132). Numerous vari-
ants of the 6,5-bicyclic system containing a to-
tal of two to four nitrogen atoms, generalized
in (1341, have been explored, such as pyrrol-

(134) V-Z = C or N; (N1 + V-Z) = 2-4 atoms


(135) Pyrrolopyrimidines-V, Z = N; W, X, Y = C
(136) Pyrazolotriazines-V, W, X = N; Y, Z = C
(137) Pyrrolopyridines-Z = N; V, W, X, Y = C

opyrimidines (135) (548, 549), pyrazolotria-


zines (136) (550-5521, and pyrrolopyridines
(137) (5531, among others (538-540), and a
pharmacophore model for this template has
been developed (540).
Although the number and location of nitro-
tion with a medium size lipophilic group (e.g., gen atoms within the bicyclic core vary among
Br, I, SCH,) enhances affinity for the human these chemotypes, in all cases the SAR of the
CRF-1 receptor (hCRFl), and lipophilic appended substituents (i.e., the phenyl ring,
groups at the 4-position (e.g., isopropyl, me- the methyl group, and the alkylamino group)
thoxy) further increase activity. Conse- remain essentially the same. Thus the choice
quently, a 2,4-disubstituted or 2,4,6-trisubsti- of a particular bicyclic system may be made for
tuted phenyl ring is a ubiquitous feature of pharmacokinetic rather than pharmacological
if
i
i 5 Structure-Activity Relationships

reasons. As with the monocyclic series the N-1


atom is required for receptor binding, and
small substituents are required at the 6-posi-
tion. On the phenyl ring, ortho substituents
enhance affinity by encouraging a non-copla-
nar relationship between the phenyl ring and
the bicyclic nucleus. At the para position, sub-
stituents up to a certain size are beneficial,
again leading to the preferred 2,4- or 2,4,6-
substituted phenyl ring. At the 4-position of
the heterocyclic ring, acyclic amines, particu-
larly unsymmetrical ones, are preferable to cy-
clic amines in terms of hCRFl affinity. Inver-
sion of the 6,5 ring system leads to a series of
5,6-bicyclic derivatives (554-557) (e.g., 1381,

NBI-30545 has shown anxiolytic activity upon


oral administration in the rodent elevated
plus maze test, albeit at relatively high doses
in which the imidazole nitrogen now provides (20 mgtkg). Another pyrazolopyrimidine,
the critical binding interaction. In addition DMP-904 (141) has high affinity (1nM) and
6,6-(558-560) and 5,54538) bicyclic deriva-
tives have been reported but few data are
available.
The 6,5-bicyclicclass has provided the most
interesting anxiolytic compounds to date. CP-
154,526 (139),a pyrrolopyrimidinederivative,
is a potent (IC,, = 2.7 nM) and selective
hCRF-1 antagonist that is able to reverse the
CRF-induced acoustic startle and fear poten-
tiated acoustic startle responses in rats (561-
563). In other models of anxiety, however,
such as conflict paradigms and the elevated
plus maze, (139) was inactive. This again
highlights the need to evaluate potential anx-
iolytics with a novel mechanism of action in
a wide variety of behavioral paradigms. NBI-
30545 (140) is a functional antagonist with
excellent hCRFl affinity (2.8 nM) (538, 564).
Antianxiety Agents

selectivity for the hCRFl receptor, is a potent


functional antagonist (10 nM) in the hCRFl
adenylate cyclase assay, and is orally available
(565). (141) was orally efficacious in the rat
lightldark open field (med = 0.3 mg/kg) and
elevated plus maze (med = 5 mglkg) models of
anxiety. The closely related pyrazolotriazine,
DMP-696 (142) also has high hCRFl affinity

effects (5681, but development was discontin-


ued because of liver enzyme elevation in a
small number of patients.
It is evident from the preceding discussion
that the CRFl antagonists reported by a num-
ber of different companies share a remarkable
structural similarity, testifying to the narrow
range of small molecules that have potent af-
finity for this receptor.

6 CURRENT DEVELOPMENTS
AND THINGS TO COME
(1.7 nM), potent functional antagonism (IC,, An ideal anxiolytic would be orally efficacious
= 82 nM) in vitro, and excellent selectivity for with a rapid onset of action, and be devoid of
the CRF-1 receptor (566). This compound has side effects such as tolerance, withdrawal, de-
a favorable pharmacokinetic profile in several pendency, sedation, motor and cognitive im-
species and has a greater oral bioavailability in pairment, interaction with CNS depressants,
the dog than that of DMP-904. (142) was less and toxicity in overdose. Such an agent would
effective than DMP-904 in the rat brightldark be effective in different anxiety disorders and
open field test, however, with a med of 3 mgkg would treat all the core symptoms of each dis-
(po) and a maximally effective dose of 10 order with a high response rate. Despite the
mgkg (po). Although the maximal effects of progress made in anxiolytic research, the cur-
DMP-904 and DMP-696 in the situational rently available antianxiety agents fall some
anxiety test were slightly smaller than those way short of this perfect profile. This fact, cou-
of 20 mgkg (po) chlordiazepoxide (57,63, and pled with the prevalence of the anxiety disor-
72%, respectively), the CRF antagonists ders, their impact on society, and the conse-
showed no sedative or ataxic effects at doses quent market size, ensures a continued
up to 100 mg/kg (po) (565, 566), indicating a intense interest within the pharmaceutical in-
greatly improved side-effect profile compared dustry in the development of new anxiolytics
to that of the benzodiazepine. Replacement of that come closer to the ideal profile. Currently,
the substituted phenyl ring with pyridine there are more biological mechanisms under
(567),in an effort to improve water solubility, investigation as potential targets than ever
culminated in R-121919 (143),a potent CRF-1 before (569). The most advanced of these ap-
antagonist with good brain penetration and proaches are those involving the GABA, sero-
reasonable bioavailability. (143) recently com- tonin, CCK, and CRF neurotransmitter sys-
pleted phase I clinical studies showing prelim- tems, all of which have produced clinical
inary signs of antidepressant and antianxiety candidates (570 -572).
6 Current Developments and Things to Come

-
As already discussed, anxiety constitutes a the regional expression of these receptors,
complex group of emotional disorders, the de- techniques such as positron emission tomog-
1 velopment, regulation, and pharmacomodula- raphy (PET) scanning may reveal the involve- -
tion of which involves a number of the brain's ment, or otherwise, of each in human anxiety.
8 major neurotransmitter systems. A clearer To design serotonergic anxiolytics, it is impor-
5
1 understanding of the influence of each of these tant to gain a fuller understanding of the var-
[ systems on the genesis, development, and ious 5HT receptors at the molecular level, par- *
!
treatment of anxiety is central to the discovery ticularly in the case of closely related
! of new and improved anxiolytics. In this re- subgroups such as the 5HT-1BiDand 5HT-2A/
: spect, molecular biology, genetics, and phar- B/C receptors. The involvement of neuropep- -
macology are throwing light on the intricate tide systems in anxiety is less well established
neurobiology of anxiety. Transgenic animal than GABA or serotonin, but antagonists at
i studies, for example, are identifying for the CRF-1 and CCK-B receptors have shown
; first time the individual GABA,/BZR receptor promising results and have exciting clinical
subtypes that mediate the anxiolytic and other potential. As the neurobiology of each path-
effects of the benzodiazepines. With the a2 way implicated in anxiety is investigated, ev-
subtype already implicated as mediating the ery result seems to bring more questions. It is
anxiolytic effects of diazepam, future work to increasingly obvious that one neurotransmit-
determine the subtypes involved in serious ter, far less one receptor or receptor subtype,
benzodiazepine side effects such as with- does not act in isolation in regulating emo-
drawal and dependency will be of tremendous tional behavior. The complex interrelation-
value in the design of truly selective and side ships between all of the neurotransmitter sys-
effect-free GABAergic anxiolytics. Things will tems associated with anxiety makes it
not be as simple as engineering a subtype-se- extremely difficult to extricate the true caus-
lective compound, however, because it is likely ative mechanism. Nevertheless, the existence
that a given subtype will participate in more of so many receptor targets that are able to
than one clinical effect. The a2 subtype, for modulate anxiety in some fashion offers nu-
example, is known to contribute to both the merous possibilities for new drug develop-
anxiolytic and myorelaxant actions of diaze- ment.
pam. Thus, to obtain real clinical selectivity, a With over 40 years of outstanding clinical
degree of partial agonism must be superim- success behind it, and a continuing research
posed on the subtype selectivity. "What is the effort today, the modulation of GABAergic
right subtype selectivity?" and "What is the transmission through the BZR remains the
right degree of partial agonism?" are ques- mechanism most likely to provide the next ad-
tions that are only now being posed in the vance in the treatment of anxiety. The efficacy
clinic. of the benzodiazepines as antianxiety drugs is
The serotonin system is intimately in- without question,-but the current challenge is
volved in anxiety, and up to seven 5HT recep- the im~rovement
* of what has become increas-
tor subtypes have been implicated to varying ingly regarded as an undesirable side-effect
degrees. Different 5HT receptors and receptor profile. The subtype-selective partial agonist
subtypes may play overlapping, or even oppos- approach holds the most promise in this re-
ing, roles in emotional behavior, and the same gard, but the extent of partial agonism re-
receptor may have different functions in dif- quired to maintain efficacy and optimize the
ferent brain regions. The sheer complexity of therapeutic index remains an open question.
this transmitter system is underlined by the Thus far, anticipated optimal profiles for anxi-
fact that in over 30 "years of active research olysis in humans have been extrapolated from
linking serotonin and anxiety, only one anxio- animal studies, and a number of studies with
lytic acting directly on 5HT receptors (buspi- partial agonists currently in progress should
rone) has been launched. From a better under- soon reveal the applicability, or otherwise, of
standing of the role of each implicated subtype these profiles in the clinic. The most advanced
will surely come improved serotonergic anxio- candidate is pagoclone (64), currently in
lytics (573, 574). As molecular biology reveals Phase 111 trials, which has already demon-
Antianxiety Agents

strated efficacy in panic disorder. In a placebo around a213 selective partial agonist 1,2,4-
controlled trial pagoclone was found to be ef- triazolopyridazines (e.g., 146) suggests the
ficacious in GAD at low doses (0.3-1.2 mg/day)
while causing minimal sedation (575). This
could not be replicated in larger trials, how-
ever, and Pfizer is no longer pursuing this
compound. Other compounds in the clinic in-
clude NGD91-3 (Neurogen) (576), NS-2710
(144) (Neurosearch)(577-580),and RWJ-51204
(81).SL-65,1498 (145) (Sanofi-Synthblabo)is

clinical candidate is from this or a closely re-


lated series. At the time of writing, NGD91-3
had shown a trend toward efficacy, but failed
to reach statistical significance in a Phase IIA
placebo and Xanax controlled study in GAD
patients (585). Thus the issue of finding the
correct degree of partial agonism, and indeed
the subtype-selective partial agonist concept
in general, still awaits verification in the clinic
with other compounds. Pregabalin (147)

(Pfizer) is a lipophilic GABA analog (586) that


is under development for a number of indica-
tions, including anxiety. (147) has shown clin-
the lead compound from a series of pyridoin- ical efficacy in late stage social phobia (587)
dole-4-carboxamides. In electrophysiological and GAD (588) studies. Pregabalin, and its
studies SL-65,1498 exhibits functional selec- close relative gabapentin, do not act at GABA
tivity for the a213 subtypes, and is claimed to receptors but likely mediate their anxiolytic
be an effective anxiolytic in animal models effects through interactions with voltage-
with a favorable separation from sedative, gated calcium channels (586).
muscle relaxant, amnestic, withdrawal, or de- At present, buspirone remains the only se-
pendency effects (581).As of August 2001, this rotonin receptor ligand available for the treat-
compound was in phase IIA trials. Merck has ment of anxiety The clinical development of
advanced an a213 agonist in to phase I1 clinical several 5HT-1A agonists (ipsapirone, zalospi-
studies (582).The recent heavy patent activity rone, flesinoxan), 5HT-2 antagonists (eplivan-
(583,584) from Merck, Sharpe, and & Dohme serin, ritanserin), and mixed 5HT-1A agonistl
1
e1 References

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reflecting that a fuller understanding of the
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C.ANTHONY ALTAR .

Department of Gene Discovery


1 Psychiatric Genomics, Inc.
Gaithersburg, Maryland
I

i
E
i
ARNOLD R. MARTIN
Department of Pharmacology
College of Pharmacy
j
; University of Arizona
j Tucson, Arizona
i
r
: ANDREW THURKAUF
j Department of Medicinal Chemistry
: Neurogen Corporation
Branford, Connecticut

Contents
1 Introduction, 600
2 Clinical Applications, 602
2.1 What Is Schizophrenia?, 602
2.2 Biochemical Basis for Schizophrenia, 602
2.2.1 Dopamine, 602
2.2.2 Serotonin, 603
2.2.3 Glutamate, 603
3 Antipsychotic Agents, 604
3.1 Therapeutic Indications, 604
3.1.1 Schizophrenia and Psychoses, 604
3.1.2 Other Indications, 605
3.2 Adverse Effects and Precautions, 605
3.2.1 Extrapyramidal Symptoms, 605
3.2.2 Tardive Dyskinesia, 607
3.2.3 Neuroleptic Malignant Syndrome, 607
3.2.4 Seizures, 608
3.2.5 Sedation, 608
3.2.6 Cognitive Impairment, 608
3.2.7 Anticholinergic Effects, 608
3.2.8 Cardiovascular Effects, 609
3.2.9 Sexual Side Effects and
Hyperprolactinemia, 609
3.2.10 Weight Gain, 610
3.2.11 Hematologic Side Effects, 610
Burger's Medicinal Chemistry and Drug Discovery 3.2.12 Hepatic Effects, 610
Sixth Edition, Volume 6: Nervous System Agents 3.2.13 Dermatologic Side Effects, 611
Edited by Donald J. Abraham 4 Animal Models of Efficacy and Side Effects, 611
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 4.1 Use of Animal Models, 611
Antipsychotic Agents

4.2 Prediction of Antipsychotic Efficacy, 611 7 Pharmacokinetics, Biotransformation,


4.2.1 Behavioral Effects of Psychostimulants, and Drug Interactions, 632
611 7.1 General Considerations, 632
4.2.1.1 Behavioral Models of 7.2 Phenothiazines, 633
Dopaminergic Overactivity, 611 7.3 Thioxanthenes, 635
4.2.1.2 Behavioral Models of 7.4 Dibenz(l,4)0xazepines, 635
Glutamaterigic Overactivity, 7.5 Dibenzo(l,4)Diazepines, 636
612 7.6 Dibenz(l,4)Thiazepines, 637
4.2.2 Prepulse Inhibition, 612 7.7 Butyrophenones, 637
4.2.3 Latent Inhibition, 613 7.8 Benzisoxazoles, 639
4.2.4 Conditioned Avoidance Response, 613 7.9 Benzoisothiazoles, 639
4.2.5 Drug Discrimination, 614 7.10 Diarylbutylamines, 639
4.3 Prediction of Side Effect Liability, 615 7.11 Molindone and Related Compounds, 640
4.3.1 Catalepsy, 615 8 Strategies for Drug Discovery, 640
4.3.2 Stereotyped Behaviors Induced by 8.1 Dopamine Receptor Subtype Approaches,
Amphetamine and Apomorphine, 615 640
4.3.3 Paw Test, 615 8.1.1 D, Selective Compounds, 640
4.3.4 EPS in Primates, 616 8.1.2 D, Selective Compounds, 643
4.3.5 Vacuous Chewing Movements, 616 8.1.3 Dopamine "D,-Plus" Agents, 645
4.3.6 Prolactin Response, 616 8.1.4 5-HTZA/D,Antagonists, 645
4.3.7 Cognitive Effects, 616 8.1.5 Aryl PiperazinesIPiperidines, 646
5 Discovery of Prototype Antipsychotics, 617 8.1.6 ArylpiperazinesPiperidines, 648
5.1 Discovery of Chlorpromazine, 617 8.1.7 Dopamine D, Partial Agonists, 649
5.2 Discovery of Haloperidol, 617 8.2 Non-Dopaminergic Approaches, 651
5.3 Advent of Atypical Antipsychotics, 618 8.2.1 Serotonergic, 651
5.4 Discovery of Clozapine, 618 8.2.1.1 5-HT2A Antagonists, 651
5.5 Discovery of Amisulpride, 618 8.2.1.2 5-HT1A Partial Agonists, 652
6 Structure-Activity Relationships, 619 8.2.2 Glutamatergic Approaches, 653
6.1 Drug Classes, 619 8.2.2.1 Inotropic Glutamate Receptors,
6.2 Tricyclic Neuroleptics, 619 653
6.3 Butyrophenones, 625 8.2.2.2 Metabotropic Glutamate
6.4 Benzamides, 627 Receptors, 654
6.5 Miscellaneous Classes, 631 9 Website Addresses, 655

1 INTRODUCTION It had been widely - believed that the occur-


rence of acute extrapyramidal symptoms
Antipsychoticagents constitute a diverse class (EPS), including pseudo-Parkinsonism, dysto-
of drugs that are effective in the treatment of nias, and akathisia, was an expected conse-
major psychoses, including those associated quence of antipsychotic drug therapy. Indeed,
with schizophrenia (Table 10.1). These agents all of the classical (or "typical") antipsychotic
were originally known as "neuroleptics" be- agents in clinical use in the United States
cause of their ability to lessen the reactivity to cause EPS to varying degrees (1,2). Further-
emotional and physical stimuli in highly agi- more, the positive correlation between neuro-
tated and/or psychotic patients, with little or leptic-induced EPS and the emergence of the
no effect on consciousness. Antipsychotic biochemically very different, long-lasting syn-
agents have also been referred to as "major drome of tardive dyskinesia (TD) reinforced
tranquilizers" to differentiate them from "mi- the belief that motor system side effects were
nor tranquilizers," such as meprobamate and necessary correlates of antipsychotic efficacy.
the benzodiazepines. The latter drugs, also re- Given these expectations, the ability of cloza-
ferred to as "tranquilosedatives" or "anxiolyt- pine to treat schizophrenia without the ap-
ics," in contrast to the antipsychotic agents, pearance of acute EPS or TD (3,4,6,17) was a
are more frequently employed to calm pa- huge step forward in the treatment of this dev-
tients suffering from anxiety. astating psychiatric condition.
Table 10.1 Antipsychotic Pharmaceuticals
Equiv.
Single Daily Dose Route(s) of
Chemical Name (Structure) Trade Name(s) Manufacturer Chemical Class (Amine Type) Dose (mg) Range (mg) Administration
Promazine HCl(6) Sparine Wyeth-Ayerst Phenothiazine (aliphatic amine) PO
Chlorpromazine HCl(1) Thorazine SmithKline Beecham Phenothiazine (aliphatic amine) PO, IM, IV,rectal
(base)
Triflupromazine HCl(9) Vesptin Apthecon Phenothiazine (aliphatic amine) IM
Thioridazine HCl(95) Mellaril Novartis Phenothiazine (piperidine) PO
Mesoridazine Besylate (96) Serentil Boehringer-Ingelheirn Phenothiazine (piperidine) PO, IM
Prochlorperazine Maleate (25) Compazine SmithKline Beecham Phenothiazine (piperazine) PO, IM
(edisylate)
Trifluoperazine HCl(97) Stelazine SmithKline Beecham Phenothiazine (piperazine) PO, IM
Fluphenazine HCl(98) Permatil, Prolixin Schering, Apothecon Phenothiazine (pipermine) PO
Fluphenazine Enanthate Prolixin Enanthate Apothecon Phenothiazine (pipermine) IM
Fluphenazine Decanoate Prolixin Decanoate Apothecon Phenothiazine (piperwine) IM
Perphenazine (26) Trilafon Schering Phenothiazine (piperazine) PO, IM
Thiothixene (99) Navane Fberig Thioxanthene (piperazine) PO
Haloperidol (55) Haldol McNeil Butyrophenone (piperidine) PO, IM (lactate)
Haloperidol Decanoate Haldol Decanoate McNeil Butyrophenone (piperrnine) IM
Pimozide (86) Orap Gate Diphenylbutylamine PO
Molindone (91) Moban Gate Indolone (aliphatic amine) PO
Risperidone (84) Risperdal Janssen Benzisoxazole (piperidine) PO
Ziprasidone (105) Geodon Pfuer Benzisothiazole (piperazine) PO, IM
Loxapine Succinate (100) Loxitane Watson Dibenzoxazepine (piperazine) PO, IM (HC1)
Clozapine (50) Clozaril Novartis Dibenzdiazepine (piperazine) PO
Olanzepine (52) Zyprexa Eli Lilly Thienobenzdiazepine (piperazine) PO
Quetiapine (53) Seroquel Zeneca Dibenzthiazepine (piperazine) PO
Antipsychotic Agents

Unfortunately, potentially fatal agranulo- alogia, anhedonia, avolution, blunted affect,


cytosis appears in 1-2% of patients treated disorganized thoughts, and social withdrawal.
with clozapine (7). This necessitates frequent Impaired cognitive function, including mem-
blood monitoring, which can be inconvenient ory and attention defects, may also occur.
and expensive. Furthermore, despite its low
2.2 Biochemical Basis for Schizophrenia
potential for causing EPS and TD, clozapine
causes other, dose-related side effects that can The concept that schizophrenia is a neuro-
limit its effectiveness in some patients. The chemical disturbance is primarily supported
precise pharmacological actions of clozapine by the fact that the clinical symptoms of the
responsible for its clinical effectiveness are disorder can be diminished or exacerbated by
still being debated. Attempts to duplicate ele- medications that exert their actions through
ments of its complex pharmacological profile specific CNS receptors. It is clear, however,
have led to the discovery of several new atyp- that schizophrenia is an illness of multiple
ical antipsychotic drugs that have been ap- symptom-defined domains, each with their
proved in the United States for the treatment own biology that coexist in individualized
of schizophrenia. combinations in patients. Expanding efforts
in basic research, including large-scale mRNA
analyses, have identified other receptors, neu-
2 CLINICAL APPLICATIONS
rotransmitters, and structural components
which contribute to the disease (8). From
2.1 What Is Schizophrenia?
these many leads, novel targets have appeared
Schizophrenia is a severe, life-long, idiopathic for medicinal chemistry and clinical develop-
psychiatric disorder with a polygenic compo- ment. While these may be loosely grouped as
nent. It is composed of severe thought disor- the monoamine (dopamine, adrenergic, sero-
ders, termed psychoses, which are character- tonin) and amino acid (primarily glutamate)
ized by illogical, delusional, or paranoid neurotransmitter systems, the interconnec-
thoughts. Schizophrenia typically has its on- tivity of these systems and increasing role of
set in early adulthood with remissions and ex- structural and synaptic deficiencies within the
acerbations throughout life. CNS make it difficult to lay the causative man-
The disorder afflicts approximately 1% of tle at the feet of any one receptor.
most populations. The signs and symptoms of
schizophrenia usually begin in late adoles- 2.2.1 Dopamine. The oldest and most en-
cence or early adulthood and are manifested in during hypothesis for the etiology of schizo-
a highly diverse and complex constellation of phrenia is that it results from a hyperfunc-
clinical presentations. These have been subdi- tioning of CNS dopaminergic systems. This
vided into two broad categories, positive and hypothesis originated with Carlsson and
negative signs and symptoms. The positive Lindquist (91,who found that dopamine turn-
components are typically the first to draw at- over as measured by homovanillic acid (HVA)
tention to the disorder and constitute the levels was increased in laboratory animals af-
more overt manifestations of psychosis. These ter the administration of neuroleptic drugs.
include false perceptions including hallucina- Subsequent research has supported the dopa-
tions (usually auditory), in which the patient's mine hypothesis and is principally based on
internal dialogue is perceived to originate the psychotomimeticeffects of drugs that aug-
from others or from inanimate sources such as ment dopamine function in the CNS, the psy-
radios or cell phones. Delusions, bizarre and chotolytic effects of dopamine-depleting drugs
often repetitive behavior patterns that are in- such as reserpine, the D, receptor antagonism
appropriate to setting, and disorganized of all antipsychotic drugs, and the increases in
speech characterize other manifestations of dopamine release and D, receptors in the
schizophrenia. The negative components are schizophrenic brain.
less spectacular, although more enduring and Individuals who chronically self-adminis-
in many respects the more disabling of the ter the dopamine-releasing drug amphet-
characteristics of the disorder. These include amine or the dopamine precursor levodopa
2 Clinical Applications
E

1F (10) often present psychotic symptoms of un- rotransmission was suspected. This was based
treated paranoid psychosis (11).Increases in on the psychotogenic and hallucinogenic prop-
E D, receptors (15, 16, 342, 343) in the ventral erties of the partial serotonin 5-HT2, receptor
1 striatum of the schizophrenic brain and in- agonist, lysergic acid diethylamide (LSD) (179
: creases in amphetamine-stimulated dopamine and on reports of abnormal CSF and circulat-
I
release in the striata of schizophrenic patients ing levels of serotonin in schizophrenics (1%
(14, 707) provide clinical evidence for height- The validity of the latter finding fell into ques-
ened limbic striatal dopamine transmission in tion as these and subsequent measurements
schizophrenia. It is not surprising therefore of cerebrospinal fluid (CSF) or peripheral se:
-
that essentially without exception, all drugs rotonin activity in schizophrenics were incon-
that treat schizophrenia are potent DJD, re- sistent and probably of no relevance to CNS
ceptor antagonists (12). A preferential antag- - function. Clinical trials with ei-
serotonergic
onism of serotonin 5HT2, or D4 receptors, or a ther 5-HT precursors or depleting agents were
more rapid dissociation from the dopamine D2 also inconclusive (19, 20).
receptor (699) may account for the atypical Noting the structural resemblance of sero-
profile of drugs such as quetiapine, aripipra- tonin to the hallucinogenic indoles dimethyl
zole, olanzapine, and clozapine. Most of typi- tryptamine (DMT)and bufotenin, researchers
cal and atypical antipsychotics occupy proposed that psychotic symptoms were
7040% of striatal D, (and probably D, recep- caused by these or similar compounds gener-
tors) at clinically effective doses (13). The an- ated in schizophrenics by the abnormal trans-
tipsychotic ineffectiveness of drugs that share methylation of endogenous indoleamines (21).
many receptor features of effective antipsy- Unfortunately, studies were unable to confirm
chotics except D, antagonism, including increases in methvlated
" indole amines in the
5HT,, antagonism (666) (see Section 8.2.1.1), plasma or CSF of schizophrenic patients ver-
implicates the D, receptor in the prime mech- sus controls (22). The transmethylation hy-
anism of their action. On the other hand, in- pothesis is also questioned by the recognition
creased CNS levels of dopamine are not an that LSD-induced psychosis differs significant
absolute predictor for psychosis; many other ways from the signs and symptoms of schizo-
agents that stimulate dopamine release such phrenia (23).
as ethanol or opiates do not produce the affec- Renewed interest in serotonin's role in
tive states seen in schizophrenia. Even the ef- schizophrenia was initiated by three major
fects of amphetamine are not reliably psy- findings. First, clozapine, thioridazine (24),
chotogenic. Lower doses can enhance focused and newer atypical antipsychotics (25) were
attention and skilled motor performance, pro- found to more potently antagonize 5-HT,, re-
cesses which are diminished in advanced ceptors than D, receptors. Second, the identi-
schizophrenia. fication of 14 serotonin receptor subtypes pro-
Developmental malformations, impaired vided new candidates for antipsychotic
neuronal innervation, diminished parenchy- etiology and targets for drug development
mal mass, metabolic compromise, and dimin- (26). A 5-HT,, partial agonist activity of clo-
ished dopamine tone in the frontal cortex typ- zapine and newer atypical antipsychotics can
ify schizophrenia but have little to do with be readily reconciled with their superior clini-
dopamine receptors. The diminished tran- cal profiles. Third, allelic variations of genes
scription of genes for synaptogenesis, myeli- for the 5-HT,, receptor have been associated
nation, metabolism, and development in the with the diagnosis of schizophrenia (27) and
schizophrenic brain (8) may explain these im- the clinical response to atypical antipsychot-
pairments and are beginning to provide a ics, for example, as shown by Arranz et al. for
novel set of targets for therapeutic interven- clozapine (28).
tion.
2.2.3 Clutamate. Glutamate and its modu-
2.2.2 Serotonin. Even before the dopa- latory receptors have been implicated in
mine hypothesis of schizophrenia became es- schizophrenia and potentially in its treatment
tablished, a role for overactive serotonin neu- with novel agents (29). After identification
Antipsychotic Agents

and characterization of the phencyclidine described their experiences with ketamine as


(PCP) binding site, it was suggested that an being similar to those that they experienced
endogenous PCP-like substance could be the during the florid periods of their illness (31).
causative agent (30). The noncompetitive N- In addition, postmortem studies have found
methyl-D-aspartate (NMDA) antagonists PCP increased densities of NMDA and non-NMDA
and MK-801 produce psychotomimetic states glutamate receptors and decreased production
similar to those seen in schizophrenic pa- and/or release of glutamate in the neocortex
tients, and the related drug, ketamine, can (38). Also, N-acetylaspartylglutamate (NAAG),
precipitate psychotic episodes in schizophren- the precursor to glutamate, and N-acetyl-a-
ics (31).To date, however, neither endogenous linked acidic dipeptidase (NAALADase), the
psychotogens nor changes in the NMDA re- enzyme that coverts NAAG to glutamate,
ceptor have been found in schizophrenia (32). are decreased in the hippocampus and fron-
A second hypothesis suggests that exces- tal cortex of schizophrenics (39). Reduced
sive release of glutamate increases intracellu- NAALADase activity could account for reduc-
lar oxidation and gradually kills the target tions in glutamate-mediated neurotransmis-
neurons (331, leading to psychosis. Several sion and a secondary up-regulation of gluta-
studies do show reduced neuron numbers in mate receptors in the neocortex.
schizophrenia versus normal tissue (34-36). Converging lines of research indicate di-
However, the reductions are relatively small minished glutamate neurotransmission in
compared with Parkinsonism, Alzheimer's de- schizophrenia. Decreases in cortical gluta--

mentia, or Huntington's disease, which are mate function would disrupt the balance be-
free of psychosis in all but the late stages. Also, tween glutamate and D, receptors, which con-
a hypothesis of enhanced glutamate toxicity is trols signaling between the basal ganglia,
inconsistent with the decreases in glutamate thalamus, and neocortex (40). A similar con-
found in schizophrenia. trol loop involving 5-HT,, and glutamate re-
A role for decreased glutamate function in ceptors has been postulated (41). The com-
schizophrenia was first proposed by Kim et al., plexity and diversity of excitatory amino acid
who found glutamate to be decreased in the receptors provides many drug targets for
CSF of schizophrenics (37). They postulated pharmaceutical intervention. No drug that
that hyperactive dopamine neurons in the combines activity at glutamate, D,, and
ventral tegmental area (VTA)stimulate D, re- 5-HT,, receptors has appeared.
ceptors, which in turn inhibits glutamate re-
lease and the activity of cortical neurons. D,
antagonism would mitigate the effects of ex- 3 ANTIPSYCHOTIC AGENTS
cessive dopamine release in schizophrenia (14,
707) and thereby disinhibit cortical glutamate 3.1 Therapeutic Indications
release.
The hypoglutamatergic hypothesis of 3.1.1 Schizophrenia and Psychoses. Anti-
schizophrenia is attractive because it is consis- psychotic drugs are primarily used to treat
tent with the lack of changes in D, number in psychotic symptoms associated with schizo-
schizophrenia, and the increases in dopamine phrenia, schizoaffective disorder, and to con-
release in schizophrenia. They are also consis- trol acute mania in patients with manic-de-
tent with the ability of the noncompetitive pressive disorder. Most antipsychotics are
NMDA antagonists PCP and ketamine to in- more effective in controlling the positive
duce behaviors reminiscent of the positive rather than the negative symptoms of schizo-
symptoms of schizophrenia in normals and phrenia. Some of the side effects associated
precipitate these episodes in patients. Ket- with their use, particularly with the use of typ-
amine was administered to schizophrenic pa- ical agents, may be mistaken for negative
tients acutely in a blinded, placebo-controlled symptoms. This confounds the assessment of
trial (31). The drug caused a dose-related ini- their effectiveness and can mislead the less-
tiation of positive psychotic symptoms that experienced practitioner to administer higher
were not blocked by haloperidol. The patients drug doses. The atypical agents are relatively
3 Antipsychotic Agents

free of neuroleptic-induced deficit symptoms ety of newer, safer agents have supplanted the
(NIDS) (42) and perhaps only for this reason use of CPZ in these indications.
seem to be superior to typical agents for treat- A number of unapproved uses of antipsy--
ing negative symptoms of schizophrenia. chotic drugs also exist. CPZ and haloperidol -
Compared with even the atypical antipsychot- were used early on to treat phencyclidine
ics, clozapine has been shown by Kane et al. to (PCP)-induced psychosis. Psychoses associ$
be effective for residual positive symptoms in ated with depression, bipolar disorder, and
the treatment of refractory patients (2, 706). Alzheimer's disease are commonly treated
With the success of the atypical agents, newer with haloperidol, risperidone, or olanzapine..
therapies are expected to show improvements Psychotic symptoms in Parkinson's disease
patients caused by levodopa and/or dopami-
in positive and at least some negative symp-
nergic agonists have been alleviated with
toms, particularly deficits in cognitive func-
quetiapine, because EPS-prone typical neuro-
tioning (43, 701). Clozapine treatment has
leptics contraindicated in Parkinson's disease.
been shown to improve several measures of
cognitive function, especially attention and 3.2 Adverse Effects and Precautions
verbal fluency, whereas other cognitive func- Antipsychotic drug therapy, particularly with
tions such as memory are impaired by cloza- typical agents, is associated with a wide range
pine (702). Risperidone may improve working of unwanted side effects (Table 10.2). Such
memory of schizophrenic patients. Overall, side effects can be troubling for patients, di-
however, the evidence shows that the im- minish compliance with their treatment, and
provement in cognitive function with typical in some cases, create serious health and safety
or atypical antipsychosis is small and of vari- risks. The most frequently observed effects re-
able clinical relevance (702, 703) (see Section sult from dose-dependent actions on the cen-
3.2.6). Similarly, atypical agents such as cloza- tral nervous system (EPS, sedation, and cog-
pine have little significant benefit on negative nitive impairment), the autonomic nervous
symptoms of schizophrenia (704, 705). system (anticholinergic symptoms) including
dry mouth, the cardiovascular system (tachy-
3.1.2 Other Indications. Some of the phe- cardia, postural hypotension, cardiac arrhyth-
nothiazines such as chlorpromazine (CPZ), mias, QT, prolongation), the endocrine sys-
triflupromazine, prochlorperazine, and per- tem (elevated prolactin release and decreased
phenazine are also used as antiemetic drugs. sexual function), and metabolism (weight
CPZ and haloperidol are effective in control- gain). The frequency and severity of dose-de-
ling intractable hiccups. Haloperidol and pendent side effects with individual antipsy-
pimozide are approved, and other antipsychot- chotic drugs can, in general, be correlated with
ics are used, to control tics associated with potencies at D,, a-1, muscarinic, and cholin-
Tourette's disorder and the agitation associ- ergic and other receptors (44-47) (see Table
ated with dementia. CPZ, thioridazine, ris- 10.2). Other adverse effects that are more se-
peridone, and haloperidol have been used in rious, less predictable, but fortunately less fre-
children to treat behavioral problems, includ- quent include tardive dyskinesia, neuroleptic
ing aggressive outbursts, hyperactivity, and malignant syndrome, blood dyscrasias, and
stereotypies associated with conduct disorder, impaired hepatic function. Dermatologic and
attention deficit hyperactivity disorder other allergic reactions and ophthalmic
(ADHD), and autism, respectively. Antipsy- changes are also less frequent.
chotics are also used to treat tics produced by
methylphenidate or amphetamine prescribed 3.2.1 Extrapyramidal Symptoms. Acute ex-
for those with ADHD. CPZ was also used long trapyramidal symptoms (EPS) consists of
ago to treat symptoms of migraine, preopera- drug-induced parkinsonism (DIP), akathisia,
tive anxiety (the first use of CPZ in man), vas- and dystonia. Because of a common link to
cular headaches, tension headaches, and as an diminished CNS dopamine function at D, re-
adjunct to control convulsions in tetanus and ceptors, DIP and idiopathic Parkinson's dis-
to treat acute intermittent porphyria. A vari- ease are indistinguishable. As in Parkinson's
Table 10.2 Receptor Binding and Side Effects of Selected Antipsychotic Drugs
Receptor Binding, pK," Side Effectsb
D2-
D ~ p a m i n e r ~ i c " ~5-HT,".'
~ ~uscarinicf~ l-Adrener& HI-~istaminic'~
Weight Anti- Orthostatic
Drug l,c m,c n,d 1,c n,e m,f n,g 1,h i n,i lj mj n,k EPS Gain Muscarinic Hypotension Sedation
Promazine 6.55 6.80 6.89 6.82 8.03 8.22 7.60 8.70 +2 +3 +2 +2
Chlorpromazine 7.60 7.72 7.74 7.15 8.37 8.59 7.55 8.05 +2 +2 +2 +3 +3
Thioridazine 7.20 7.59 7.80 7.74 8.15 8.30 7.60 7.80 +1 +3 +3 +3 +3
Mesoridazine 7.72 7.16 8.70 8.74 +1 +3 +3 +2 +3
Prochlorperazine 8.15 8.15 6.27 7.62 7.72 +3 +1 +1 +2
Trifluoperazine 8.36 8.59 7.62 6.18 7.17 7.62 6.87 7.21 +3 0 +1 +1 +1
Perphenazine 8.85 5.82 8.00 8.10 +2 +2 +1 +1 +2
Fluphenazine 8.43 9.10 7.60 5.72 7.89 8.05 7.24 7.68 +3 +1 +1 +1 +1
Thiothixene 8.35 9.35 7.44 5.54 7.96 7.96 7.43 8.22 +3 +2 +1 +2 +1
Haloperidol 8.36 8.40 8.69 7.35 6.52 4.05 5.46 8.21 7.58 4.66 5.72 5.92 +3 +1 +1 +1 +l
Pimozide 8.44 7.60 7.70 5.96 +2 -1 +2 +1 +2
Molindone 6.92 3.41 5.60 3.91 +2 0 +1 +1 +2
Risperidone 8.39 9.39 <5 8.61 7.48 +1 +1 0 +l +1
Ziprasidone 8.17 8.68 5.61 7.88 7.19 +1 0 0
Loxapine 7.15 6.35 7.55 8.31 +2 +l + 1 +2 +3
Clozapine 7.42 6.74 6.75 7.54 8.20 7.92 7.48 7.77 8.05 7.65 7.55 8.55 8.97 0/+1 +3 +3 +2 +3
Olanzepine 7.20 8.63 7.26 7.24 8.92 +1 +3 +3 +1 +1
Quetiapine 6.14 6.56 5.97 7.28 8.08 0/+1 +1 0 +2 42
ONegative logarithm of the dissociation constant, KD.
b+lmild, +2 moderate, +3 severe.
c3H-Spiperonedisplacement.
d3H-Haloperidoldisplacement.
e3H-Ketanserindisplacement.
DH-QNB displacement.
g3H-Dexetimidedisplacement.
h3H-WB4101displacement.
'3H-Prasocin displacement.
J3H-Mepyraminedisplacement.
"H-Doxepin displacement.
'Ref. 45.
"Ref. 46.
"Ref. 47.
Antipsychotic Agents

disease, the cardinal signs of DIP are bradyki- considered to be less typical variants of TD.
nesia, muscle rigidity, and resting tremor fre- TD most commonly manifests during periods
quently accompanied by a stooped posture, an of dose reduction or abrupt withdrawal of neu-
unsteady gait, seborrheic dermatitis, and ex- roleptic medication. In the early days of anti- -
cessive salivation. Akathisia is described by psychotic therapy, it was an accepted clinical
patients as an inner restlessness and an in- practice to allay the symptoms of TD by ini
ability to remain still while seated or standing. creasing the dose of a typical antipsychotic
Acute dystonia is characterized by involun- drug, or by changing from a less potent to a
tary, sustained muscle contractions that may more potent drug (e.g., CPZ to fluphenazine or _
temporarily cease, only to be repeated in a haloperidol).
slow writhing motion. Dystonic reactions may The precise biochemical mechanisms giv-
be manifested as oculogyric crises, torticollis, ing rise to TD are poorly understood, but prob-
tongue thrusting, cramping of the hands or ably include effects on GAl3Aergic neurons
arms, and laryngeal spasm. within the substantia nigra (44,261). Dopami-
EPS associated with antipsychotic therapy nergic D, receptor antagonists (i.e., typical
tends to lessen with dosage reduction. The neuroleptics) alleviate the symptoms for a
conjoint use of the same anticholinergic time, whereas dopaminergic D, receptor ago-
agents employed as adjuncts in the treatment nists and cholinergic muscarinic antagonists
of Parkinson's disease tends to ameliorate worsen the symptoms of TD. A direct correla-
DIP and dystonia, but has less effect on aka- tion between the tendency of antipsychotic
thisia. The frequency and intensity of EPS drugs to cause acute EPS in the short term
correlate with the antagonist potencies of the and the risk of TD in the long term has been
typical neuroleptics at dopaminergic D, recep- established (49). Thus, the incidence of TD is
tors. Thus, the high potency agents (like flu- much higher with typical, than with atypical,
phenazine and haloperidol) cause a higher in- antipsychotic drugs. The ability of clozapine to
cidence of EPS, while the lower potency ameliorate TD caused by other antipsychotic
agents (particularly thioridazine and mesorid-
-
drugs (50) demonstrates active protective
mine, which also antagonize muscarinic re- mechanisms of its action beyond D, antago-
ceptors) cause a lower incidence of EPS. Clo- nism.
zapine and other atypical agents generally do
not cause EPS. Dose-dependent EPS has been 3.2.3 Neuroleptic Malignant Syndrome.
reported to occur with the putative atypical Neuroleptic malignant syndrome (NMS) is a
antipsychotic drug risperidone, but only at rare, but potentially lethal, adverse effect that
levels above the recommended daily dosage of has been reported with virtually all typical an-
2-10 mg daily (48, 694). The absence of EPS tipsychotic drugs in current clinical use. NMS
seen with the atypicals has been attributed to is a complex syndrome consisting of hyper-
several mechanisms and will be discussed in thermia, frequently associated with severe
Sections 6.4 and 9.3. EPS (dystonia and parkinsonism), autonomic
nervous system instability, myoglobinuria,
3.2.2 Tardive Dyskinesia. Tardive dyskine- and increased serum creatinine phosphoki-
sia (TD) is a late-appearing and sometimes nase (CPK) levels. NMS has most frequently
irreversible syndrome that may occur after been reported in agitated male patients receiv-
prolonged treatment with antipsychotic med- ing high and rapidly escalating intramuscular
ications. It occurs more frequently in older pa- doses of antipsychotic drugs (51). Comorbid
tients and is characterized by involuntary, medical conditions, such as agitation and de-
quick, repetitive movements of the face, eye- hydration, seem to play a role in the manifes-
lids, mouth (grimaces), tongue, extremities, tation of NMS. A rechallenge of patients who
and trunk. These disturbing choreiform move- have recovered from NMS with the same or a
ments may be accompanied by slow, twisting different antipsychotic drug is generally not
movements of the body and dystonic postures. associated with a reoccurrence of NMS symp-
The appearance of late developing symptoms toms. The elucidation of the pathophysiologi-
of tardive dystonia and akathisia are generally cal basis for NMS has been confounded by the
Antipsychotic Agents

complexity of symptomology. Guerra has of- ing with their significant HI-antihistaminic
fered a hypothesis for the etiology of NMS in- potencies. Less sedation is generally seen with
volving dysregulated sympathetic nervous risperidone. Fortunately, the sedative effects
system hyperactivity (52). of these drugs tend to abate with prolonged use.

3.2.4 Seizures. The lowering of the thresh- 3.2.6 Cognitive Impairment. Studies at-
old to seizures in susceptible patients has long tempting to determine the cognitive effects of
been known to be a property of antipsychotic antipsychotic drugs in schizophrenic patients
drugs. The aliphatic phenothiazines seem to have yielded conflicting results. The use of
present a slightly higher risk than do the pi- conventional neuroleptics has shown either no
perazine phenothiazines or haloperidol. How- impairment, some impairment, or even im-
ever, the overall incidence of actual seizures
provement of cognition (56-59) and the issue
provoked by the typical antipsychotics is esti-
is even somewhat controversial for the atypi-
mated to be less than 1%,so there is some
disagreement about comparative risk (53). cal agents (702, 703). Side effects of typical
Clozapine, on the other hand, was associated antipsychotic drugs can potentially impair
by Welch et al. with a dose-related seizure in- performance in tasks intended to measure
cidence of 3% or greater (54). A correlation cognitive effects. EPS, in particular akathisia,
between seizure-inducing propensity and the caused by the more potent neuroleptics, can
central antimuscarinic potencies of antipsy- impair performance requiring motor re-
chotic drugs has been proposed (55), but other sponses. Sedation can interfere with perfor-
equally plausible mechanisms should also be mance in tasks requiring attention and vigi-
explored. In general, concern about the possi- lance. The addition of anticholinergic drugs to
ble occurrence of drug-induced seizures minimize EPS associated with conventional
should not represent a contraindication to an- neuroleptics disrupts short-term memory in
tipsychotic medication use. The risk can usu- schizophrenic patients (58). This is consistent
ally be minimized by the appropriate choice of with the well-known, adverse effects of anti-
antipsychoticagent, dosage reduction, and the cholerinergic agents on memory and cognitive
concomitant use of anticonvulsant drugs, if performance in normal persons (60). In a re-
needed. view of adverse neurobiological effects arising
from long-term use of typical neuroleptics,
3.2.5 Sedation. Conventional antipsychot- Jeste et al. (61) conclude that persistent cog-
ics cause sedation to varying degrees. Drug- nitive impairment associated with their
induced sedation can cause daytime somno- chronic use has not been clearly established.
lence and can facilitate the induction of sleep
day or night. In the early use of CPZ for the 3.2.7 Anticholinergic Effects. Antipsychotic
treatment of agitated psychotic patients, seda- drugs having relatively high affinities for
tion was initially seen as a beneficial effect. blocking muscarinic cholinergic receptors can
For the long-term treatment of schizophrenia, cause a variety of atropine-like side effects,
however, drug-induced sedation is undesir- such as dry mouth, blurred vision, constipa-
able, can contribute to negative symptoms, tion, urinary retention, and tachycardia. Such
and be mistaken for the impaired cognition annoying side effects are usually transient and
frequently associated with the disorder. Seda- seldom dangerous. Elderly patients, however,
tive effects correlate with the HI-antihista- are more susceptible to problems of constipa-
minic and possibly a,-antiadrenergic poten- tion, paralytic ileus, and urinary retention.
cies of the classical antipsychotic drugs. Thus, Patients with cardiovascular disease may be
agents with low D, potency are more sedating compromised by tachycardia induced by these
than the high potency agents, because the rel- drugs. The piperidine substituted phenothia-
ative contribution of HI and a, antagonism zines, thioridazine, and mesoridazine, and to a
are more significant relative to D, potencies. lesser extent CPZ, cause the most anticholin-
Among the atypical agents, clozapine and ergic effects among the classical antipsychot-
olanzapine are particularly sedating, in keep- ics. Clozapine and olanzapine have the highest
i
3 Antipsychotic Agents

I
incidence of anticholinergic side effects among larization warranted Caley and Cooper to rec-
r
i
the atypical antipsychotic drugs. ommend its use onlv " as a second-line
7 treatment in patients with comorbid cardio- -
3.2.8 Cardiovascular Effects. Many of the vascular risks (697). Torsade de pointes has -
. cardiovascular side effects of antipsychotic also been associated with the use of intrave-
medications result from their actions on the nous haloperidol (67). It is likely that many ofF
i autonomic nervous system. For example, the the unexplained deaths of younger patients in
; tachycardia seen with certain drugs is because Great Britain in the 1980s attributed to high
of their antimuscarinic effects (see Section dose pimozide may have been caused by its -
3.2.7). Postural hypotension caused by some arrhythmogenic effects (68).
agents is believed to be caused by a,-adrener- Torsade de pointes is known to be triggered
gic blockade. The lower potency phenothia- by hypokalemia and by the class I11 antiar-
zines, CPZ, thioridazine, and mesoridazine, rhythmic drugs that interfere with potassium
cause the highest incidence of postural hypo- channels. Potassium channel blockers prolong
tension, whereas this side effect rarely occurs the QT, interval by inhibiting the rapid com-
with haloperidol. Among the atypical agents, ponent of the delayed rectifier current, I,
clozapine and risperidone cause a higher inci- (69).Recently the human gene HERG (human
dence than do olanzapine, quetiapine, or aripi- ether-a-go-go-related gene) that encodes for a
prazole. The dizziness experienced by most protein associated with I,, has been trans-
patients is usually transient and not serious, fected into mammalian cell lines (70) and em-
especially if the antipsychotic dosage is ti- ployed to screen antipsychotic drugs for car-
trated gradually. However, postural hypoten- diotoxic effects (71-73). Haloperidol (71),
sion, possibly coupled with sedation, can pose thioridazine (72), and the otherwise promis-
a serious risk of hip fracture in elderly ing atypical antipsychotic drug sertindole (73)
. are all high affinity antagonists for the HERG
Certain antipsychotic drugs exert direct potassium channel protein. These antipsy-
quinidine-like actions on the heart (62).These chotics bear more than a casual structural re-
dose-dependent changes, which are readily ob- lationship to certain other non-cardiac drugs
served in the electrocardiograms (ECGs) of known to cause torsade de pointes arrhyth-
patients include the following: QT, prolonga- mias (63, 64), such as the HI-antihistaminic
tion, abnormal T-wave morphology, and wid- drugs, terfenadine and astemizole, and the
ening of the QRS complex. Drug-induced pro- 5-HT, agonist and prokinetic drug, cisapride.
longation of the QT, interval can trigger the
initiation of torsade de pointes, a polymorphic 3.2.9 Sexual Side Effects and Hyperpro-
ventricular tachycardia that is often fatal (63, lactinemia. Clinical evaluation of the sexual
64). Abnormal ECG effects in psychiatric pa- function effects of antipsychotic agents are
tients were first observed with the phenothia- fraught with methodological difficulties in-
zines, CPZ and thioridazine (65). Based on cluding reduced sexual performance in un-
case reports, thioridazine seems to be the medicated schizophrenics. The few well-con-
worst offender, having been implicated in sev- trolled studies that have appeared have
eral instances of sudden death attributed to involved male subjects (74, 75).
ventricular tachycardia (66; 695). A close ana- Some of the effects of antipsychotic drugs
log, mesoridazine, can also cause ventricular on sexual function have been attributed by
arrhythmias. Chlorpromazine and trifluoper- Aizenberg et al. to increased prolactin secre-
mine seem to cause fewer ECG abnormalities. tion by the anterior pituitary (74, 761, other
There is no association of alterations in QT effects may result from their specific auto-
intervals with the use of olanzapine, quetiap- nomic actions (75). Prolactin secretion by the
ine, or risperidone (695). Ziprasidone mod- anterior pituitary is tonically inhibited by the
estly prolongs the QT interval, but there is no hypothalamus, with dopamine acting as the
evidence to suggest that this leads to torsade prolactin release-inhibiting factor (PIF).
de pointes or sudden death (695). Neverthe- Thus, conventional neuroleptics cause dose-
less, its potential effects on ventricular repo- related increases in serum prolactin levels (hy-
Antipsychotic Agents

perprolactinemia) and corresponding prolac- Endocrine actions of antipsychotic drugs


tin-induced side effects. In women, such side could also contribute to weight gain. It has
effects include menstrual irregularities, breast been suggested that hyperprolactinemia in-
swelling and tenderness, galadorrhea, and de- duced by typical neuroleptics could promote
creased sexual desire. Men can experience hy- weight gain through an effect on gonadal ste-
pospermatogenesis, impotence, and loss of li- roidogenesis (81). In a relatively small study
bido because of increased serum prolactin. (811, significant weight gains along with de-
Atypical neuroleptics cause minimal effects on creased androgen levels were observed in men,
serum prolactin. Risperidone causes hyper- but were not observed in women, who experi-
prolactinemia only at the upper end of the enced reduced estrogen levels. Because the
therapeutic dose range. Other troubling side atypical antipsychotic drugs confer minimal
effects in male subjects, such as erectile dys- effects on prolactin secretion, it is very un-
function, priapism, and ejaculatory dysfunc- likely that weight gain caused by clozapine or
tion are likely caused by a-adrenergic block- olanzapine can be attributed to their effects on
ade (75). gonadal steroids. On the other hand, both clo-
zapine and olanzapine increase plasma levels
3.2.1 0 Weight Gain. Increased appetite of triglycerides (82, 83) and leptin (841, the
and weight gain can occur with many antipsy- lipid-regulating hormone secreted by adipo-
chotic medications (77). Significant weight cytes (85).
gain can affect patient compliance and can
also pose serious risks for adult onset type I1 3.2.1 1 Hematologic Side Effects. The prin-
diabetes and a variety of cardiovascular dis- cipal effects of antipsychotic drugs, notably
eases in older patients. Clozapine and olanza- clozapine, on the hematologic system were
pine seem to cause more weight gain and shown by Lieberman et al. (86) to involve leu-
incidence of type I1 diabetes than the phe- kocytosis and leukopenia. These usually occur
nothiazines, risperidone, or thiothixene (75). during the first few months of therapy and
Clozapine and olanzapine elevate serum tri- frequently resolve within a few days after re-
glycerides and diminish insulin sensitivity, re- moval of clozapine (86). The more serious and
sulting in hyperglycemia. These actions can frequently fatal complication of agranulocyto-
precede and contribute to the effect of weight sis is a very rare occurrence with antipsychotic
gain. Haloperidol, loxapine, ziprasidone, and drugs except clozapine. Early reports of cloza-
aripiprazole seem to have minimal effects on pine-induced agranulocytosis in Finland (87)
body weight or glucose metabolism. Several were so serious that they effectively prevented
neurotransmitter systems have been impli- its approval in the United States until the use
cated in the enhanced appetite and weight of the drug in treatment-resistant patients be-
gain associated with antipsychotic drugs (78). came evident (2, 706). An extensive survey of
Drugs that facilitate serotonin (5-HT) neuro- psychiatric patients treated with clozapine in
transmission have been found to decrease ap- Great Britain and Ireland found that 2.9% de-
petite (satiety) and thereby promote weight veloped neutropenia and 0.8% developed
loss (79). Conversely, drugs that antagonize agranulocytosis (88). Fatalities rarely oc-
serotonin at 5-HT, receptors increase food curred with proper hematologic monitoring
consumption and promote weight gain (79, (88). Elucidation of the mechanism of clozap-
80). a,-Adrenergic receptors are implicated in ine-induced agranulocytosis has attracted
neuroleptic drug-induced weight gain, poten- considerable interest (86, 89-94). Clinical ob-
tially through effects on energy use. The con- servations suggested that an immune-medi-
nection between histamine receptors and ated hypersensitivity reaction was responsible
weight gain is based on the observations that (86). This suggestion was later supported by
many classical HI-antihistaminic drugs cause the discovery of a serum factor in patients
weight gain and that the antipsychotic drugs with clozapine-induced agranulocytosis (89).
associated with the greatest weight gains have
the highest binding affinities at HI-histamin- 3.2.1 2 Hepatic Effects. Liver abnormali-
ergic receptors (79). ties have been observed with many antipsy-
4 Animal Models of Efticacy and Side Effects

chotic drugs since the introduction of CPZ tempt to mirror specific symptoms of schizo-
(95).Mild-to-moderate increases in transami- phrenia. Of these behaviorally isomorphic
nase enzymes are frequently seen during the models (1071, the few that have face validity -
first few weeks of therapy. Such findings are likely to become particularly useful for -
rarely justify discontinuation of therapy be- identifying atypical antipsychotic drugs (105,
cause the levels usually return to normal. A 106, 108, 109).
-P
cholestatic-like jaundice, accompanied by ab- The concept of schizophrenia as a neurode-
dominal pain and idiosyncratic fever and velopmental disorder has inspired attempts to
chills, affects up to 2% of patients taking CPZ create adverse and early postnatal events in -
(95). This non-dose-dependent cholestasis animals to model the psychopathological pro-
has also been reported with haloperidol (96) cesses underlying the disorder (109, 110).
and has rarely been reported for clozapine. These neurodevelor~mental models include
prenatal malnutriGon, viral infection and
3.2.1 3 Dermatologic Side Effects. Allergic hypoxia, disrupted neurogenesis by X-ray irra-
skin reactions associated with antipsychotic diation or neurotoxins in utero, adverse post-
drugs range from urticaria and macropapular natal ex~eriential factors such as maternal de-
rashes to erythremia multiforme. Such reac- privation and social isolation, and postnatal
tions seem to be uncommon with the newer brain damage created by hippocampal, neocor-
atypical agents. Photocontact urticaria (loo), tical, or thalamic lesions (109-111).With the
photosensitivity (sunburn) (101),and deposits possible exception of maternal deprivation
in the lens (700) have been observed with CPZ and social isolation, these models have not
and other phenothiazines including mesorid- been sufficiently characterized pharmacologi-
azine. The occurrence of hyperpigmentation cally to be used for antipsychotic drug screen-
of the skin seems to be associated with higher ing.
doses of phenothiazine-type neuroleptics in
chronically treated patients (102, 103). It has 4.2 Prediction of Antipsychotic Efficacy
been suggested that light-generated free radi-
cal species, possible interacting with melanin 4.2.1 Behavioral Effects of Psychostimulants.
in the skin, may be responsible for both the The psychosis-inducing properties of the psy-
hyperpigmentation (102,103) and photosensi- chostimulants amphetamine (121) and PCP,
tivity phenomena (101). (115) in human volunteers are well known.
Both drugs also exacerbate psychotic symp-
toms in schizophrenic patients (115,121,122).
4 ANIMAL MODELS OF EFFICACY
However, the constellation of symptoms elic-
AND SIDE EFFECTS
ited by the two psychostimulants differ signif-
icantly. Amphetamine induces predominantly
Because of its genetic complexity and uncer-
positive symptoms such as paranoia in volun-
tain etiology, schizophrenia, like so many neu-
teers, and tends to worsen such symptoms in
ropsychiatric disorders, has resisted the devel-
schizophrenics. Certain negative symptoms
opment of suitable animal models. Early
may actually be improved by amphetamine
progress in the field was hampered because of
(123). PCP induces positive and negative psy-
the prevailing belief that schizophrenia was a
chotic symptoms in normal volunteers and
social or psychological disorder rather than a
worsens a broad spectrum of psychotic symp-
neurodevelopmental brain disorder.
toms in schizophrenics (122). Because of the
psychotomimetic effects of amphetamine and
4.1 Use of Animal Models
PCP, both drugs have been used as animal
After the introduction of the first neuroleptic models against which novel antipsychotic
drugs, many animal models were developed to drug action could be predicted.
screen new compounds for potential antipsy- 4.2.1.1 Behavioral Models of Dopaminergic
chotic activity. These models predict both an- Overactivity. The initial behavioral animal
tipsychotic efficacy and side effect liability in models for identifying potential antipsychotic
humans (104-106). Other animal models at- drugs were based on the dopamine theory of
Antipsychotic Agents

schizophrenia (9). The antagonism of in- treatment with clozapine, and to a more par-
creased locomotor and stereotypic behaviors tial degree, remoxipride and sertindole, re-
induced by dopamine stimulants like apomor- verses deficits in social interaction in rats
phine and amphetamine, the induction of cat- induced by PCP (109,119, 134, 135). Haloper-
alepsy, and the disruption of the conditioned idol, chlorpromazine, and risperdal are not ac-
avoidance response each result from the tive. This is in keeping with the unique effi-
blockade of Dfl, dopaminergic receptors cacy of clozapine in ameliorating negative
(108, 112). The concept of limbic selectivity symptoms in schizophrenic patients (2). The
(10, 11) further resolves these models, effectiveness of olanzapine only at higher
whereby antipsychotic activity results from doses (119,135) was confirmed by more recent
the blockade of mesolimbic D, receptors, while studies that, however, failed to demonstrate
EPS is produced by mesostriatal D, blockade. an effect for the newer antipsychotic drug
The phenothiazine derivative, thioridazine, quetiapine (136).
and clozapine were the first neuroleptics to The behavioral despair of mice forced to
exhibit some degree of functional limbic selec- swim without escape is measured by their im-
tivity on chronic administration (113,114). In- mobility during a retest under the same con-
creased locomotor activity induced by low (0.5 ditions. Immobility in the forced swim test
mgjkg) doses of amphetamine is largely medi- (FST) is reversed by antidepressant drugs
ated in the nucleus accumbens (124, 125). All (137), whereas PCP enhances the immobility.
typical and atypical antipsychotics antagonize Pretreatment with clozapine and risperidone,
hyperactivity in rats induced by low dose am- as well as the 5-HT, antagonists, mianserin
phetamine (126,127,112), making this simple and ketanserin, attenuated the PCP-induced
animal model a useful initial screen for poten- increase in immobility, whereas haloperidol
tial antipsychotic drugs. This model is not en- and antidepressants have no effect (138,139).
tirely selective, however, because drugs lack- The PCP enhancement of the FST may pro-
ing antipsychotic activity in humans, such as vide a more selective animal model for the neg-
the GABA agonist muscimol, also antagonize ative symptoms of schizophrenia.
amphetamine-induced locomotion (128). PCP and other NMDA antagonists increase
4.2.1.2 Behavioral Models of Glutamateri- cortical glutamate efflux (140, 141). This
gic Overactivity. The observation that psy- prompted the suggestion that the psychotoge-
chotic-like symptoms can be induced in hu- nic action of PCP may result from a potentia-
man volunteers by the psychomimetic drug tion of glutamatergic effects at non-NMDA re-
phencyclidine (PCP) (115) led to an interest in ceptors, in addition to their block of NMDA
the examination of PCP-induced behaviors in receptors. Several metabotropic glutamate re-
animals as models for screening potential an- ceptor subtypes regulate glutamate efflux
tipsychotic drugs (116) (see Section 8.2.2). The (142). Moghaddam and Adams (143) have
potent noncompetitive NMDA receptor antag- shown that the group I1 metabotropic gluta-
onist properties of PCP provided an additional mate agonist LY 354740 [(+)-2-amino-
hypothesis for the etiology of schizophrenia bicyclo[3.1.Olhexane-2,6-dicarboxylate] pre-
(117). This hypothesis has been tested in a vents PCP-induced locomotion and stereotypy
wide range of PCP-induced behavioral effects and prevents the disruptive effects of PCP on
in rodents, including increased locomotor and working memory. These effects were achieved
stereotyped behaviors 116-118, decreased at doses of LY 354740 that did not affect spon-
social interaction (118, 1191, and deficits in taneous locomotion or dopaminergic neuro-
prepulse inhibition (120). transmission, suggesting that metabotropic
Hyperlocomotion and stereotyped behav- glutamate agonists might represent a new
iors induced in rodents by noncompetitive class of antipsychotic drugs.
NMDA antagonists such as PCP and dizo-
cilpine are antagonized by a wide range of an- 4.2.2 Prepulse Inhibition. Abnormalities in
tipsychotics (116, 117, 129-133). PCP can information processing and attention mecha-
model in rats the negative symptomatology of nisms have long been recognized as hallmark
social interaction (119, 134, 135). Chronic characteristics of schizophrenia. Prepulse in-
4 Animal M of Efficacy and Side Effects

hibition (PPI) is the reduction-in the startle in experimental animals and in humans. Con-
reflex response produced by a weak (non- sequently, the LI paradigm has been proposed
startling) sensory stimulus given just before as an animal model of schizophrenia to predict -
the startling stimulus. PPI is a measure of antipsychotic activity (165, 169).
sensorimotor gating or information process- Amphetamine disrupts the LI response in
ing and is reliably impaired in schizophrenic rats (170,171), and this is reversed by haloper-,
patients (144, 145). Deficits in PPI are be- idol, clozapine, and sertindole (172, 173) and
lieved to reflect an inability to adequately in- the 5-HT,, antagonist MDL 100,907 (174).
hibit irrelevant sensory information leading to The 5-HT, agonist DOI, when administered -
sensory overload and cognitive fragmentation. -
in the pre-exposure phase only, disrupts LI
The cross-species nature of PPI supports its
and this disruption is prevented by haloperi-
use as an animal model with potential face,
dol, clozapine, risperidone, and MDL 100,907
predictive, and construct validity (146). PPI in
animals is impaired by the psychotomimetic (175). This disruption could be because of ef-
agents amphetamine (144), PCP (147), and fects of DO1 on state-dependent learning
other NMDA antagonists (148, 149), and by rather than on attentional processes (175).
5-HT,, agonists (150, 151). Potentiation of the LI response in rats has
Most antipsychotics, but also many non-an- been consistently demonstrated for classical
tipsychotic drugs, reverse deficits in PPI in- antipsychotics (169, 176) and for clozapine
duced by amphetamine or apomorphine (152, (169, 172, 173, 177, 178), remoxipride (178),
153). In contrast, D, receptor antagonists sertindole (179), and MDL 100,907 (174). Be-
such as haloperidol fail to reverse deficits in cause very few of the newer antipsychotic
PPI induced by PCP or dizocilpine (153-155), drugs have been investigated for their effects
while such deficits are, at least in part, re- on LI, and MDL 100907 is not an effective
versed by clozapine (156), remoxipride (157), antipsychotic, further studies with these
olanzapine (1581, and quetiapine (155). Ris- drugs are required to validate the predictive-
peridone fails to reverse the effect of PCP ness of the LI model.
(155),but it antagonizes the disruption of PPI Although LI and PPI both reflect the ability
induced by the 5-HT, agonist DO1 (150,153). of the organism to ignore irrelevant stimuli,
Rats reared in isolation after weaning also they differ in many respects. PPI is a sensori;
experience deficits in PPI (159) and decreased motor gating process that does not require
conditioning and relies on mechanisms that
social interaction. This effect has been attrib-
uted to enhanced dopaminergic activity (160). filter exteroceptive stimuli for their physiolog-
ical or cognitive significance. LI is a cognitive
Isolation rearing deficits are maximal at pu-
process, requiring preconditioning, and re-
berty (161, 162) and thus parallel the ontog-
eny of schizophrenia in humans. The disrup- flects a subject's ability to adjust behavior to
tion of PPI in young rats reared in isolation is changing conditions. In contrast to PPI, LI is
reversed by a broad spectrum of antipsychotic not disrupted by PCP (180).
drugs including haloperidol, risperidone, clo-
zapine, olanzapine, and quetiapine (153,163). 4.2.4 Conditioned Avoidance Response.
Perhaps the oldest animal model to predict
4.2.3 Latent Inhibition. Latent inhibition potential antipsychotic drug efficacy is the
(LI)is like PPI but includes a greater cognitive conditioned avoidance response (CAR) (108,
component. It is a retarded acquisition of a 112, 181, 182). In the conditioned reinforce-
conditioned response that occurs when a sub- ment model, experimental animals are trained
ject is exposed to the conditioning stimulus to perform a certain response to avoid a mild
before the conditioning trials (164,165). Defi- shock. Trained avoidance responses may be
cits in LI reflect the inability of the subject to active (pressing a lever, climbing a pole, or
ignore irrelevant stimuli and have been dem- jumping out of a box) or passive (remaining in
onstrated in many (164-167), but not all the darker of two compartments). Classical
(168), studies of schizophrenic patients. Like antipsychotic drugs and benzodiazepines re-
PPI, latent inhibition has been demonstrated duce avoidance responding at doses that do
Antipsychotic Agents

not impair natural (untrained) escape re- a partial agonist at M, and M, receptors and
sponding (183); antidepressants impair both an antagonist at MI, M,, and M, receptors
escape and avoidance responding (184). (201). AMPNkainate receptor antagonists
CAR is inhibited by a wide variety of struc- also cause a neuroleptic-like suppression of
turally different D, antagonists (185-188). CAR (203).
There is a positive and significant correlation
between anti-avoidance activities of various 4.2.5 Drug Discrimination. Drug discrimi-
antipsychotic drugs in rats and their D, recep- nation has been used for many years to detect
tor blockade (186)and their average daily clin- the predominant receptor activities occurring
ical dose in treating schizophrenia (189). in vivo. These inferences are based on whether
Somewhat conflicting results have been ob- behavioral responses in humans or animals
tained for clozapine in CAR tests in different that are sustained by exposure to a reference
animal species (186, 190, 191). A biphasic ef- compound are also maintained by the test
fect has been reported in mice and in squirrel compound, such as one with antipsychotic
monkeys, wherein lower doses of clozapine ac- properties (204). Drug discrimination studies
tually increase avoidance, while higher doses can identify antagonist agents that block con-
antagonize the response (190).Studies in rats ditioned responses, and agonist miomics that
have shown that clozapine blocks CAR at sustain conditioned responses. Such tests can
doses that interfere (191) or do not interfere identify antipsychotics with similar pharma-
with motor function (186, 189). Remoxipride cological properties but are not necessarily
(189), risperidone (1921, olanzapine (193), predictive for the treatment of schizophrenia.
quetiapine (1941,and ziprasidone (195) are all Systemic administration of classical anti-
active in the CAR test. psychotics or clozapine block amphetamine-
The complexity of the CAR test is evident induced discriminative stimulus responses in
from the variety of drugs that either suppress the rat (205,206). The amphetamine response
or enhance responses. Wadenberg and Hicks can also be blocked by direct injection of the
(196) conclude that CAR is a sensitive test for drug into the nucleus accumbens (207).While
potential antipsychotic drugs that act by vari- classical antipsychotics completely inhibit the
ous receptors, particularly those in the nu- response, clozapine and olanzapine are some-
cleus accumbens shell. a1-Adrenergic recep- what less active, risperidone and remoxipride
tor antagonists inhibit CAR (197). This may are weakly active, and sertindole and quetiap-
contribute to the antipsychotic effectiveness ine were inactive (208, 209). Based on these
of many neuroleptics, because almost all of findings, it has been proposed that the antag-
them bind and probably antagonize the a1 re- onism of the amphetamine discriminative
ceptor. Suppression of CAR by cholinergic po- stimulus response may be an indication of
tentiators like arecoline, pilocarpine, and phy- neuroleptic-induced deficit properties (209).
sostigmine was observed many years ago (198, Antipsychotic drugs also seem to inhibit the
199). The muscarinic cholinergic antagonist discriminative stimulus effects of hallucino-
scopolamine attenuates the impairment of genic 5-HT agonists like DOI, DOM, and LSD
CAR induced by D, antagonists, but enhances in proportion to their 5-HT,, antagonist po-
the suppression of CAR caused by the selective tencies (209-211).
Dl antagonist SCH 23390 (2001, suggesting a Early studies indicated that PCP-induced
very different mechanism for the effect of Dl discriminative stimulus responses are not an-
receptors in the CAR paradigm. Partial mus- tagonized by haloperidol (212, 213), and con-
carinic agonists including PTAC and RS86 in- flicting results have been obtained with
hibit CAR (201,202). PTAC exhibits a similar NMDA antagonists including dizocilpine
pharmacological profile to that seen with atyp- (214), whereas the metabotropic glutamate
ical neuroleptics, including a limbic-selective agonist LY 354740 is inactive (215).
inhibition of dopamine cell firing and inhibi- Drug discrimination has also been used to
tion of amphetamine induced c-fos expression compare antipsychotic drugs that act through
in the nucleus accumbens (201). Preliminary different receptor mechanisms. The close
receptor selectivity data suggest that PTAC is structural analogs olanzapine and quetiapine
4 Animal Models of Efficacy and Side Effects 61 5

generalize to the clozapine discriminative chotics (50). The induction of catalepsy re-
stimulus in rats, whereas haloperidol, remo- flects the potential of a drug to cause EPS.
xipride, chlorpromazine, and fluphenazine are Many of the newer antipsychotics, for exam- -
ineffective (216-218). Seroquel, haloperidol, ple, the benzamides (188), risperidone (192), .
i and thioridazine partially generalized, but ris- olanzapine (193), ziprasidone (2311, and aripi-

i
i
peridone, sertindole, and amisulpiride, a D,/
D,-antagonist (2191, failed to generalize (220).
In a study conducted in squirrel monkeys,
prazole (232, 233), induce catalepsy only at
high doses. Some drugs lacking neuroleptic ac-
tivity, such as opioids (234) and muscarinic
T

quetiapine fully, and olanzapine partially, agonists (2351, potently induce catalepsy. .
generalized to the clozapine stimulus, Muscarinic antagonists, on the other hand, re-
whereas risperidone, sertindole, and remo- verse the cataleptogenic actions of haloperidol
xipride failed to show generalization (221). (236).
Olanzapine itself also elicits a discriminative
stimulus in rats (222). The olanzapine re- 4.3.2 Stereotyped Behaviors Induced by
sponse generalized to clozapine, chlorproma- Amphetamine and Apomorphine. Stereotypy
zine, and thioridazine, as well as to the 5-HT,, responses in rodents consist of repetitive sniff-
antagonist ritanserin and to scopolamine. A ing, licking, biting, and gnawing (237) because
full generalization to the clozapine response of excessive activation of striatal D, receptors
was achieved with muscarinic antagonist sco- (226,228). The EPS potential of antipsychotic
polamine (2201, reflecting the prominent anti- drugs is also evaluated by their ability to an-
, muscarinic action of clozapine. A partial gen- tagonize stereotypy induced in rats by rela-
eralization occurred with the a1-adrenergic tively high doses of amphetamine (5 mg/kg) or
antagonist prazosin and the a2-adrenergic an- apomorphine (1mg/kg) (229, 238-240). Clas-
-
tagonist idazoxan (220). Given the most com- sical antipsychotics and the selective D, an-
plex receptor pharmacology of clozapine and tagonist SCH 23390 fully and potently antag-
its chemical analogue olanzapine, it is not sur- onize the stereotyped behaviors induced by
prising that many antipsychotic drugs gener- amphetamine or apomorphine (238,239,241).
alize to their discriminative stimulus cues Consistent with their atypical classification,
(220, 223). thioridazine (239, 240), clozapine (239, 240),
sertindole (242), quetiapine, and ziprasidone
4.3 Prediction of Side Effect Liability
are ineffective even at the highest doses
While EPS and catalepsy in experimental an- tested, whereas remoxipride, risperidone, and
imals are no longer considered to be necessary olanzapine antagonize amphetamine-induced
consequences of antipsychotic drug action stereotypy only at relatively high doses.
(224, 225), even the newest atypical antipsy-
chotics block D, receptors to varying degrees 4.3.3 Paw Test. In the paw test, rats are
(12,13), and with the exception of quetiapine, placed on a platform with their fore- and hind-
can induce EPS, catalepsy, and increase se- limbs lowered into four separate holes. The
rum prolactin at high doses (226-228). Thus, paw test determines the effects of drugs on the
tests for such liabilities remain in most anti- spontaneous retraction of extended forelimbs
psychotic screening batteries. and hindlimbs (243). The test was originally
developed to study the effects of GABAergic
4.3.1 Catalepsy. CPZ and reserpine were drugs on motor behavior mediated in the dor-
the first neuroleptics found to create a state of sal striatum (243). It was soon discovered that
tonic immobility, or "catalepsy," in experi- classical antipsychotics such as haloperidol
mental animals. In the catalepsy test, rats or and CPZ increase the time for retraction of the
mice are placed in an unusual position and the hindlimb (HRT) and the forelimb (FRT) with
time required for the animal to correct this equal potencies, whereas thioridazine and clo-
unusual position is determined. All typical an- zapine increase HRT at lower doses than were
tipsychotics induce catalepsy (2291, whereas required to increase FRT (244). It was pro-
clozapine does not (230), and it can even re- posed that FRT models the EPS effects of neu-
verse catalepsy induced by typical antipsy- roleptics, whereas HRT models their thera-
Antipsychotic Agents

peutic effects (244). In addition to thioridazine the use of monkeys and the long-term dura-
and clozapine, the D,-selective antagonist tion of their treatment (257).
benzamides, the Dl-selective antagonists SCH
23390 and SCH 39166, and the mixed receptor 4.3.5 Vacuous Chewing Movements. The
antagonists risperidone, olanzapine and chronic administration of classical antipsy-
sertindole, all increase HRT at significantly chotic drugs to rats induces oral dyskinesias,
lower doses than those required to increase termed vacuous (or purposeless) chewing
FRT (245,246). The predictive validity of the movements (VCMs) (258-260). This behavior
paw test is questioned (112) because SCH has been proposed as a model for orifacial TD
39166 is not an effective antipsychotic (248). in humans. Chronic treatment with clozapine
In general, however, drugs lacking neuroleptic produces far fewer VCMs than does haloperi-
do1 (261,262). Rats treated for 6 months with
activity were inactive in the paw test. These
clinically effective doses of olanzapine or
included opiates, benzodiazepines, antihista-
sertindole produced very few VCMs (263).
mines, and tricyclic antidepressants (246, Notwithstanding the limited number of new
247). Scopolamine antagonizes the increase in antipsychotic drugs that have been investi-
FRT induced by haloperidol, but not its in- gated, the VCM model seems to have use for
crease in HRT, supporting the hypothesis that the preclinical assessment of potential new
FRT is related to EPS (244). drugs for their TD-inducing liability (257),
and without limitations inherent in the sensi-
4.3.4 EPS in Primates. The ability of anti- tized primate model.
psychotic drugs to induce acute dystonia and
other neurological side effects in nonhuman 4.3.6 Prolactin Response. Classical anti-
primates closely mirrors these responses in psychotic drugs stimulate prolactin release
humans. Cebus apella monkeys are sensitized from the pituitary gland through the blockade
by long-term treatment with haloperidol to of D, receptors innervated by tuberoinfun-
produce a nonhuman primate model of dibular dopamine neurons (264).The selective
chronic EPS resulting in tardive dyskinesia Dl antagonist SCH 23390 does not stimulate
(TD) (249-252). Some of the haloperidol- prolactin release (265), consistent with the
treated monkeys develop a prolonged dyski- sole presence of D, receptors in the pituitary.
netic syndrome resembling clinical TD, and The correlation between serum prolactin in-
these are used to study the potential of anti- creases and antipsychotic potencies in hu-
psychotic and other drugs to cause or treat TD mans (266) is explained by the common D,
(251, 252). Clozapine does not elicit dystonia mechanism for both actions. Although cloza-
in sensitized monkeys and is virtually free of pine (265) and aripiprazole (267) can increase
EPS in humans. Quetiapine is also devoid of serum prolactin in rats, neither antipsychotic
EPS potential in the dystonia model, after elevates prolactin in humans (268-270). More
both oral (194) and intraperitoneal (253) ad- minor effects on human serum prolactin typ-
ministration. A large separation between pre- ify the newer antipsychotic drugs, particularly
dicted EPS and clinically effective doses was aripiprazole, risperidone, olanzapine, and zi-
found for sertindole, whereas olanzapine, prasidone (421, and these will be described in
quetiapine, and remoxipride gave an interme- greater detail in the following sections dedi-
diate separation. Haloperidol, risperidone, cated to these drugs.
and ziprasidone had little separation
(254-2561, suggestive of EPS liability. The 4.3.7 Cognitive Effects. Along with the
strength of the Cebus monkey dystonia model overt psychotic symptoms that characterize
of TD is that the symptoms closely parallel the schizophrenia, deficits in cognitive function
symptoms of TD in humans, including the in- are commonly manifested by impairments in
dividual vulnerability factor wherein some attention, information processing, and mem-
monkeys develop TD while others do not ory (14, 701-703). While antipsychotic drugs
(257).Limitations are mainly the expense and can ameliorate impaired attention and infor-
ethical considerations of the model because of mation processing, their effects on memory
i 5 Discovery of Prototype Antipsychotics
t
E
deficits are less clearly established (see Sec- by Laborit to calm patients afflicted with
tion 3.2.6). In fact, some studies in rats have schizophrenia who had been treated primarily
shown that classical antipsychotics actually by social isolation or physical restraints in
induce short-term memory deficits (271,272). mental institutions. Their unprecedented im-
In the Morris water tank model of spatial provement heralded a revolution in the treat-
memory (273), low doses of haloperidol and ment of this terrible disease. CPZ and related
risperidone decrease spatial memory in a dose- drugs enabled many institutionalized patients '
dependent fashion. These drugs also decrease to reenter society and home, something that
swimming speed, suggesting that impairment had been the exception rather than the rule.
of motor function related to D, antagonism This led to a marked decrease in the number of -
(274) may be a contributing factor. Ziprasi- hospitalized patients, from 500,000 in 1955 to
done and olanzapine impair spatial memory at 222,000 in 1983.
relatively high doses but do not affect swim- Most patients who returned to society were
ming speed (275). Clozapine slightly impairs able to function moderately well, but if they
cognitive performance initially but is without stopped their medication their condition dete-
effect in later trials. Sertindole and quetiapine -
riorated. Also, CPZ and com~ounds related to
have no effect on either spatial memory. this phenothiazine series produced motoric
The same group of antipsychotic drugs side effects, including extrapyramidal side ef-
have been evaluated for their effects on work- fects (EPS) that resemble Parkinson's dis-
ing memory (276,277) in a visual spatial ver- ease. These symptoms could be severe and de-
sion of the delayed non-matching to position veloped in up to 90% of patients on typical
paradigm (278, 279). Haloperidol and risperi- antipsychotic drugs. This condition often pro-
done exhibit marked inhibitory effects in low gressed to irreversible tardive dyskinesias, in-
doses, whereas considerably higher doses of voluntary- movements of the limbs and facial
clozapine, olanzapine, and ziprasidone are re- muscles that resemble the symptoms of Hun-
quired to produce similar effects (276).Sertin- tington's disease. In addition, such typical an-
dole and quetiapine are inactive at the doses tipsychotics, although they were effective in
tested (276). Long-term treatment reveals a treating the positive or florid symptoms of
continued memory impairment of memory by schizophrenia, did not ameliorate the negative
haloperidol, the development of tolerance to symptoms of the disease.
the effects of clozapine on memory, and con-
5.2 Discovery of Haloperidol
tinued lack of impairment by sertindole (277).
Haloperidol was discovered in the Janssen
Laboratories in 1958 (280,315,320,322). It is
5 DISCOVERY OF PROTOTYPE
a butyrophenone derivative and was pursued
ANTIPSYCHOTICS
because of its ability to block the behavioral
activating effects of amphetamine in rat mod-
5.1 Discovery of Chlorprornazine
els. The amphetamine models were used as
In the late 1940s, Laborit administered the screening tools, because symptoms observed
antihistaminic phenothiazine derivative, in paranoid schizophrenia were noted to be
promethazine, before surgery to ameliorate similar to those that developed in chronic am-
the symptoms of surgical shock. He observed phetamine abusers. The behavioral profile of
that promethazine decreased the patients' haloperidol was qualitatively similar to that of
concerns and fears of the impending surgery. CPZ, but haloperidol required up to 50-fold
In 1950, optimization of this early lead pro- lower doses to exert the same behavioral ef-
duced chlorpromazine (CPZ) a drug that dem- fects as CPZ. Around this time, the term "ma-
onstrated significant efficacy in reducing pre- jor tranquilizer" began to be replaced by the
operative fears. It is this kind of indifference term "neuroleptic." The compound was pur-
to impending stress that may form the basis sued very vigorously, and the initial clinical
for the predictive nature of the conditioned results were published only 10 months after
avoidance response (CAR) test for antipsy- the initial synthesis of the compound. Halo-
chotics (see Section 4.2.4). CPZ was also used peridol is still one of the most widely pre-
Antipsychotic Agents

scribed neuroleptics in the United States understand the relationships between chemi-
(281), partly because of its inexpensive cost, cal structure and biological effectiveness after
its potency, and availability as a decanoate the discovery by Kuhn in 1957 of the first tri-
preparation for intramuscular depot adminis- cyclic antidepressant drug imipramine. This
tration that provides long-term efficacy and sparked major interest in a number of phar-
increased compliance (282). maceutical companies to investigate variants
of such structures. Although somewhat sim-
5.3 Advent of Atypical Antipsychotics
plistic, the hypothesis developed was that in
Classical neuroleptics of the phenothiazine, such linear tricyclic systems, all of which con-
butyrophenone, and thioxanthene type cause tained a basic side-chain, if the two aromatic
undesirable side effects, which at one time rings were in the same plane, i.e., flat, as was
were considered to be an inevitable conse- the case with 6:6:6 systems, the resulting mol-
quence of their potent antagonism of D, recep- ecule was most likely to exhibit antipsychotic
tors. The search for atypical antipsychotic properties, whereas in the 6:7:6 systems
compounds focused initially on maintaining where the two aromatic rings are "twisted" or
the generally favorable efficacy while decreas- non-planar, the molecule was more likely to
ing the severity or incidence of these side ef- have antidepressant properties. Indeed, such
fects, particularly the EPS. A large number of an approach led to the discovery of the imipra-
structurally diverse compounds have been in- mine analogs, clomipramine and amitripty-
vestigated to this end. These compounds have line, and also to the discovery of amoxapine
varying degrees of receptor affinities in addi- (284). However, surprisingly, clozapine was
tion to a high D, affinity for serotonergic, his- found not to be an antidepressant but an effec-
taminergic, muscarinic, cholinergic, and tive antipsychotic agent devoid of extrapyra-
non-D, dopamine receptors. The tricyclic an- midal side effects. The drug was successfully
tipsychotic, clozapine, and the benzamide, introduced in some European countries in
amisulpiride, are associated with fewer EPS 1968, but the finding of agranulocytosis in a
and preferentially increase dopamine turn- Finnish study, where eight patients died,
over in the mesolimbic system, unlike the clas- nearly ended the further development of the
sical antipsychotics, such as haloperidol and drug. The incidence of agranulocytosis in
CPZ, that elevate dopamine turnover to the schizophrenic patients treated with clozapine
same degree in mesolimbic and striatal brain is 1-2% (285). Consequently, clozapine was
areas. This finding indicates that the limbic only used as second line therapy when at least
and prefrontal areas of the brain may be anti- two other standard antipsychotic drugs had
psychotic target sites, whereas dopamine re- failed. It was not until the 1980s in the United
ceptor blockade in the striatum is thought to States that clozapine began to find acceptance,
be more responsible for the induction of EPS. as evidence mounted that it was effective
against both positive and negative symptoms
5.4 Discovery of Clozapine
of schizophrenia. The careful blood monitor-
Classical antipsychotic agents induce EPS on ing of patients treated with clozapine has dra-
chronic administration and also do not treat matically decreased the lethality from agran-
up to 30% of psychotic patients. Clozapine, a ulocytosis in the United States. The search for
tricyclic benzodiazepine derivative, was the clozapine-like compounds (286) with compa-
first antipsychotic drug to display a dramati- rable effectiveness but without the toxicologi-
cally different pharmacological profile and did cal problems has been a quest for the past 20
so both in animals and clinically. This profile years. The success of this search has required
created the concept of a new class of "atypical" the painstaking elaboration of mechanisms by
antipsychotic drugs. which clozapine exerts its therapeutic and tox-
Clozapine has had a checkered history from icological effects (287).
its initial discovery in the late 1960s by Ger-
5.5 Discovery of Amisulpride
man and Austrian clinicians (283) to its redis-
covery in the United States in the 1980s. It With the discovery of atypical agents such as
was synthesized initially as part of an effort to clozapine and thioridazine, companies began
6 Structure-Activity Relationships

searching for other classes of compound that the diphenylbutylamine, pimozide (121, the
would be effective antipsychotics devoid of the indoline, molindone (13),and the dibenz[b,fl-
EPS problems of the classical drugs and also (1,4)oxazepine,loxapine (14). Drugs generally -
the toxicological liabilities of clozapine. A se- classified as atypical include: the benzisox-
ries of benzamides was developed starting mole, risperidone (15),the benzisothiazole, zi-
from the structure of the local anesthetic, pro- prasidone (16),the dibenzCb,fl(l,4)diazepine,
cainamide, that led progressively to the anti- clozapine (17), the thienobenz[b,fl(l,4)mepine,
emetic compound, metoclopramide, and the olanzapine (I€!),and the dibenzCb,fl(l,4)thia-
observation that it demonstrated some weak zepine, quetiapine (19) (Table 10.3).
.
antipsychotic properties. Further optimiza-
6.2 Tricyclic Neuroleptics
tion of this benzamide structure led to the de-
velopment of sulpiride, which possessed sig- After the introduction of chlorpromazine (1)
nificant antipsychotic activity and had a lower (CPZ) as a treatment for schizophrenia, thou-
incidence of EPS than classical agents (288). It sands of new agents based on its tricyclic to-
was also found somewhat later that members pology were prepared and examined pharma-
of this class compound were generally highly cologically. The neuroleptic potential of these
selective for the dopamine D, family of recep- agents was determined through a number of
tors (289, 290), although varying degrees of standardized animal tests, most notably those
selectivity across the D, receptor subtypes of motor activity and conditioned response as
(D,, D,, and D,) were found. Indeed, struc- described in Section 5.3. These assays served
tural features of the substituted benzamides to rank order the neuroleptic "potency" of new
were later incorporated into compounds de- agents relative to CPZ. This classification be-
signed to specifically block the dopamine D, came known as the "chlorpromazine index,"
receptor (see Section 8.1.1). Although exten- and the biological potencies of compounds
sive variants of sulpiride have been investi- within a selected behavioral paradigm were
gated (291), only racemic sulpiride and expressed relative to CPZ whose index was
amisulpride have been marketed widely out- unity. Although receptor binding theory and
side the United States. The active enantiomer analysis were a number of years off, these
of amisulpride, S-amisulpride, is the only an- tests were often remarkably accurate at pre-
alog still under active clinical development. A dicting the rank order of affinity for the dopa-.
highly promising analog, remoxipride (292, mine D, receptor subtype.
293), produced good efficacy against both pos- The tricyclic antipsychotics may be dis-
itive and negative symptoms of schizophrenia sected into three substructures (Fig. l O . l ) ,
and no troublesome anticholinergic effects. those being the pendent amine functionality
Unfortunately, remoxipride produced unac- (Site A), the diary1heterotricyclic (Site C),and
ceptable toxicity of aplastic anemia, and clini- the intervening alkyl chain (Site B) (295).
cal trials were discontinued in 1993. However, When considering the effect of structure on
this class of compound has provided some ex- neuroleptic activity, it is informative to exam-
cellent pharmacological "tools" and radioli- ine each of the three substructures of the tri-
gands because of their high selectivity for the cyclic~in isolation to see how individual
D, receptor (294). changes within each of these regions impacts
the pharmacological properties of the result-
ant compound.
6 STRUCTURE-ACTIVITY RELATIONSHIPS
The distance between Sites A and C is crit-
ical for neuroleptic activity, with a three car-
6.1 Drug Classes
bon chain being optimal. Shortening the chain
Antipsychotic drugs currently approved for to two carbons has the effect of amplifying the
clinical use in the United States are summa- anticholinergic and antihistaminic properties.
rized in Table 10.1. Drugs classified as typical The amino ethyl derivatives diethazine (2) has
include the following: several phenothiazine proven useful in the treatment of Parkinson's
derivatives (1-9), the thioxanthene, thiothix- disease, while promethazine (3)is effective as
ene (lo), the butyrophenone, haloperidol (111, an antihistamine.
620 Antipsychotic Agents

Table 10.3 Effects of Aryl Substitution in 10-(3-Dimethylaminopropy1)phenothiazines

Chlorpromazine
Index Block of
Conditioned
No. U V W X Y Z Response in Rats

Whereas small alkyl substituents such as


methyl are tolerated at the C2 carbon, larger
substituents (i.e., R = phenyl) that restrict the
free rotation decrease neuroleptic potency.
Additionally, if rotation is restricted through
ring formation as in (4), the chlorpromazine
index is greatly reduced (295). Rotation re-
striction through ring formation at the 3-posi-

; z
Site A ; Site B I Site C

Figure 10.1. Subtructures of the tricyclic


antipsychotics.
6 Structure-Activity Relationships

tion of the aminopropylon side-chain provides response blocking activity relative to the cor-
thioridazine (5), which is equipotent to chlor- responding alkyl (13 and 14) or alkoxy (12)
promazine (1)(297). derivatives (298.299).
A number of polysubstituted derivatives -
have been examined (16-20). In each of these
cases, a marked decrease in neuroleptic po-
tency was reported (300,301). i~
Nature of the Amino Group. The size and
nature of the basic amino group has consider-
able influence on the behavioral profile of the -
phenothiazine neuroleptics (Table 10.4). A
tertiary m i n e is optimal, both mono and des-
methylchlorpromazine are several times less
active than the parent molecule in rat condi-
tioned response (302). In many cases, larger
(4) Chlorpromazine index <0.1 N-alkyl groups decrease neuroleptic potency
(Table 10.4). The diethyl (21), pyrrolidinyl
(22), morpholinine (231, and thiomorpholine
(24) analogs of CPZ show decreased chlor-
promazine indices in the rat conditioned re-
sponse assay. In contrast, the N-meth-
ylpiperazine compound prochlorperazine (25)
has enhanced potency, as do a number of other
piperazines (26-28) (296). The azaspiranyl
analog (29) produced pronounced CNS de-
pression and sedation lasting more than 48 h
(303).
Variations Within the Tricyclic Topology.
With an eye toward maintaining the diary1na-
(5) Chlorpromazine index 1 ture of the tricyclic site C, a wide variety of
creative variations of CPZ were prepared. In-
troduction of other group VI elements in place
Effect of Aromatic Substitution Within the Tri- of the sulfur in the phenothiazines produced
cyclic System. The influence of aromatic sub- the corresponding phenoxazine and phe-
stitution on the pharmacological profile of the noselenazine derivatives. As shown in Table
tricyclic antipsychotics is fairly straightfor- 10.5, the phenoxazines are markedly less
ward. For the purposes of this discussion we active than the phenothiazines (304a,b),
will examine the effect of varying substituents whereas the phenoselenazines fall somewhere
within the 10-(3-dimethylaminopropyl) phe- in between (305). The diminished activity of
nothiazines (Table 10.3),although these influ- the phenoxazines may be a result of the short-
ences are applicable across the various classes ened oxygen-carbon bond length, which would
of tricyclic neuroleptics. tend to pull the two aromatics closer together
All other factors being equal, substitution and at a tighter angle. The carbon (acridan)
at position 2 provides compounds of enhanced derivative (35) resemble the phenosel-
potency in blocking conditioned response in enozines, although the disubstituted acridan
rats relative to both the parent compound and (36) is essentially inactive (306).
also compounds having the identical substitu- A unique series of neuroleptics results from
ent at positions 1, 3, or 4. The electronic na- the replacement of the nitrogen within the
ture of the substituent also plays a role in de- phenothiazine ring system with a methine
termining the efficacy in this model. Electron carbon. The introduction of the double bond
withdrawing groups such as chloro (1)and tri- within the propylamino chain provides for
fluoromethyl (9) show superior conditioned geometric isomers. The geometry, wherein the
Antipsychotic Agents

Table 10.4 Effect of Variation of the Basic Amino Group of


10-(3-Aminopropy1)phenothiazines

(CHd3R
CPZ Index Blockade
of Conditioned
No. R X Fksponse in Rats

I:1:
2-substituted aromatic ring and the amino-
ethyl substructures are on the same side of the
double bond, is referred to as "cis," and the C1
isomers having this configuration have been
shown to possess enhanced neuroleptic po-
tency relative to the "trans." For instance,
chlorprothixine (371,the direct cis thioxan-
thene analog of chlorpromazine, showed sim- N(CH3)z
ilar activity to CPZ in conditioned behavioral
tests in rats. The trans isomer (38)displayed (37)
6 Structure-Activity Relationships 623

Table 10.5 Effect of Modifying Heteroatom at Position 10 of Phenothiazines

(CH2)3N(CH3)2 P
Chlorpromazine Index Blockade
No. Y of Conditioned Response in Rats

penthixol (40) and flupentixol (41) could


produce compounds with high potency rela-
tive to chlorpromazine (310). In contrast to

much less activity (307). Similarly, decreased


activity was observed for the reduced com-
pound (39) (308).

the diminished activity of phenoxazines rela-


tive to phenothiazines, within this tricyclic
template, the xanthenes seem equipotent to
the corresponding thio derivative. The 2-tri-
fluoromethyl derivative (42) presented condi-
tioned response blocking potency similar to
that of CPZ. This latter point brought into
question the postulate that sulfur at the 9 po-
sition optimally positioned the two aromatics
relative to each other.
The structure-activity relationships of the The phenothiazines and thioxanthenes
thioxanthenes mimic that of the phenothia- have the characteristic of two phenyl groups
zines. Aromatic substitution at the 2 position fused to a central six-member ring giving a
enhances neuroleptic potency (309). Replace- so-called 6-6-6 system. An ethylene is a com-
ment of the dimethyl amino function by se- monly used bioisostere for a thio linkage in
lected piperazine derivatives as in clo- medicinal chemistry. Continued research in
Antipsychotic Agents

the area of the tricyclics led to the use of this


and other two-atom linkages to provide the
6:7 :6 ring system.
During clinical studies of dibenzazepine de-
rivatives, it was observed that imipramine
(43), unlike the thioxanthenes, was a rela-

tively ineffective antipsychotic agent but


seemed to have efficacy in the treatment of
"

depression. Indeed this was found to be a gen-


eral property of aminoalkylated derivatives of
6: 7 :6 compounds. While unsubstituted aro-
matic com~oundsof this class showed almost
exclusively as antidepressants, they display
central depressant activity in rats, whereas Another important class of neuroleptics is
their deschloro analogs are much weaker. the dibenzazepines, which are represented
Two-substituted derivatives had observable graphically in Fig. 10.2. N-Methylpipera-
neuroleptic actions. The dibenzl3,eloxepin de- zinodibenzo[b,fl(l,4)diazepines and related
rivatives, (45) and (46) (pinoxepine), showed azepines, oxazepines and thiazepines, have all
chlorpromazine indices of 1 and 6, respectively been tested clinically and have been shown to
(311,312). be effective in schizophrenic patients (314,
An entirely new class of neuroleptic agents 315) Compounds of this class produce seda-
based on the 6-7-6 template are the dibenz tion, as well as antiadrenergic and anticholin-
fi,flthiepins. Representative of this class is oc- ergic effects. Pronounced extrapyramidal
toclothiepine (47), which is approximately six symptoms are also generally observed with
times more potent than chlorpromazine in de- this family of agents. An important exception
pressing spontaneous motor activity in the ro- is the dibenzodiazepine clozapine GO), which
torod test (313). is an unusual antipsychotic agent in that it
6 Structure-Activity Relationships

apc1
pCl N-

(47)
ClH3 '2H3
(48) X = 0 oxyclozapine
(49) X = S clotiapine
(50) X = NH clozapine
(51) X = CH2 perlapine

Q ~ ! ~ ~ H ap
~ N-

Q b
"O)

o
(52)
(53)

Figure 10.2.

does not produce extrapyramidal side effects. of this class showed high neuroleptic potency
Indeed, clozapine has been used to suppress relative to chlorpromazine. The most effective
the motor effects of tardive dyskinesia (316). compounds of this class are of the following
The reasons for this unique profile are a mat- general structure.
ter of continuing debate and research.
Two drugs related to clozapine include the
almost identical compound, olanzapine (52),
and quetiapine (53).Both confer similar anti-
psychotic profiles and a minimal propensity to
elicit extrapyramidal side effects (317, 318).
Olanzapine has also found use in the treat- FX
<
E&
-
ment of tardive dyskinesia (319).
Comparison of the behavioral potencies
and dopamine D, receptor binding of some of
6.3 Butyrophenones
these compounds are displayed in Table 10.6.
The butyrophenone antipsychotics were dis- The first of these drugs to be introduced for
covered during studies of modified meperidine treatment of psychosis was haloperidol (54).
derivatives (320). These compounds, which The relatively low toxicity of haloperidol rela-
possess a tertiary amine at the fourth carbon tive to chlorpromazine resulted in its wide ac-
of the butyral chain, could be made to possess ceptance and it remains an important drug.
minimal analgesic activity by the addition of a Related to haloperidol are methylperidol
substituent at the 4-position of the aromatic (55), trifluperidol (56), and compound (57).
ring. Many of the clinically tested compounds Comparison of these analogs shows that po-
626 Antipsychotic Agents

Table 10.6 Behavioral and Dopamine D, Binding Data for Selected Butyrophenones

Rat
Dog Jumping Amphetamine L3H] Haloperidol
Box Testa Jumping ~ t e r e o t ~ p y 6 Binding IC,,
No. Name R (Refs. 314, 320) Box Testa (Ref. 321) (nit0 (Ref. 322)
(1) Chlorpromazine
(54) Haloperidol

(55) Methylperidol

(56) Trifluperidol

(57) Peridol

(58) Haleperidide

(59) Paraperidide

(60) Floropipamide

(61) Spiperone
6 Structure-Activity Relationships

Table 10.6 (Continued)

.+"
\ /
Rat
Dog Jumping Amphetamine L3H1 Haloperid&
Box Testa Jumping Stereotypyb Binding IC,,
No. Name R (Refs. 314,320) Box Testa
(Ref. 321) (nM) (Ref. 322)
.
500 33 33 0.33
Q
;r""
..
NN
-$-J

(64) Fluoanisone 3
EN^
CH30, 5 3

(65) Azaperone n ?--7 ND ND 9 10


NuNw
"Animals are trained to jump to avoid an electric shock prepulsed by an auditory slgnal. Potency in inhibiting this
avoidance relative to chlorpromazine
bStereotypicalgnawing and chewing in response to 10 mgkg amphetamine I.V.
"L3H1spiperone binding, datum from Ref. 323.

tency and dopamine binding are enhanced by who were administered the antiemetic agent
substitution on the piperidino phenyl ring. Re- metoclopramide (66) exhibited behavioral
placement of the tertiary hydroxyl of haloper- properties consistent with antagonism of do-
idol by amides as in (58) and (59) produced pamine receptors (325). Metoclopramide initi-
effective compounds, as did simultaneous re-
placement of the aromatic by piperidine (60). 0
A cyclic variation of the 4-amino-4-carbox-
-
amido vattern can be seen in spiperone (61).
nl
"l'/\vilN,,,N(Et)z
A

which possess high affinity for the D, receptor.


is observed for benzimidaza-
NH2JJbc:
" .
N-Arvl -
viverazine derivatives (X = N) tend ..
( 66 )
show activities that are significantly atten-
ted relative to the piperidines. A substitu-
ated an acute dystonic reaction in a subset of
(64) or an electron lone pair (65) adjacent - the drug (326), a phenomenon
-

to the ~ o i noft attachment to the viverazine is


A .
.
--L:
1JauenLs wuung:--
...be explained
.mat. could by dopamine blockade
within the striatum.
Medicinal chemistry efforts in this area
.
auicklv determined that
..-... the
- - - . ------.-
~
2-methnxvhen7-
---- - ---------- - ----
J

The origin of the benzamide antipsychotics amide substructure was crucial to the elicita-
arose from the astute observation that rodents tion of behavioral effects in rodents. The 2-me-
Antipsychotic Agents

thoxybenzamide antiemetics metoclopramide,


clebopride (67) and sulpiride (68) were com-
pared for their ability to act as dopamine an-
tagonists in rodents against tigan (69), which

screen, sulpiride displayed an atypical profile


in that the stereotypyhyperactivity ratio for
(8)-sulpiride was approximately three versus
a value of one for haloperidol.
Although atypical, sulpiride had relatively
lacks this substituent. While all of these com- low antipsychotic potency (328), possibly be-
pounds inhibited apomorphine induced cir- cause of low bioavailability and poor brain
cling in animals with unilateral nigrostriatal penetration (329). These liabilities, coupled
dopamine lesions, tigan did so only at doses with the apparent atypical profile of sulpiride,
7-100 times higher than the other agents. spurred research in the benzamide area.
Similarly, the doses of tigan required to ele- An immediate improvement in the drug
vate the dopamine metabolite homovanillic properties could be obtained by the replace-
acid (HVA) in striatal and limbic area were ment of the sulfamido group with a more li-
8-200 times higher (327). pophilic group such as halogen. Compound
Benzamides with 2-pyrrolidinylmethyl (70) inhibited apomorphine-induced stereo-
side-chains were an area of intense investiga- typy in rats at a 30-fold lower dose than
tion. Some representative examples are shown sulpiride (330). Whereas the racemic 2,6-di-
in Table 10.7. Optimal 1-substituents of the methoxy derivative (71) was equipotent with
pyrrolidine ring were small alkyl, cycloalkyl, sulpiride against apomorphine mediated be-
or benzyl. In the case of alkyl substituents, the haviors, the S-enantiomer of the 3-bromo-2,6-
(5')-enantiomers were more active at blocking dimethoxy derivative (remoxipride) (72)
D, receptors, whereas the reverse was true for closely resembled haloperidol in its ability to
the 1-benzylpyrrolidinederivatives (327). Re- block apomorphine-induced hyperactivity.
moval of the N-substituent resulted in dimin- The sevenfold ratio of stereotypy to hyperac-
ished activity. tivity for remoxipride suggested a low propen-
One of the earliest benzamides to be put sity to produce EPS in the clinic. Remoxipride
into clinical practice was sulpiride. A classic was briefly used in clinical practice, but the
screening method for selection of compounds development of aplastic anemia in a minority
having a preference for mesolimbic over stria- of patients led to its eventual withdrawal
tal D, receptors is the determination of a high (331).
ratio of blockade of DA agonist-induced ste- The dibromo derivative (74). . showed in-

reotypies (striatal) versus agonist-induced hy- creased activity over remoxipride, although
peractivity (limbic). Based on this behavioral the latter showed a better separation in the
Table 10.7 Behavioral Properties and D, Binding Affinities of 2-Methoxybenzamides

Blockade of Apomorphine ED,,


(pmolkg I.P.) Ratio [3HlSpiperone
Stereohvl
" a "
Binding:
No. Isomer X Y Z Hyperactivity Stereotypy Hyperactivity (If&,, nkl
(68) S SO,NH, H H 65.6 212 5.8 233
i5
a (70) S Br H H 3.0 6.3 2.1 46
(71) RIS H OCH, H 71 101 1.4 15,300
(72) S Br OCH, H 0.86 6.5 7.6 1570
(73) R Br OCH, H 120 >I96 >1.6 >10,000
(74) S Br OCH, Br 0.44 2.1 4.8 -
(75) RIS C1 OCH, H 30.8 42.7 1.4 -
(76) RIS C1 OCH, C1 3.1 5.4 1.74 -
(77) S Br OH H 0.06 0.32 5.3 12
(78) S H OH Br 6.2 6.6 1.07 56
(79) S C1 OH H 0.20 0.87 4.4 39
(80) S H OH C1 0.87 2.5 3.1 64
(81) S C1 OH C1 0.13 1.80 13.8 32
(82) S Et OH C1 -7 0.09
Haldoperidol 0.29 0.27 0.93 12
Antipsychotic Agents

stereotypy/hyperactivityratio. Substitution of
chlorines for bromine in both cases led to di-
minished activity and a more typical behav-
ioral profile (75 and 76).
Analysisofthehuman metabolitesofremox-
ipride identified two products resulting from
demethylation (332). The 3-bromo-6-methoxy
salicylamide (77) (FLA 797) showed a much
greater affinity for the D, receptor than did Figure 10.3. Solid state conformation of FLA 797.
either its isomer (FLA 908) (78) or the parent
compound. This result lead to speculation that amide substructure is the preferred conforma-
the neuroleptic activity of remoxipride was tion for binding of the benzamide neuroleptics
caused by this metabolite. to the receptor.
The 100-fold increase in affinity of FLA 797 Raclopride presents an exceptional separa-
tion between striatal- and limbic-mediated be-
over remoxipride was puzzling. Determina-
haviors. Although it has been suggested that
tion of the logP values for remoxipride and
raclopride is able to differentiate between re-
FLA 797 found them to be nearly identical (2.1 gional subclasses of D, receptors (3371, this
versus 2.0), indicating a similar partitioning has never been clearly substantiated in the
between octanol and water. This result is laboratory for this or any antipsychotic at the
somewhat surprising because the free hy- level of receptor binding.
droxyl group of (77) would be expected to as- Another benzamide of interest is ami-
sociate with water. A larger difference was sulpiride (83). Clinical trials have shown
found for logP where FLA 797 was found to be
more lipophilic than remoxipride (1.7 versus
0.7). However, this difference seems unlikely
to fully explain the difference in in uitro activ-
ity.
X-ray crystal structures of both compounds
were performed and indicated major differ-
ences in the conformations of the two benz-
amides (333). For remoxipride, the phenyl
group and the amide carbonyl are oriented al-
most perpendicular to each other. This orien- amisulpiride to be efficacious against the pos-
tation precludes the formation of a hydrogen itive symptoms of schizophrenia at doses that
bond between the amide hydrogen and the or- have only a low propensity to induce EPS ef-
tho methoxy group. Such hydrogen bonds fects (338). In accordance with other benz-
have been noted in other types of ortho benz- amide neuroleptics such as sulpiride and
amides (334). raclopride, amisulpiride is highly selective for
The 6-methoxysalicylamide displayed a the D, and D, receptor subtypes for which it,
planar conformation wherein a pseudo-ring is like most antipsychotics, has similar affinity
stabilized by a hydrogen bond between the (-2 nM). The high selectivity of (83)for the D,
phenol and the carbonyl oxygen. As depicted receptor family, coupled with its clinical pro-
in Fig. 10.3, this conformation also allows for file, bring into question previous theories that
an additional interaction between the amide the atypical nature of drugs such as clozapine
hydrogen and the remaining ortho methoxy. is a result of their interaction with one or a
Such additional hydrogen bonds have been number of other non-dopaminergic receptors
found in the related 2-methoxysalicylamides (339,340).
raclopride (81) (335) and eticlopride (82) Considerable evidence exists that D, re-
(336).The exceptional dopamine D, affinity of ceptors are presynaptic autoreceptors that
these compounds relative to remoxipride sug- are preferentially localized in limbic area
gests that this planar orientation of the benz- (341-343). The atypical nature of amisulpiride
6 Structure-Activity Relationships

has been speculated to result from its prefer-


ence for limbic presynaptic autoreceptors at
doses below those that produce significant
postsynaptic D, receptor occupancy (344). Its
atypical profile and that of other drugs may
also be derived from an ability to block limbic
D, receptors, which are increased in schizo-
phrenia and normalized by a variety of anti-
psychotics (341).

6.5 Miscellaneous Classes


In addition to the tricyclics, the butyrophe-
nones, and the benzamides, a variety of other Butaclamol(87) and dexclamol(88) are ef-
structural types have been exploited for their fective neuroleptics that are distantly related
neuroleptic potential. Risperidone (84) is rep- to the tricyclics. Their use is limited by a high
propensity to initiate EPS.
The clinical effectiveness of oxypertine (89)
led eventually to the evaluation of the te-
tralone derivative (90)(346).A blending of the
indole and tetralone structures of (89) and

resentative of a series of conformationally re-


stricted butyrophenones (345).
A primary metabolic pathway for the buty-
rophenone class of compounds is the reduction (87) R = t-butyl
of the carbonyl group. Modification of this (88) R = isopropyl
functionality led to the development of the di-
phenylbutylpiperidines as long-acting anti-
psychotics. Fluspirilene (85) and pimozide
(86) are the direct analogs of spiperone and
benperidol.
Antipsychotic Agents

(90)produced a series of Mannich bases of pyr-


role ketones, such as molindone (91), which
displays a typical neuroleptic profile (347).
The conformationally restricted analog (92)

7 PHARMACOKINETICS,
BIOTRANSFORMATION,
AND DRUG INTERACTIONS

7.1 General Considerations


The antipsychotic drugs represent a chemi-
cally diverse group of compounds with varied
has antipsychotic activity in the avoidance pharmacokinetic properties (351-353). Most
test in rats in the potency range of haloperidol antipsychotics are highly lipophilic molecules
and over five times the potency of molindone (354, 355) that cross lipoidal membranes
(348). This result establishes the special re- readily. They tend to distribute rapidly to tis-
quires of the binding pharmacophore within sues that are well supplied with blood, espe-
this series. cially the lungs, skeletal muscle, liver, and
Imidazalones presented as a novel struc- brain. When administered orally, most anti-
tural class of neuroleptic agents when AL 1965 psychotic drugs are well absorbed, but many
(93) was investigated in the treatment of undergo substantial first pass metabolism.
Consequently, systemic bioavailabilities (F)
for antipsychotics vary over a broad range (F
= 10 - 80%). The comparatively high fraction
of drug bound to plasma proteins (f) = 7599%
does not markedly affect the pharmacokinet-
ics of most antipsychotic drugs, because of
their comparatively large volumes of distribu-
tion (V,= 20 Lkg; range, 30-60 Lkg) and the
low affinity of binding to plasma proteins. Sys-
temic clearances of these drugs are generally
high (approximately 30-60 L/h) as are their
hepatic extraction ratios. Most antipsychotic
drugs exhibit biphasic (or polyphasic) phar-
schizophrenic psychosis (349). Although (93) macokinetics with relatively short plasma
resembled haloperidol in efficacy, a high inci- half-lives (t, = 2.5 h; range, 1-8 h) and long
dence of extrapyramidal effects were reported. elimination half-lives (t, = 24 h; range, 8-150
Another oxindole, sertindole (941, has been h). The renal excretion of unchanged drug is
shown to be active against both positive and negligible for most clinically useful antipsy-
negative symptoms (350). chotic drugs.
7 Pharmacokinetics, Biotransformation, and Drug Interactions 633

The main modes of biotransformation of IM dose (366). Approximately 91-99% of CPZ


antipsychotic drugs involve oxidative pro- in plasma is estimated to be protein-bound
cesses mediated by genetically controlled mi- (367).
crosomal oxidases (phase I), followed by con- The net effect of first pass metabolism on.
jugative (phase 11) reactions in many cases. the therapeutic efficacy of CPZ is difficult to
Enterohepatic recycling may occur for certain evaluate because of the formation of numer-
phase I1 metabolites, especially glucuronides ous metabolites, some of which possess biologT
or ring-hydroxylated metabolites. Although a ical activity (356, 357). Numerous sites of at-
majority of phase I metabolites are inactive, or tack by microsomal oxygenases are possible,
considerably less active than the parent drug, and indeed most of these reactions occur in-
some ring hydroxylated and N-dealkylated experimental animals and/or humans. In fact,
metabolites have sigmficant activity (356359) of the 168 possible metabolites postulated for
and may contribute to the overall pharmaco- CPZ (3681, more than 45 have been isolated
logical properties of the administered drug. from various human body fluids (357).
The existence of active metabolites, each with Phase I reactions of chlorpromazine that
distinct pharmacokinetic properties compared have been reported include the following: oxi-
with the parent drug, complicates attempts to dative N-demethylation to yield the corre-
correlate assays of parent drug in the plasma sponding primary and secondary amines
with therapeutic responses and adverse reac- (368-371); aromatic hydroxylation to yield
tions. phenols (369-376); N3-oxidation to yield the
The steady-state concentrations of antipsy- N-oxide (371, 372, 376, 377); S-oxidation to
chotic drugs after multiple dosing have been yield sulfoxide (369-373) and sulfone (378);
measured to establish a relationship between oxidative deamination of the amino propyl
plasma concentrations and clinical efficacy or side-chain (probably preceded by N-demethyl-
to monitor adverse effects (360-363). The ma- ation) to yield the carboxylic acid (371, 379);
jority of drugs in the class seem to exhibit lin- N1-dealkylation to yield chlorophenothiazine
ear pharmacokinetics, despite the wide inter- and its oxidized metabolites (373); N-oxida-
individual variations in pharmacokinetic tion of the demethylated amines to yield hy-
properties observed for specific agents. Linear droxylamines (380, 381); and both oxidative
pharmacokinetics allows the dosage to be (373,375) and reductive (382,383) dechlorina-
readily adjusted if the steady-state plasma tions. Direct N-glucuronidation of CPZ to
concentration is in the sub-therapeutic or form the quaternary N-glucuronide, a phase I1
toxic range. reaction, has also been reported (384,385).
Ring hydroxylation occurs mainly at the 7
position of CPZ (369-375) with lesser
7.2 Phenothiazines
amounts of 3-hydroxy (371, 374, 375) and
The prototypical antipsychotic drug chlor- trace amounts of 8-hydroxy metabolites also
promazine (CPZ) has been the focus of more formed. Further hydroxylation of the 3- and
pharmacokinetic and biotransformation stud- 7-hydroxy metabolites to form 3,7- and 7,8-
ies than any other antipsychotic drug. The dihydroxy derivatives may also occur (376,
pharmacokinetic parameters for CPZ were 386). Hydroxy metabolites of CPZ are excreted
shown by Yeung et al. to display high inter- in the urine largely as their 0-glucuronides.
individual variability even in healthy human Numerous experimental animal studies
volunteers (364). Thus, wide between-subject have been carried out on several major and
variations in half-life, volume of distribution, minor metabolites of CPZ to determine if its
steady-state volume of distribution, and mean therapeutic and/or toxic actions can be attrib-
residence time values are observed, whereas uted to one or more metabolites. These studies
systemic clearance is less variable (364). CPZ are described in detail in the previous edition
experiences extensive first pass metabolism of this series (387) and will not be recounted
leading to a systemic oral bioavailability of less here.
than 10% relative to a single IV dose (365) or Despite the keen interest in CPZ metabo-
an average of around 30% relative to a single lites, only 7-hydroxy-CPZ has been evaluated
Antipsychotic Agents

and found to be effective in schizophrenic pa-


tients (388). This metabolite has also been
found in the CSF of CPZ treated patients in
concentrations comparable with that of the
parent drug (389). CSF concentrations of N-
demethyl chlorpromazine in patients treated
with CPZ are lower (390). Chetty et al. (391)
suggest that six CPZ metabolites achieve suf-
ficient plasma concentrations to influence the
overall therapeutic response. The ratio of
7-hydroxy-chlorpromazineto chlorpromazine
sulfoxide was found to be greater in the
plasma of responding than in non-responding
schizophrenic patients (392, 393).
In general, other phenothiazine antipsy-
chotic agents seem to undergo biotransforma-
tions similar to those that occur with CPZ sponding promazines; apparently, this is a
(370,394-404).Some differences exist, based result of successive oxidations on the pipera-
on specific ring or side-chain substituents. zine ring (406-408).
Thioridazine (95) is oxidized on the 2-thio- After oral administration of thioridazine to
schizophrenic patients, the 5-oxide achieves
the highest plasma level, followed by mesorid-
azine, sulforidazine, and N-desmethyl thiorid-
azine (356. 413). On the other hand. concen-
trations of thioridazine in postmortem brain
samples were higher than any of its metabo-
lites in schizophrenics treated with the drug
(414). Thioridazine is bound to plasma pro-
teins to a higher degree than are either of its
active metabolites (415). Individual patient re-
sponses and side effect profiles of thioridazine
may be influenced by debrisoquine hydroxyla-
tor status (mediated by the 2D6 isoform of cy-
tochrome P450, CYP2D6), because higher
plasma levels of thioridazine and its inactive
5-sulfoxide metabolite were seen in Door, com-
pared with extensive, debrisoquine metiboliz-
methyl group to form the sulfoxide, mesorid- ers among healthy human volunteers admin-
azine (96) (397-400), a clinically employed an- istered a single oral dose of thioridazine (416).
tipsychotic drug in its own right, and the Conversely, lower plasma levels of the active
sulfone, sulforidazine (397-400). The side- metabolites mesoridazine and thioridazine
chain piperidine ring is oxidized to form lac- were observed in poor metabolizers than in
tam metabolites. The asymmetric center extensive metabolizers (416). Both 2- and
present in the piperidinyl ethyl side-chain al- 5-sulfoxidation of thioridazine seem to be me-
lows the formation of diastereoisomeric ring diated by cytochrome P450 oxygenases,
sulfoxide (404,405) and N-oxide (405) metab- whereas N-oxidation is catalyzed by a flavin
olites. Piperazinylpropyl-substituted phe- monooxygenase (417). Drug interaction stud-
nothiazines such as prochlorperazine (251, tri- ies of thioridazine with the serotonin selective
fluoperazine (961, perphenazine (261, and reuptake inhibitor (SSRI) antidepressants flu-
fluphenazine (96) form the same 10-(3-amin- oxetine and fluvoxamine, known inhibitors of
opropyl) phenothiazine metabolites that re- CYP oxidations, indicate the potential for clin-
sult from N,N-demethylation of the corre- ically significant interactions (418,419).
7 Pharmacokinetics, Biotransformation, and Drug Interactions 635

Of the numerous phenothiazines possess- tion of paroxetine, an SSRI that inhibits


ing piperazinylpropyl side-chains, fluphena- CYP2D6 (434). Indeed, DNPZ exhibited a
zine has been the most studied in terms of its more favorable 5HT2/D2ratio of receptor po-
pharmacokinetic properties. The apparent tencies, suggestive of atypical activity (432),
reason for the interest in fluphenazine is that than did perphenazine or 7-hydroxy-per-
it is available in both oral and depot injectable phenazine (433).
dosage forms. Oral fluphenazine experiences P

extensive first pass metabolism (419-422) to 7.3 Thioxanthenes


form numerous metabolites, all of which are Thiothixene (99) is the only thioxanthene de--
less active than the parent drug (410, 420- rivative that continues to be marketed for the
-
426). A distribution study of orally adminis- treatment of psychotic disorders in the United
tered fluphenazine using radioimmunoassay
established that brain concentrations of flu-
phenazine exceeded plasma concentrations by
10 to 27 times (420). The inactive sulfoxide
was the major metabolite found in brain, while
brain levels of 7-hydroxy-fluphenazine and
fluphenazine-N-oxide were very low (420). It
was concluded that metabolites do not con-
tribute to the pharmacology of fluphenazine
and that only the plasma level of the parent
drug needs be monitored for correlation to
therapeutic response.
A comparison of biotransformation pat-
terns in patients receiving oral fluphenazine
versus intramuscularly injected fluphenazine
decanoate revealed a significant first pass ef-
States. The two principal metabolites, thio-
fect (422,427). Thus, plasma ratios of fluphen-
thixene sulfoxide and N-desmethyl thiothi-
mine sulfoxide and 7-hydroxy-fluphenazine to
xene, are formed by CYP 450 oxidations (435).
fluphenazine were much higher after oral ad-
The CYP isozymes involved are not knowh
ministration compared with intramuscular
with certainty. However, the hepatic clear-
administration of fluphenazine decanoate.
ance of thiothixene was increased by the
The plasma ratios of fluphenazine-N-oxide to
CYP3A4 inducer carbamazepine and de-
.
flu~henazinedid not differ between the two
creased by the CYP3A4 inhibitor cimetidine
dosage forms. In a study measuring fluphena-
(436). The CYP2D6 inhibitor paroxetine, how-
zine serum levels during reduced dose flu-
ever, had no effect on thiothixene clearance
phenazine decanoate maintenance therapy at
(437).
two dose levels. it was determined that serum
levels could be monitored at maintenance
doses (429,430).
The hepatic clearance of perphenazine (26) The pharmacokinetics of loxapine (100) have
was found to depend on the CYP2D6 genotype been reviewed along with its pharmacody-
(430). Pollock et al. observed that elderly pa- namic properties (438). The drug is rapidly ab-
tients treated with perphenazine who were ef- sorbed after oral absorption, with peak plasma
ficient CYP2D6 metabolizers developed fewer levels being achieved within 1-2 h. No oral
EPS than patients who were poor 2D6 me- bioavailability data are available for loxapine,
tabolizers (431). They hypothesized that the but it is evident that it is extensively metabo-
principal perphenazine metabolite, N-dealkyl lized in the liver and rapidly distributed into
perphenazine (DNPZ) might be responsible the tissues.
(431). Consistent with this hypothesis, the Loxapine undergoes several phase I oxida-
CNS side effects of perphenazine were poten- tions (439, 440), including the following: N-
tiated in another study by the coadministra- demethylation to form amoxepine, a clinically
Antipsychotic Agents

tion at the piperazine 3-position to form the


lactam (1781, aromatic hydroxylation (454,
455, 457), and presumed oxidative displace-
ment of the 3-chloro substituent by hydroxyl
and thiomethyl groups (456) have also been
reported. The structures of phenolic metabo-
lites are not known with certainty, but are
suggested to be 2-hydroxy-clozapine and 7-hy-
droxy-clozapine based on chemical synthesis
and radioimmunoassay (455). Three unidenti-
fied polar metabolites, presumed to be phe-
nolic and constituting up to 20% of total me-
tabolites, were formed in human liver cell
useful antidepressant drug (358); aromatic preparations in vitro (457). In a more recent
hydroxylation to form 7-hydroxy- and 8-hy- study using 14C-labelledclozapine in human
droxy-loxapines; and N-oxidation on the 4-pi- volunteers (4581, the major metabolic path-
peridinyl nitrogen atom to form the N-oxide. ways were found to involve N-demethylation,
The phenolic metabolites are excreted in the N-oxidation, aromatic oxidation at the 7- and
urine as glucuronide and sulfate conjugates 8-positions, and sulfate and glucuronide con-
(439, 440). Some 8-hydroxy-loxapine is con- jugations. The major urinary components
verted to the methyl ether (439, 440). Direct were 8-hydroxy-desmethyl clozapine, its gluc-
N(4)-glucuronidationto form the quaternary uronide, 7-hydroxydesmethyl clozapine, and
glucuronide also occurs (441). its sulfate, and clozapine-N-oxide. The pri-
mary fecal metabolite was clozapine-N-gluc-
uronide. In a separate in vivo study, a rela-
The pharmacokinetics of clozapine (50) have tively small amount (about 3%) of the N(4)-
been studied extensively (451-453). After sin- piperazinyl glucuronide of clozapine was
gle and multiple oral doses, plasma concentra- identified (441). Olanzapine (52) is exten-
tions of clozapine reach peak levels in 4 h and sively metabolized by a combination of oxida-
decline in a biphasic manner consistent with tion and glucuronidation reactions in animals
first order absorption and elimination (453). and in man (468-470). Only about 10% of un-
The systemic bioavailability of clozapine is ap- changed drug is excreted in the urine and fe-
proximately 50% after oral administration ces. A novel tertiary m i n e glucuronide, olan-
and results from a moderate amount of first zapine-10-N-glucuronide, is the principal
pass metabolism. The elimination half-life of urinary (13%)and fecal (7%)metabolite in hu-
clozapine ranges from 6 to 33 h (average, 16 h) mans (468,470). Considerably lesser amounts
(452). The drug is 90-95% bound to plasma of the quaternary 4-N-glucuronide are also
proteins. Clozapine is extensively metabo- formed. Oxidative N-dealkylation, formation
lized, predominantly through the cytochrome of the 4'-N-oxide, and oxidation of the thienyl-
p450 enzymes 3A4 and 1A2 (6981, resulting in methyl group to give the 2-hydroxymethyl-
only 2 4 %of unchanged drug appearing in the and 2-carboxylic acid derivatives also occur
urine and feces. Urinary excretion of metabo- (468). The metabolic profiles of olanzapine in
lites accounts for approximately 50% of an various animal species were similar to that in
orally administered dose of clozapine, with humans in many respects (469). The major dif-
about 30% recovered as metabolites in the fe- ferences were that the 10-N-glucuronidewas
ces (451). not detected in any other species and that ar-
Clozapine is metabolized by a number of omatic hydroxylation to form various 7-hy-
oxidative pathways (454-457). The most im- droxy derived metabolites was a significant
portant of these are N-demethylation and N- pathway in some species (469).
oxidation on the N4-piperazinyl nitrogen to Some of the oxygenases involved in specific
give the major metabolites, desmethyl cloza- olanzepine oxidations have been determined
pine and clozapine-N-oxide (454-457). Oxida- (472). Oxidative demethylation of olanzepine
7 Pharrnacokinetics, Biotransformation, and Drug Interactions 637

is apparently catalyzed by CYPlA2, because mean terminal half-life of about 6 h. Oral ab-
this transformation is enhanced by cigarette sorption of the drug is rapid with peak plasma
smoke and the inducer carbamazepine and in- levels achieved within 1.5 h. Quetiapine is -
hibited by fluvoxamine. The formation of the widely distributed throughout the body with -
2-hydroxy-methyl metabolite catalyzed by an average volume of distribution of 10 L/kg.
CYP2D6 is considered to be a minor pathway The extent of plasma protein binding is 83%at,
and not likely to lead to clinically significant therapeutic blood concentrations.
drug interactions (472). A flavin nonooxygen- Quetiapine is extensively metabolized by
ase (FM03)is thought to be responsible for the cytochrome P450 oxidation. Less than 5% of _
4-N-oxide (472). unchanged drug is excreted. The major path-
Oxidative metabolism of clozapine was way involves CYP3A4 oxidation to the sulfox-
found to correlate with caffeine metabolism ide (473, 475). Other important reactions in-
(462) and is thus largely carried out by cyto- clude oxidation of the side-chain alcohol to the
chrome P4501A2 (CYPlA2). No correlation carboxylic acid, aromatic oxidation to the phe-
with CYP2D6 polymorphism was found (461, nolic 7-hydroxy-metabolite, and oxidative N-
462). Several interaction studies of clozapine dealkylation of the entire side-chain (473,
with SSRI antidepressants have been reported 475). Inducers of CYP3A4 (phenytoin and car-
(465-469). Fluvoxamine increased plasma bamazepine) significantly increased quetiap-
concentrations of clozapine in schizophrenic ine clearance, whereas ketoconazole, an inhib-
patients (463,464), presumably through inhi- itor of CYP3A4, significantly increased plasma
bition of CYPlA2 catalyzed N-demethylation levels of the drug (475).
(465). Fluoxetine was found to increase the
7.7 Butyrophenones
plasma concentrations of clozapine and its
major metabolites, suggesting that this SSRI The member of the butyrophenone class of an-
must interfere with pathways other than N- tipsychotic drugs that has been studied the
demethylation and N-dealkylation (466). Two most extensively is haloperidol (476). The
other SSRIs, paroxetine (463) and citalopram drug is rapidly and almost completely ab-
(467), had no apparent effects on clozapine sorbed after oral administration. Significant
levels. first pass metabolism in the liver largely ac-
The biotransformation (468-470) and clin- counts for the systemic bioavailability of,
ical pharmacokinetics (471) of olanzapine around 60% for haloperidol by the oral route
have been investigated extensively. The drug (477). Haloperidol is 90-92% bound to plasma
exhibits dose proportional linear pharmacoki- proteins. Peak plasma levels of haloperidol are
netics in therapeutic dose ranges (471). Olan- achieved in 1.7-3.2 h, and the drug is rapidly
zapine is bound to both albumin and a-1-acid distributed to well-perfused tissues such as
glycoproteins in the plasma. The mean elimi- the lungs, skeletal muscle, and brain, with a
nation half-life in healthy adults was 33 h and terminal half-life ranging from 6 to 33 h. Re-
the plasma clearance averaged 26 L/h. distribution of haloperidol to adipose tissue
apparently does not occur significantly (478).
7.6 Dibenz(l,4)Thiazepines
Haloperidol undergoes extensive metabo-
Quetiapine (53) is the only dibenz(l,4)thia- lism to form a myriad of primary and second-
zepine derivative currently available in the ary metabolites (479-486). The principal
United States. Very few publications have phase I reactions involve the following: oxida-
been devoted to its biotransformation and tive N-dealkylation to initially form 4-fluoro-
pharmacokinetics (473, 474). Much of the fol- phenylbenzoylpropionaldehyde (which is rap-
lowing information has been obtained from idly oxidized to the acid) and 444-
data on file from the manufacturer (475). chloropheny1)-4-hydroxypiperidine(479, 480,
Quetiapine exhibits dose proportional lin- 483-485); N-oxidation to form haloperido1-N-
ear pharmacokinetics within the clinical dose oxide (485); and reversible reduction of the
range with accumulation that is predictable carbonyl group to the alcohol, or reduced hal-
on multiple dosing. Clearance of quetiapine is operidol(481,487). A phase I1 metabolite, hal-
largely through hepatic metabolism with a operidol-0-glucuronide, accounts for as much
Antipsychotic Agents

as 60% of total haloperidol metabolites ex- The structural similarity of the pyridinium
creted in the urine (486). Reduced haloperidol metabolite (102) to 1-methyl-4-phenylpyri-
is also hydroxylated at the 2'-fluorophenyl dinium (MPPt) (103), the toxic metabolic
ring position and this phase I metabolite is
excreted in the urine as the sulfate and gluc-
uronide conjugates (486). The quaternary N-
glucuronide of haloperidol apparently does
not form (441). Formation of the dehydration
product of haloperidol, i.e., the 1,2,5,6-tetra-
hydroperidine derivative (101), is thought to
product responsible for the Parkinson's disease-
inducing agent 1-methyl-4-phenyl-1,2,3,6-tet-
rahydropyridine (MPTP) (104), prompted the

occur spontaneously in vivo (482-485). This


metabolite, together with its N-oxide, are be-
fascinating suggestion that this metabolite
lieved to be the sources of the corresponding
might be responsible for the persistence of
pyridinium species (102) that has been identi-
EPS even after the discontinuation of haloper-
idol (484, 485, 502, 503). Indeed, (101) was
found to be toxic to dopaminergic neurons in
rat brain through inhibition of mitochondrial
electron transport, a mechanism shared with
MPPt (502). Both MPP and (102) exhibited
comparable toxicity to serotonergic neurons,
but MPP+ was more toxic to DA-neurons
(502). The pyridinium metabolite (102), like
fied as a minor metabolite of haloperidol in MPPt, was also toxic to dopaminergic neuro-
animals and humans (482-485). blastoma cells in culture (503), but differed
The biotransformation of haloperidol is de- from MPPf in the time course of its toxicity.
creased in poor, compared with extensive, me- Because (102) is found in rat brain after
tabolizers of debrisoquine (497). Plasma levels administration of haloperidol or its dehy-
of reduced haloperidol on the other hand, are drated metabolite (101) (504, 505), it is likely
higher in poor metabolizers than in extensive that despite its positive charge, (102) formed
metabolizers (497), presumably in part be- by hepatic metabolism crosses the blood brain
cause of reduced oxidation of reduced haloper- barrier. It is also possible that some (102) is
idol by CYP2D6 in poor metabolizers (488, formed in the brain. In fact, (101) and (102)
497). Other CYP2D6-mediated oxidations of were found in postmortem brain tissue from
haloperidol or reduced haloperidol may also schizophrenic patients treated with haloperi-
contribute to the higher levels of reduced hal- do1 (506). However, the presumed precursor
operidol in poor metabolizers. Systematic (101), unlike MPTP, is not a substrate for
evaluations of the cytochrome P450 isozymes MA0 B, but is instead an irreversible inhibitor
involved in the oxidative metabolism of halo- of the enzyme in human platelets (507). Sev-
peridol revealed a dominant role for CYP3A4 eral haloperidol metabolites, including (101)
in the N-dealkylation process (498-501) and and (102), are potent inhibitors of 3H-dopa-
an important role in the oxidation of reduced mine and 3H-norepinephrine uptake in rat
haloperidol (498). CYP2D6 apparently is less striatal and hippocampal slices (508). The
important (498,500). pyridinium metabolite (102) also seemed to
7 Pharmacokinetics, Biotransformation, and Drug Interactions
B
i
enhance dopamine release, suggesting that it
may induce amphetamine-like neurotoxicity.
Halliday et al. showed that baboons treated
/6 with (101) developed urofacial dyskinesia that
could be correlated with the destruction of
; neurones in the nucleus basilis of Meynert
(509).

7.8 Benzisoxazoles
humans (517)through aldehyde oxidase (697). -
The pharmacokinetics of risperidone, the first Four principal routes of metabolism were
member of this structural class to be marketed identified: N-dealkylation of the arylethyl
worldwide, has been studied in experimental side-chain attached to the 4'-piperazinyl ni-
animals (510) and in humans (511). Risperi- trogen; oxidation of the sulfur, resulting in the
done (84) is well absorbed after oral adminis- sulfoxide and the sulfone; reductive cleavage
tration and rapidly distributed to the tissues of the benzoisothiazolyl ring; and hydrolytic
(70%absolute oral bioavailability). It is exten- cleavage of the C=N bond of the isothiazolyl
sively metabolized in the liver at three differ- ring.
ent sites in the molecule (510, 511). Hydroxy- Eleven days after the administration of a
lation at the 9 position is mediated by single 20-mg oral dose of 14C-labeled ziprasi-
CYP2D6, while oxidative N-dealkylation is ap- done (517) to human volunteers, 20% was re-
parently not affected by debrisoquine hy- covered in the urine and 66% in the feces. The
droxylator polymorphism (511,512). Opening absorption was rapid and the, ,C for free
of the isoxazole ring also occurs in humans, drug and metabolites occurred at 2-6 h post-
but is a less important pathway (511). In the dose. The mean peak serum concentration of
rat, some oxidation also occurs at the 7 posi- unchanged ziprasidone was 45 ng/mL with a
tion of risperidone to provide minor amounts mean area under the curve (AUC) of 336 ngkl
of 7,9-dihydroxy- and 7-keto-9-hydroxy me- mL. On the basis of AUC values, approxi-
tabolites (510). In humans, peak plasma levels mately 46% of the circulating radioactivity
of 9-hydroxyrisperidone, the major metabo- was attributed to unmetabolized ziprasidone.
lite, are reached in 3 h with extensive metabo- Less than 5% of the administered dose was
lizers and in 17 h with poor metabolizers. The excreted as unchanged drug.
terminal half-lives of risperidone averaged 3 h Metabolites apparently do not contribute
in extensive metabolizers and 20 h in poor me- to the pharmacological activity of ziprasidone
tabolizers. The average terminal half-lives of in vivo because the sulfone and sulfoxide me-
9-hydroxyrisperidone are 21 h and 30 h in ex- tabolites exhibit low affinities at 5-HT, and D,
tensive and poor metabolizers, respectively. receptors (517). Limited investigations of cy-
The fractions of risperidone and 9-hydroxyris- tochrome P450 isoforms responsible for the
peridone bound to proteins in the plasma are primary oxidative metabolic reactions for zi-
90% and 77%, respectively. Because the phar- prasidone indicate a major role for CYP3A4
macological activity of 9-hydroxyrisperidone oxidation to the sulfone, shown by Prakash et
is nearly equivalent to that of risperidone, the al. (518), and virtually no role for CYP2D6
steady-state levels of antipsychotic species are (518,519).
similar in poor and extensive metabolizers.
7.1 0 Diarylbutylamines
7.9 Benzoisothiazoles
The pharmacology and pharmacokinetics of
The atypical antipsychotic drug ziprasidone pimozide (861, the most important member of
(105) (514) was approved for the treatment of this class of neuroleptics, have been reviewed
schizophrenia in the United States in early (520). Pimozide is well absorbed after oral ad-
2001. Studies of the biotransformation of this ministration and is widely distributed into the
benzoisothiazolederivative reveal that it is ex- tissues. It has an elimination half-life of
tensively metabolized in rats (515,516) and in around 55 h, despite extensive hepatic metab-
Antipsychotic Agents

olism (521, 522). Phase I oxidative N-dealky- The Dl-like receptors include Dl and D,, while
lations occur on the bis(4-fluoropheny1)-butyl the D,-like receptors encompass D,, D,, and
side-chain of pimozide to form bis(4-fluoro- D, (531, 532). The D, receptor subtype has a
pheny1)butyric acid and N-Cpiperidinylben- short (D,,) and long (D,,) protein form that
zimidazolin-2-one, and at the 4-position of the results from alternative transcription of the
piperidine ring of pimozide to form 1-Cbis(4- D, gene. The difference between the two re-
fluropheny1)-butyllpiperidonol and benzimi- ceptors is a 29 amino acid peptide coded by an
dazolin-Pone. None of the metabolites of exon that has been spliced out of the third
pimozide that have been isolated from experi- intracellular loop of DZL.The D, receptor also
mental animals or humans seem to be phar- has several variants, and the D, receptor has
macologically active (520). multiple variants that are characterized by a
The principal cytochrome P450 isoform in- different number of repeating units also lo-
volved in pimozide oxidation is CYP3A4 cata- cated in the third cytoplasmic loop of the re-
lyzed N-dealkylation (523). CYPlA2 seems to ceptor protein (533).
also be involved. Pimozide may also interfere
with the metabolism of substrates by 8.1.1 D, Selective Compounds. In general,
CYP2D6. Potentiation of pimozide-induced the typical^ antipsychotics interact with the
cardiotoxicity (prolongation of the QT inter- D,, D,, and D, receptor subtypes but are more
val) in patients by clarithromycin-induced in- potent in their affinities at the D, receptor,
hibition by CYP3A4 N-dealkylation has been with Ki around 1-5 nM and about 10-fold less
reported (524). potency at the D, and D, receptors. Clozapine,
however, has its greatest affinity at the D, re-
7.1 1 Molindone and Related Compounds ceptor subtype, with a Kiof 21 nM, in contrast
to its 230 nM potency at the dopamine D, re-
The clinical pharmacodynamics and pharma- ceptor (534). In addition, 10-30% increases in
cokinetics of molindone (91) have been re- D, and D, receptors (535) and sixfold in-
viewed (525).The drug is reputed to be rapidly creases in the D, receptor subtype (536) have
absorbed after oral administration and rapidly been reported in schizophrenic brains, com-
metabolized. Only 2 3 % of the unchanged pared with normals, although the latter find-
drug can be recovered in the urine and feces. ing remains controversial. Autoradiographic
Molindone has a very short half-like (1.5-2 h) analyses with the D, selective ligand ,H-NGD
and is 1.5-1.7 times more bioavailable after 94-1 show D, sites to be dense in rat and hu-
intramuscular, rather than oral, administra- man hippocampus, hypothalamus, and neo-
tion (526). Molindone is less lipophilic than cortex, among other brain regions, and to be
most antipsychotic drugs and has a lower frac- absent in the striatum (537). These findings
tion (around 75%) that is bound to proteins in suggested that a D,-specific compound might
the plasma (527).Clinical studies indicate that treat schizophrenia as effectively as clozapine
the antipsychotic effectiveness of molindone but without the D, antagonist-mediated EPS
lasts more than 24 h (525,528,5291, suggest- or the clozapine constellation of side effects.
ing that one or more active metabolites may Given these initial technical hurdles, a ma-
contribute to its actions in vivo. jor effort was undertaken to discover potent,
specific D, receptor antagonists (538).
8 STRATEGIES FOR DRUG DISCOVERY Whereas the D, hypothesis may yet prove cor-
rect, it remains unclear as to whether antipsy-
chotic effects can be obtained with selective D,
8.1 Dopamine Receptor Subtype Approaches
antagonists such as NGD 94-1, L-745-870, or
Dopamine receptors were first classified into sonepiprazole, or the mixed 5-HT,,/D, antag-
Dl and D, subtypes (530). As a testament to onist fananserin. Each of these compounds
the validity of this initial classification, the have failed to show efficacy in the treatment of
five subsequently cloned dopamine receptors schizophrenia. However, the unique polymor-
fall into structural and functional groupings phism~of the D, receptor gene have lead to
-

commensurate with the D, or D, subtypes. numerous attempts to associate this receptor


k

8 Strategies for Drug Discovery

with other CNS disorders. Associations seem to the D, and D, but not D, receptors. Isos-
to be with ADHD, substance abuse (heroin but teric replacement of the arnide functionality
not alcohol), and novelty- or risk-seeking with a pyrrole as in (107) lea to a related series
traits (539) but not with obsessive compulsive
disorders, Parkinson's disease, schizophrenia,
psychoses, mood disorders, or Tourette's
syndrome.
The quest for D,-selective ligands (540444)
began with the knowledge that the sulpiride
class of atypical antipsychotics bound specifi-
cally to members of the D, family of receptors.
One early investigation showed that confor-
mationally restricted benzamide analogs of
sulpiride-like molecules retained dopaminer-
gic selectivity after replacement of the carbox- that maintained many of the pharmacological
amide with a pyrrole ring. This was shown in characteristics of the benzamides. Extension
the case of the 2-phenyl pyrroles (545) and the of this strategy to the butyrophenones pro-
corresponding 1-phenyl pyrrole derivatives vided (108)with high affinity for D, receptors
(540). This series is closely related to NGD
94-1, the first potent and specific D, antago-
nist to be developed clinically. NGD 94-1
binds to the D, receptor with a 3.6 nM affinity
(541). Clinically, NGD 94-1 is subject to rela-
tively rapid (<1h) hydroxylation in the pyrim-
idine ring to produce the corresponding 5-hy-
droxy pyrimidine derivative. This metabolite
is also a potent D4-specificligand, but has par-
tial D, agonist properties (546). [,H]NGD
94-1 was synthesized (547) and used to local-
ize and map D, receptors in the brains of rats,
and normal and schizophrenic humans (548- (545). The analogous 2-phenylimidazole com-
550). Attempts were made to block the 5-hy- pound (109)also showed strong affinity for D,
droxylation by incorporation of a fluorine sub- as well as D, receptors (554). When the piper-
stituent at the 5-position of the pyrimidine.
While this was successful, development of the
resulting compound NGD 94 -2ISch-66712
was discontinued because of a potent inhibi-
tion of human liver cytochrome P450 2D6
(CYP2D6) (551). Some compounds like
nemonapride (106)bound equally at all three

mine linked aromatic was either 2-pyrimidyl


(110)(NGD 94-1) or 2-pyridyl (111)'the first
true selectivity for the D, receptor subtype
emerged (541). Compounds (110) and (111)
displayed both high affinity and selectivity for
receptor subtypes, whereas amisulpiride (219, D, receptors (K, of D, = 4 nM, Ki of D,/D, =
552) and YM-43611(553)bound about equally 590 nMand Ki of D4 = 8 nM,Ki of D,/D4 = 260
Antipsychotic Agents

nM,respectively). Attenuation of quinpirole-


induced inhibition of forskolin-stimulated
CAMPproduction in D,-expressing CHO cells
identified (110) as a functional antagonist at
the receptor.
The structural diversity of D, selective li-
gands is illustrated further by the examples of
compounds (112-118)(555-562).While a true

pharmacophore for the D, receptor is still


emerging, aryl or arylalkyl piperazine and pi-
peridine substructures are highly represented
within this set of examples.
Compound (112) (L-745,870) possessed
high affmity for the receptor (Ki = 0.5 nM) and
selectivity over D, (D,/D, = 2200) (555). Be- side effect models, (112) did not induce cata-
haviorally, (112) did not antagonize amphet- lepsy or modify apomorphine stereotypy.
amine-induced hyperactivity in rats. In the While the lack of motoric side effects was en-
8 Strategies for Drug Discovery

ceptor sites (569). Efforts focused on the re-


placement of the substituents on the
benzamide aromatic ring and on the modifica:
tions of the N-phenylalkyl group on the basic
nitrogen, which lead to analogs that were
more selective for D, than D, receptors. Vari-
ation of the benzamide to the corresponding
naphthamides also produced D, rather than
D, selective ligands (570). However, the halo-
couraging, the behavioral transparency of genated phenylpiperazinonaphthamide (1201 -
(112) in the classic efficacy model placed the
mechanism in question. Clinical trials with
(112) in schizophrenic patients showed the
compound to be ineffective (563). Clinical re-
sults of sonepiprazole (113)were similarly dis-
appointing.

8.1.2 D, Selective Compounds. Essen-


tially, all clinically effective antipsychotic
drugs are antagonists of D, and D, receptors
(564).It has been hypothesized that the block- was identified as a partial D, agonist with a
ade of dopamine D, and D, receptors in the high selectivity for D, versus D, receptors
nucleus accumbens and olfactory tubercle (571). A related compound, the methoxynaph-
may be associated with antipsychotic effects thamide nafadotride (121), is a D, selective
and that blockade of the D, receptors in the antagonist with a D,/D, Ki ratio of 10 (572).
caudate putamen, where D, receptors are rel-
atively sparse, is responsible for the EPS side
effects (565). D, receptors mediate the rein-
forcing effects of the psychostimulant cocaine
(566), and thus, D, antagonists may block co-
caine dependency. Thus, a preferential DJD,
receptor antagonist may represent a superior
target for the development of antipsychotic
agents with a lower risk of EPS (567, 568).
As with the D, selective compounds, the
search for D,-specific ligands began with the
benzamide, or sulpiride class of drugs that
N,N-Di-n-propyl derivatives of 5- or 7-hy-
have selective, nanomolar affinity for D, and
droxy-2-aminotetralin, e.g., (R)-(+)-7-OH-DPAT
D, receptors. The aza bicyclononane (119)dis-
(122) and (S)-(-)-5-OH-DPAT, and the corre-
played a sixfold preference for D, over D, re-
sponding indane derivatives, exemplified by U
99194 (123), were identified as potent and rel-
atively selective D, agonists (575). However,
Antipsychotic Agents

these agonists lacked sufficient selectivity to


allow a clear discrimination between D, and ment of the hydroxy substituent increased the
D, receptor function in vivo. The first com- D,/D, selectivity somewhat, incorporation of
pounds to show a high degree of D, specificity the biphenylcarboxamidobutyl type substi-
were the biphenylamides exemplified by GR tution found in GR10361 produced highly po-
103691 (124) (576). It has a moderately high tent and specific D, receptor antagonists,
affinity for 5-HT,, and a-, receptors, has a exemplified by S 33084 (127) (578). This, in
high D, affinity (Ki5 nM),and exhibits a 100- turn, formed the basis for the discovery of
fold selectivity over Dl, D,, and D, receptors. the 4-quinoline carboxamide derivative
The constrained fluorene amide derivative, SB-277011(128), reported to be a potent and
NGB 2904 (125) (577), possesses high affinity selective D, receptor antagonist with high oral
(Ki1.5 nM)at the D, receptor where it is a full bioavailability and CNS penetration (579).
antagonist, and greater than a 150-fold selec- The inability of even high doses of SB-277011
tivity over all other dopamine, 5-HT,, and a-, to induce catalepsy or elevate serum prolactin
adrenergic receptors. An extension of the supports the hypothesis that a selective dopa-
amino tetralin approach lead to a series of con- mine D, antagonist would have a reduced lia-
strained benzopyranopyrrolidine derivatives, bility to induce EPS or hyperprolactinemia.
such as (1261,that displayed a comparable de- Its fate regarding clinical trials is unclear. Se-
gree of DJD, selectivity to the original amino lective D, antagonists represent a new, but
tetralins, and whereas appropriate replace- still unproven, approach to the treatment of
Strategies for Drug Discovery

schizophrenia and related disorders. Func- 5-HT,, antagonist/5-HT,, partial agonist / D,


tional synergy between D, and D3antagonism antagonist model (coined here as the "5HT-
has been hard to study given the lack of D,- 1A/2A/D2" model).
and D3-selective compounds. The use of such Autoradiographic studies conducted in
newly discovered compounds will include eval- uitro (580) were the first to identify the high
uations of the hypothesis presented here that affinity binding of [ 3H]spiroperidol to 5-HT2
preferential Dfl, antagonism is a useful receptors in the frontal neocortex, an area re-
strategy for treating psychoses including sponsible for executive cognitive functioning.
those associated with schizophrenia. This and subsequent studies (24, 585, 5861,
including in uiuo radioligand binding (5871,
8.1.3 Dopamine "D,-Plus" Agents. As noted confirmed the SDA hypothesis with a broad
in Section 8, all antipsychotics except arnisul- variety of antipsychotic drugs by showing that
piride interact with a wide array of receptors. 5-HT,, receptors were preferentially occupied
The potent D, antagonism of all antipsychot- over D, receptors by atypical antipsychotics,
ics including amisulpiride has kept open the whereas the converse was true for typical an-
exploration of novel D, antagonists that bind tipsychotics (584). The SDA hypothesis has
to other receptors, such as D,, adrenergic or been confirmed with human brain imaging
serotonergic receptors. This constitutes the studies (699), and postulates that this activity
"D, plus" approach for novel, atypical anti- confers atypical properties by virtue of dimin-
psychotics. ished EPS. The ratio of potencies at these re-
ceptors is more relevant than potency alone,
8.1.4 5-HT,,/D, Antagonists. The most because several atypicals, e.g., clozapine show
validated D,-plus approaches are the ones that moderate and low affinity at these sites, but
involve dopamine and serotonergic receptors. still favor 5HT2, > D,.
These include 5-HT,/D, receptor antago- Consistent with these findings, 5-HT,, an-
nism (the "SDA hypothesis"), the 5-HT,, par- tagonists reverse catalepsy induced by typical
tial agonist/D, antagonist model, and the antipsychotics such as haloperidol (585).
Antipsychotic Agents

and is caused by the internalization and deg-


radation of the 5-HT,, receptor complex (582).

8.1.5 Aryl Piperazines/Piperidines. There


are two major structural classes that confer
concomitant 5-HT,, and D, antagonism. These
are the aryl piperidineslpiperazines and some
tricyclic systems. One of the first clinical stud-
ies to assess the role of serotonergic blockade
in antipsychotic therapy was conducted on se-
Chronic clozapine treatment reduces 5-HT,,
toperone (129),a 5-HT,/D, antagonist that
receptor densities in the neocortex without af-
showed promising results but was later dis-
fecting striatal D, receptor densities, empha-
continued because of bioavailability issues
sizing its preferential interaction with the
5-HT,, receptor in vivo (586). 5-HT,, recep- (588).
tor down-regulation is produced by 5-HT, Risperidone (84) has a DJ5-HT,, ratio of
agonists as well as antagonists like clozapine, 20 (Ki for D, and 5-HT,, 3.1 and 0.16 nM,
8 Strategies for Drug Discovery

respectively). It arose from a structural hy- than to the typical antipsychotic, haloperidol.
bridization of the selective 5-HT,, antagonist Further evidence for the value of a high D2/5-
ritanserin (130),where the fused pyrimidine HT, affinity ratio in this series of compounds
side-chain was retained, and a 1,2-benzisox- may be found with a metabolite of tiasperone-
azole-3-yl piperidine, reminiscent of the aryl (5931, where hydroxylation of the six-mem-
piperidines in the potent D, blocker, haloper- bered imide ring showed somewhat decreased
idol, was substituted. Clinical experience with D, receptor affinity relative to tiasperone buT
risperidone has confirmed its antipsychotic ef- had similar 5-HT, receptor affinity. This com-
ficacy with reduced propensity to induce EPS pound exhibited good inhibition of the condi-
(589). Similar effects are observed with ocap- tioned avoidance response in rats and did not-
eridone (1311, a compound structurally re- induce catalepsy. A series of thieno[3,2-clpyri-
lated to risperidone but with a D,/5-HT, ratio dine and furo[3,2-clpyridine compounds
of only 5 (590). structurally related to tiosperone have similar
Another member of the benzisoxazolyl pip- profiles and demonstrate that a higher 5-HT,
eridine class is HP-873 (132), which has a fa- affinity can compensate for high D, affinity
vorable D,/5-HT, ratio of 17. In contrast with (594). These compounds block conditioned
the typical antipsychotics, HP-873 also in- avoidance responses in rats despite weak D,
creases social interaction in rats, suggesting affinity (Ki 115 nM) provided that potent
an ability to ameliorate negative symptoms 5-HT, affinity was present. They also did not
(591). induce catalepsy, again suggesting an atypical
Sertindole (94) was selected from a series of profile. Using a variant of the spiro-imide side-
N-phenylindolyl-piperidines and has Ki7sof chain in tiosperone, the effect of varying the
0.39 and 4.1 nM at the 5-HT,, and D2recep- aryl group of the arylpiperazine demonstrated
tors, respectively, and a favorable ratio of 10.5. that a 1,2-benzisothiazolegroup was superior
Sertindole blocks the hyperactivity in rats in- over other aryl groups in both in vitro and in
duced by dopamine infusion into the nucleus vivo testing and retained a favorable DJ5-HT,
accumbens without causing the rebound hy- affinity ratio of 7. The structurally related
peractivity after cessation of treatment seen compound in which the 1,2-benzoisothiazole
with typical antipsychotics. Although sertin- nitrogen has been replaced by C-H to yield
dole has a low propensity to induce catalepsy, the corresponding benzothiophene, showed a
both the direct analog in which the chloro sub- similar in vivo profile with 5-HT, affinity (Ki
stituent is replaced by cyano and also the cor- = 20 nM) and a D,/5-HT, affinity ratio of 26
responding piperazine and tetrahydropyri- (595). SM-9018 (134) is another variant with
dine analogs have more classical D,/5-HT, the 1,2-benzothiazolylpiperazineimide struc-
ratios favoring D, affinity and thus potently ture and shows affinity for D, (Ki = 5 nM) and
induce catalepsy (592). 5-HT, (Ki = 0.61 nM)receptors, in vivo block-
A series related to risperidone, which was ade of dopamine-mediated behaviors, and a re-
not designed to incorporate 5-HT,, antago- duced tendency to induce catalepsy (596). Be-
nist activity, resulted in tiaspirone (133).This cause the compound also has potent 5-HT-,,
analog has a D,/5-HT, ratio of 21, similar to receptor affinity (Ki = 2.9 nM),it is possible
that found for risperidone. The behavioral that this also contributes to the in vivo profile
profile of tioperone was closer to clozapine (597, 585).
Antipsychotic Agents

Of particular interest are 5-HT-lA1-2AiD2 positive and negative symptoms of schizophre-


compounds (with 5-HT,, partial agonist, nia. Risperidone also has a potent affinity at
5-HT,, antagonist, and D, antagonist affini- a,-adrenoreceptors and is an antagonist at the
ties). These include a series of 1-naphth- H, histamine receptor. Adverse EPS side ef-
ylpiperazines (135) (598) and the related and fects, such as tardive dyskinesia and involun-
tary tremors, are less common with risperi-
done than with other typical antipsychotics,
particularly haloperidol. Risperidone is more
effective than conventional antipsychotics at
improving overall cognitive function, particu-
larly working memory, attention, and alert-
ness (606). However, not all medical experts
agree with this conclusion but suggestethat
depressive symptoms may be more amenable
far more potent 1,2-benzothiazolylpiperazine to treatment with risperidone, possibly be-
analog, ziprasidone (105) (599). Ziprasidone cause of its 5-HT,, antagonism.
has a favorable D,/5-HT, ratio of 11.4 based Sertindole, a D, antagonist with prominent
on Ki values of D, = 4.8 nM and 5-HT, = 0.42 activity in the limbic system, also has potent
nM (600). Ziprasidone is also a potent, partial and long-lasting affinity at 5-HT,, and a,-
agonist at 5-HTIAreceptors (601). Thus, the adrenergic receptors. It is practically devoid of
structurally very different 1,2-benzisoxazole- EPS side effects but had to be withdrawn from
and 1,2-benzothiazole-based compounds, the market in the UK because of reports of
with their two side-chain variants of heterocy- cardiac arrhythmias and sudden death. This is
7

cles linked by two atoms or imides linked by presumably because of sertindole's effect at
four atoms, seem to have validated the SDA voltage-gated I, ion channels that control
hypothesis and added an important role for heart rythm (607). Sertindole is contraindi-
partial agonism at the 5-HT,, receptor (602, cated in patients with a long QT interval or
603). Ziprasidone has been marketed in Swe- those receiving drugs known to prolong the
den since 2000 and in the United States since QT interval (608,609). Development of sertin-
2001 as an oral and injectable atypical antipsy- dole has been suspended in most countries,
chotic. The EPS that would otherwise be ex- and it remains unclear whether sertindole will
pected from its high D, antagonist affinity is be approved in the United States or reintro-
probably minimized by its potent antagonist duced in Europe.
affmity at 5-HT,, receptors (599,602) and its A series of 6-aminoalkyltetrahydroindol-4-
potent, partial agonist affinity at 5-HT,, re- ones related to molindone (91) show potent
ceptors (604,605). affinities for D, and 5-HT,, receptors (610).
Molindone exhibits many similarities to typi-
8.1.6 Arylpiperazines/Piperidines. Risperi- cal neuroleptics, including D, antagonism, an-
done, a potent SDA, is a highly successful tipsychotic efficacy, and EPS (611). Zotepine
atypical antipsychotic drug introduced to clin- (136) is a potent D, and 5-HT,, antagonist
ical practice in the mid-1990s. It treats the with high affinity for the 5-HT, receptor.
8 Strategies for Drug Discovery 649

8.1.7 Dopamine D, Partial Agonists. There


is now evidence to support the original pro-
posal of Arvid Carlsson et al. (613, 614) that -
partial D, agonists can treat psychosis by ac- .
tivating presynaptic D, autoreceptors and de-
creasing dopamine synthesis and release. In
-F
support of this bold proposal, D, agonists, and
even partial agonists, have been shown to im-
prove negative symptoms of schizophrenia. _
Unfortunately, except for (-)3PPP (137), in
-
which modest efficacy was seen (617), most of
these drugs also exacerbate positive symp-
toms and show diminished efficacy with
chronic administration. This has been ob-
served for the full agonists bromocriptine
(615) and N-propylnorapomorphine (616),
and the partial agonists terguride (138)(618)
and OPC-4392 (139) (619). Nevertheless,
these studies provided valuable clinical evi-
dence that excess D, (and probably D,) recep-
tor stimulation can contribute to positive
symptoms of schizophrenia and even arnelio-
rate negative symptoms.
As described in Section 2.2.1, the positive
symptoms of schizophrenia are believed to
arise from an excess of dopaminergic activity
in mesolimbic circuits, while the negative
symptoms may arise from too little dopami-
nergic activity in mesocortical circuits. The.
excessive postsynaptic signaling can be di-
rectly blocked by traditional postsynaptic D,
antagonists. In theory, a similar therapeutic
result could occur by decreasing the amount of
dopamine that is released from the presynap-
tic neuron. The electrical activity, biosynthe-
sis, and release of dopamine from such neu-
rons is under the negative control of D,
autoreceptors that reside on the dopaminergic
Zotepine has been launched in the UK and neuron cell body and axon terminal
Japan and seems particularly effective in pa- (620-622). Dopamine itself released from pre-
tients with negative symptoms (612). Studies synaptic neurons, or dopamine agonist drugs,
suggest a less cataleptogenic profile than the stimulate these D, autoreceptors. Because of a
butyrophenone antipsychotics. preferential sensitivity of the autoreceptor to
Antipsychotic Agents

activation by partial agonist signaling, partial


D, agonists can activate the feedback system
while producing little if any agonism at
postsynaptic D, receptors.
A number of compounds have been synthe-
sized with the goal of such autoreceptor ago-
nist properties. These include OPC-4392 (619),
UH232, (-1-3-PPP (623-6251, pramipexole
(140), roxindole (1411, and talipexole (142).
The partial agonists terguride (618) and SDZ
HDC 912 (143)(626) have shown partial effec-
tiveness on the negative but not positive as-
pects of schizophrenia. Most commonly, such
agents exacerbate the positive symptoms, as action of DU 127090 or aripiprazole. While DU
seen with apomorphine, (-)3-PPP, and OPC- 127090 produced a favorable ratio of activity
4392. Another such compound, DU 127090 in the conditioned avoidance response (CAR)
(134) (627) is in phase I1 clinical trials for test versus the induction of catalepsy, it in-
schizophrenia. DU 127090 is a partial agonist duced about one-half the dystonia in haldol-
at the D, family of dopamine receptors that sensitized monkeys produced by haloperidol
can block high levels of dopamine signaling (630).
but also stimulate D, receptors when dopa- Another novel antipsychotic, aripiprazole
mine tone is low. Its potency at D, (1nM') > D, (OPC-14597) (144) (619, 631) is a potent and
= D, > 5-HT1A (10 nM) > 5-HT,, (0.5 pit?). partial D2 agonist (632). While structurally
As determined by the reversal of CAMPaccu- very different from DU 127090, aripiprazole
mulation, DU 127090 produces a potent, par- has a remarkably similar profile to DU
tial agonist effect that is below that of the par- 127090. Aripiprazole binds potently to both
tial agonist terguride (627). The suppression the human D, receptor (Ki = 1 nM)(633) and
of dopamine release by DU 127090 was stron- to the human 5-HT,, receptor (Ki = 1.65 nM)
ger than expected for such a partial agonist, (6281, and displays potent, but partial agonist
because it was with aripiprazole, which pro- effects at both (628, 633, 634). Aripiprazole is
duces little if any change in striatal or cortical an effective, rapid-acting antipsychotic that
dopamine release (640)and metabolism (641). induces little or no EPS (635-637). In animal
This suggests that another mechanism, such models of presynaptic dopamine function,
as more complete D2 agonism, or partial aripiprazole decreases dopamine synthesis
5-HT,, agonism (6291, may contribute to the (619) and the firing rate of mesolimbic dopa-
8 Strategies for Drug Discovery

mine neurons (638). Unlike other dopamine has a high affinity for 5-HT, receptors rekin- -

agonists, it decreases spontaneous locomotion dled interest in the potential involvement of


at both low and high doses. In models of this receptor in the action of atypical antipsy-
postsynaptic striatal function, aripiprazole chotics and in the etiology of schizophrenia.
shows little propensity to induce rotation in 5-HT, receptors are comprised of A, B, and C
animals with unilateral nigrostriatal dopa- subtypes. Most medicinal chemistry efforts
mine lesions, nor does it induce stereotypy or have been directed toward combining 5-HT,,
increase locomotion in reserpinized or halo- antagonism with a somewhat lower potency
peridol-sensitized rats (632). Nevertheless, it for D, receptor antagonism. Selective 5-HT,,
inhibits stereotypy, locomotion, and rotation antagonists relatively devoid of D, affinity
induced by a full agonist, such as apomor- were also made to treat schizophrenia, as effi-
phine, and does so at lower doses than those cacy, and not simply diminished side effects as
required to induce catalepsy or ptosis (639). As initially proposed (24), were seen as potential
a result of this partial agonist action at actions of 5-HT,, antagonism. The first com-
postsynaptic D, receptors, aripiprazole be- pound to have a reasonably selective 5-HT,,
haves like a functional antagonist when it affinity was ritanserin (650), a mixed
competes with exogenously administered full 5-HT,, antagonist. Clinical studies with
D, agonists or dopamine. The potent, partial ritanserin indicated that it is effective in anx-
agonism of aripiprazole at D, receptors may iety (651) and alcohol dependence (652). Clin-
account for the modest changes in cortical or ical trials in schizophrenic patients, however,
striatal dopamine release, and the subtle in- gave conflicting results (653). No effects were
creases in dopamine metabolism in these re- observed using ritanserin as an add-on medi- '

gions determined by in vivo microdialysis cation to neuroleptic therapy (654).


(640) and brain tissue measurements (641). A radical extension of the SDA concept pro-
Aripiprazole produces little or no change in duced the naphthsultam series, which was
prolactin release in rat (642) or human (635) typified by fananserin (655,656). Fananserin
studies. As evidenced by the small increases in (145) is a potent and selective antagonist at
dopamine metabolism, and other antagonist-
like activities shown previously in vivo (632,
643, 644), aripiprazole can exert competitive
antagonist properties as a result of its potent
D, receptor binding but low D, intrinsic ago-
nist activity. Other receptor actions of aripi-
prazole, particularly its equally potent, partial
agonist activity at 5-HT,, receptors (6281,
may also be explained by the small or amelio-
rating effects of 5-HT,, agonism on dopamine
synthesis (645), metabolism (6291, release the human 5-HT,, receptor (Ki = 0.26 nM)
(646, 6471, and catalepsy (648, 649). with moderate affinity for the a, receptor (Ki
= 38 nM) and little or no D, receptor affinity
8.2 Non-Dopaminergic Approaches (F> 1 pkf) (657). Subsequently, fananserin
was found to have potent affinity at the D,
8.2.1 Serotonergic receptor (K, = 2.9 nM) (658), and in vivo, to
8.2.1.1 5-HT2A Antagonists. As described reduce behavior elicited by DA agonists such
in Section 8.1.4, the discovery that clozapine as apomorphine and amphetamine. It is also
Antipsychotic Agents

inactive in models of EPS liability (659). The serin, fananserin, and MDL 100907, it seems
ineffectiveness of fananserin (2) as well as the that 5-HT,, receptor antagonism by itself is
selective 5-HT,, antagonist ritaneserin as an- insufficient to produce robust antipsychotic
tipsychotics would tend to rule out 5-HT,, effects. The ability of 5-HT,, antagonism to
and D, antagonism as sufficient targets by diminish EPS induced by D, blockade and
themselves for antipsychotic drug discovery, treat anxiety associated with the disease (24,
and reinforces the critical presence of D, 580, 584, 667, 668) are likely components of
antagonism. atypical antipsychotic agents.
One sufficiently selective agent has arisen 8.2.1.2 5-HTIA Partial Agonists. Like
to test the hypothesis that 5-HT,, receptor 5-HT,, antagonism, 5-HT,, receptor agonism
antagonism alone can treat psychosis. MDL can produce anxiolytic effects and diminish
100907 (146) is an N-phenethylpiperidine de- the catalepsy induced by D, antagonists in ro-
rivative with at least 100-fold higher affinity dents (111, 597, 646) and primates (3). The
(1.5 nM)at human 5-HT,, receptors than at specific role of 5-HT,, agonism in these effects
human D, and 5-HT,, receptors (660). was confirmed by the ability of selective
MDL100907 exhibited an antipsychotic profile 5-HT,, antagonists to block the 8- OH,DPAT-
in a number of animal models for schizo- induced reversal of catalepsy (585, 597). The
phrenia. As with atypical antipsychotics, median raphe nucleus seems to be a critical
MDL100907 decreased hyperactivity induced site for this action, because infusions of
by amphetamine (661) and by PCP (662). It 8-OH,DPAT into the raphe but not into stria-
also decreased the deficits in prepulse inhibi- tal projection areas can reverse the catalepsy
tion induced by MK-801 (663) and failed to induced by the D, antagonist raclopride (645).
induce catalepsy, normally a predictor for Elevations in serum prolactin produced by
EPS. Positron emission tomography (PET) haloperidol can also be attenuated by partial
studies conducted in humans by Wong et al. 5-HT,, agonists (669). Intrinsic 5-HT,, re-
showed that low plasma levels of MDL100907 ceptor agonist activity is a property of mainly
caused by a single oral 20 mg dose produced the newest antipsychotic drugs. These include
the desired high degree of cortical 5-HT,, re- nemonapride (5971, ziprasidone (195, 670,
ceptor occupancy (664). 6711, and aripiprazole (6281, and the original
In an initial confirmation of the preclinical 5-HT,, partial agonist, clozapine (672). An-
findings, a phase I1 clinical trial using 10-40 other compound, PD 158771 (147) (673), was
mgofMDL 100907 per day for 6 weeks showed shown by Akunne et al. to be a D2D3 partial
improved Parkinson rating scale (BPRS) agonist and 5-HT,, agonist with preclinical
scores relative to placebo and no EPS liability properties that are very similar to those of
(665). A larger phase I11 trial showed some aripipirazole. This profile is consistent with
minor improvement in positive symptoms at the lack of elevations in serum prolactin seen
the 10-mg/day dose, but this effect disap- in clinical trials with the mixed DJBHT,,
peared at the 20-mgJday dose, compared with partial agonist aripiprazole (269,270) and the
placebo. Functional PET scans of selected pa- D, antagonistl5-HT,, partial agonist ziprasi-
tients in the trial showed minor metabolic done (195, 670, 671, 674).
changes in the frontal cortex at the 10 but not Among these drugs, clozapine, aripipra-
20 mg dose. Clinical trials of MDL100907 have zole, and PD 158771 can decrease dopamine
been halted, presumably because of limited ef- and serotonin synthesis in the neostriatum,
ficacy (666). Between the findings with ritan- and most of these drugs share a similar behav-
8 Strategies for Drug Discovery

ioral profile suggestive of low EPS liability be constructed from either doublets ( N R l d
(645, 673, 675). Again consistent with partial NR2y) or triplets (NRlx/NRZy/NRZz or N R l d
.
-
5-HT,, agonism (and 5-HT,, antagonism), NR2y/NR3) of these subunits (678). A glycine
some of these compounds are anxiolytic in pre- modulatory site resides on the NR1 subunit,
clinical tests including the Vogel conflict test, and its occupation is required for receptor ac-
social contact test, and the elevated plus maze. tivation (679). A inhibitory site, identified by
As with aripiprazole (232), most of these com- the binding of ifenprodil, is present on recep-
pounds are also weaker at inducing catalepsy tors containing the NR2 subunit (680).
or blocking apomorphine-induced stereotypy The noncompetitive NMDA antagonist ion
than in preventing apomorphine-induced channel blockers such as PCP (148) and the
climbing. It may be that the potent, partial competitive antagonists such as CGS 19755
5-HT,, agonism of these compounds miti- (149) are both psychotomimetic in humans
gates against D, antagonist effects, including
the propensity to produce EPS (597,647,649,
675) and elevation of serum prolactin (669).
Partial 5-HT,, agonism may also lessen the
depression and anxiety that frequently accom-
pany psychosis (662, 668, 672). The effective-
ness of ziprasidone or clozapine against the
negative symptoms of schizophrenia may also
derive from their intrinsic partial 5-HT,, ago-
nism, which mediates the selective increases
in frontal cortex dopamine release produced
by either drug (647).

8.2.2 Glutamatergic Approaches. As de-


scribed in Section 4.3 and reviewed by Goff
and Coyle (676), deficiencies in the excitatory
amino acid glutamate have been implicated in
the etiology of schizophrenia, and thus its re-
ceptors and biosynthetic enzymes provide
novel drug targets. The identification of nu-
merous ionotropic and metabotropic gluta-
mate subtypes, their multiple subunit combi-
nations, and allosteric binding sites increase (681). Thus, it seemed reasonable that com-
the number of targets that could be involved in pounds that facilitated ionotropic glutamate
schizophrenia. receptor function had the potential to be anti-
8.2.2.1 lnotropic Glutamate Receptors. psychotic. The discovery that the glycine mod-
Ionotropic NMDA receptors are formed from ulatory site on NR1 must be occupied simulta-
combinations of the NR1, NR2, and NR3 sub- neously with glutamate to affect excitatory
units. NR1 has eight isoforms (A-H), NR2 has neurotransmission, led to efforts to produce
four (A-D), and NR3 is unique. The NR1 sub- specific glycine agonists for this site. Glycine
unit is absolutely required for a functional itself is poorly transported into the CNS and
NMDA receptor (677). NMDA receptors can has some toxicity on its own. Thus, glycine
Antipsychotic Agents

mimetics such as the partial agonist D-cy-


closerine and the glycine prodrug milacemide
(150) have been examined in clinical trials

213 receptor agonists such as LY354740 (151)


(682). The partial agonist properties of D-cy- and LY379268 (152) and the selective mGlu
closerine (683) might be responsible for the 213 receptor antagonist LY341495 (153)(685,
ambiguous results obtained from the clinical 686).
trial.
An alternative possibility, of increasing gly-
cine levels by inhibiting glycine uptake, was
tested by treating rats with the glycine re-
uptake inhibitor glycyldodecylamide (6841,
which is well absorbed by the rat brain. Behav-
iorally, glycyldodecylamide attenuated PCP-
induced hyperactivity in rats, a marker of an-
tipsychotic potential. This result supports the
idea that agents that facilitate glutamate neu-
rotransmission may have roles as antipsy-
chotic agents.
8.2.2.2 Metabotropic Glutamate Receptors.
Unlike the classic ion-gated NMDA receptors, Group I1 mGlu agonists such as LY354740
there exists eight related "metabotropic" glu- and LY379268 attenuate PCP-evoked ambu-
tamate (mGlu) receptors, termed mGlul-8. lations and fine motor movements, as do clo-
These subtypes are grouped according to their zapine and haloperidol. Consistent with a
agonistlantagonist pharmacology and their mechanism involving mGlu213 receptors, in-
secondary messenger systems. Group I mGlu hibition of these PCP precipitated behaviors
receptors (mGlul and mGlu5) are coupled to by LY379268, but not clozapine or haloperi-
phospholipase C activation, whereas group I1 dol, were reversed by LY341495 (691). In con-
(mGlu2 and mGlu3) and group I11 receptors trast, clozapine and haloperidol potently block
(mGlu4 and mGlu6-8) are negatively coupled amphetamine-stimulated increases in locomo-
to adenylate cyclase. tion and stereotypical movements, whereas
A large number of specific mGlu agonists doses of LY354740 and LY 379268 that block
and antagonists exist to enable antipsychotic PCP-evoked behaviors in rats had less consis-
drug discovery (685, 686). Group I1 metabo- tent effects on amphetamine-induced behaviors.
tropic glutamate receptors seem to be the The treatment of the negative symptoms of
most promising because they are richly ex- schizophrenia has always proved challenging.
pressed in the prefrontal cortex and hip- The reduced cognitive abilities and social
pocampus (687,688). Excessive glutamatergic withdrawal that typify negative symptoms
transmission in these areas is suspected to and contribute in a major way to the adequate
promote anxiety (689) and seizure disorders function of schizophrenics (701). Negative
(690). mGlu2 receptors are presynaptic auto- functions are thought to occur from decreased
receptors that dampen glutamatergic excit- dopamine neurotransmission in the prefron-
ability in a use-dependent manner (691). In- tal cortex. Recent findings show this to be as-
vestigation into the role of group I1 receptor sociated with the inheritance of an allele for
autoreceptors has been greatly facilitated by catechol-o-methyl transferase (COMT),which
the identification of metabotropic glutamate increases the thermal stability and thus activ-
References

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(693). http://www.merck.com/pubs/mmanual-
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CHAPTER ELEVEN

Investigative Agents for Use in P

Neurodegenerative Conditions
JAMES DAVID ADAMS
JR.
Department of Molecular Pharmacology and Toxicology
USC School of Pharmacy
Los Angeles, California

THOMAS F. WOOLF
HyBar BioScience, LLC
Ann Arbor, Michigan

Contents
1 Introduction, 674
1.1 Alzheimer's Disease, Parkinson's Disease,
Amyotrophic Lateral Sclerosis, Multiple
Sclerosis, and Other Neurodegenerative
Conditions, 674
1.2 Stroke and Other Ischemic Conditions, 675
2 Necrosis and Apoptosis, 676
3 DNA Damage and Repair, 677
3.1 DNA Damage, 677
3.2 DNA Repair, 677
3.3 PARP and DNA Repair, 677
4 Cellular Energetics, 679
4.1 PARP Inhibitors, 680
4.2 NAD Glycohydrolase Inhibitors, 686
4.3 NAD Precursors and Cellular Energetics,
687
5 NMDA Receptor Antagonists, 689
6 Nitric Oxide Synthase Inhibitors, 695

Burger's Medicinal Chemistry and Drug Discovery


Sixth Edition, Volume 6: Nervous System Agents
Edited by Donald J. Abraham
ISBN 0-471-27401-1 0 2003 John Wiley & Sons, Inc.
investigative Agents for Use in Neurodegenerative Conditions

1 INTRODUCTION active than natural forms. It is not clear


whether ginkgo preparations improve cogni-
This chapter discusses strategies for the devel- tive function through antioxidant or other
opment of drugs to treat stroke, ruptured mechanisms. However, several antioxidants,
berry aneurysm, traumatic brain injury, and including vitamin E, have been suggested to
similar conditions. The strategies of interest be effective in the treatment of the disease.
to this chapter involve inhibition of radical Alzheimer's disease is also treated with acetyl-
formation, enhancement of repair of damaged cholinesterase inhibitors. The newer highly
DNA, augmentation of cellular energetics, and potent, reversible acetylcholinesterase inhibi-
inhibition of excitotoxic mechanisms. Nitric tors, such as donepezil, improve cognitive
oxide synthase (NOS) inhibitors and N-meth- measurements in about 25% of patients by 24
yl-D-aspartate (NMDA) receptor antagonists weeks of treatment.
can inhibit free-radical production and are be- Parkinson's disease is caused by the oxida-
ing used or investigated in several neurode- tive stress-induced loss of dopaminergic neu-
generative conditions. DNA repair can be in- rons and can be effectively treated with levo-
fluenced by poly(adenosine 5'-diphosphate- dopa in combination with dopa decarboxylase
ribose) polymerase (PARP) inhibitors that are inhibitors such as carbidopa or catechol-0-
being actively investigated in stroke. PARP in- methyltransferase inhibitors such as tolca-
hibitors, nicotinamide adenine dinucleotide pone. Levodopa is well known to increase the
(NAD) glycohydrolase inhibitors, and NAD life spans of patients with Parkinson's disease.
precursors can influence cellular energetics It may do this by enhancing brain dopamine
and may be important in the treatment of levels and inhibiting tyrosine hydroxylase,
stroke. Inhibition of excitotoxic mechanisms which produces oxygen radicals. Several dopa-
involves inhibitors of NMDA receptors and ni- mine receptor agonists are available for use in
tric oxide synthase. Many of the agents dis- Parkinson's disease and are extensively used
cussed in this chapter are being investigated in patients suffering from the adverse effects
in several neurodegenerative conditions. of levodopa. Anticholinergics such as trihexy-
phenidyl are also used in Parkinson's disease.
1.1 Alzheimer's Disease, Parkinson's
Amyotrophic lateral sclerosis is currently
Disease, Amyotrophic Lateral Sclerosis,
treated with riluzole, which improves survival
Multiple Sclerosis, and Other
in 30% of patients. Riluzole, a n NMDA re-
Neurodegenerative Conditions
ceptor antagonist, is discussed later in this
This chapter does not extensively discuss Alz- chapter. A clinical trial of gabapentin, a (y
heimer's disease, Parkinson's disease, amyo- aminobutyric acid (GABA) agonist, in amyo-
trophic lateral sclerosis, multiple sclerosis, or trophic lateral sclerosis demonstrated little ef-
some rare neurodegenerative diseases because ficacy. Antioxidants have also not demon-
they have been discussed previously (1).Alz- strated significant efficacy so far.
heimer's disease is still poorly understood. For Multiple sclerosis is treated with interferon
instance, it could be caused by plaque forma- beta, glatiramer acetate, and steroids. Glati-
tion, tangle formation, or free-radical forma- ramer is a random copolymer of L-alanine, L-
tion. Alzheimer's disease is widely treated in glutamate, L-lysine, and -tyrosine in a ratio of
Europe with ginkgo preparations. Gingko pro- 6/1.9/4.7/1.About 30% of patients using glati-
duces a small improvement in cognitive func- ramer experience fewer relapses than do con-
tion in patients. Structure-activity correla- trols. Interferon beta appears to abolish re-
tions in neurodegenerative models for lapses in about 10% of patients. Steroids are
ginkgolides, or flavonoids found in ginkgo, used to treat acute exacerbations. A wide
have not been published. In addition, there range of immunomodulatory drugs are either
have been few attempts to synthesize new used or being investigated, including azathio-
ginkgolides or flavonoids that may be more prine, cladribine, cyclophosphamide, immu-
1 Introduction 675

Recent Citations for Drugs Used in Alzheimer's Disease, Amyotrophic Lateral Sclerosis (ALS),
and Multiple Sclerosis (MS).Ache Refers to Acetylcholinesterase.
Agent First Author Citation
- --

Ginkgo B. S. Oken Arch. Neurol., 56, 1409-1415 (1998)


Ginkgo P . L. Le Bars Dementia Geriat. Cognit. Disord., 11,230-237 (2000)
Antioxidants D. Pratico Am. J. Med., 109,577-585 (2000) P
Ache inhibitors P . Camps Mol. Pharmacol., 57,409417 (2000)
Ache inhibitors W . J. Krall Ann. Pharmacother., 33,441-450 (1999)
Ache inhibitors D. L. Bai Curr. Med. Chem., 7,355-374 (2000)
ALS drugs 0 . Hurko J. Neurol. Sci., 180,21-28 (2000)
Glatirarner acetate M . Filippi Neurology, 57,731-733 (2001)
Steroids F . Brusaferri J. Neurol., 247,435-442 (2000)
M S drugs J . Bryant J. Neurol. Neurosurg. Psychiat., 70,574-579 (2001)

noglobulin, methotrexate, and mitoxantrone. drug to penetrate through the blood-brain


Mitoxantrone was approved for use in multi- barrier and remain in the brain. However, a
ple sclerosis in November 2000. All of the drug must not be too lipophilic. Drugs that are
agents used in this disease modify the immune too lipophilic do not penetrate rapidly into the
system, especially T-cell responses. brain. These drugs may be transported in the
blood bound to lipoproteins, vitamin E for in-
1.2 Stroke and Other Ischemic Conditions stance. Such drugs may gain access only to the
The major clinical approach to stroke cur- endothelial lining of the brain vasculature. It
rently is prevention. Stroke can be prevented is possible that these drugs may then slowly
in some patients by cessation of lifestyle prob- penetrate into the brain.
lems such as smoking, excessive alcohol con- Another concern with drugs used to treat
sumption, and obesity. These lifestyle prob- conditions such as stroke is that patients may
lems lead to heart disease and atherosclerosis be unconscious. Therefore, the drug must be
that can lead to stroke. Adequate treatment of delivered intravenously by injection or intra-
hypertension, heart disease, hypercholesterol- gastrically by feeding tube. Intravenous drugs
emia, and coagulation problems may be of must be adequately soluble in aqueous sol-
some benefit in the prevention of stroke in vents to allow injection into the blood. Drugs
other patients. Drugs such as aspirin, antico- administered intragastrically must not cause
agulants, antihypertensives, and lipid choles- vomiting, which is dangerous in unconscious
terol-lowering agents, such as statins and nia- patients.
cin, have been recommended for use in stroke Drugs used in the treatment of neurode-
prevention. However, these drugs may be of generation must not greatly interfere with
little value for decreasing infarction in a pa- normal neurotransmission. In other words,
tient who has already suffered from a stroke. normal neurotransmission should continue or
This chapter focuses on agents that may be of should not be greatly altered in the presence of
use in decreasing infarction in stroke patients. the drug. This is a concern with atropine-like
Treatment of neurodegenerative condi- drugs that can induce hallucinations at high
tions presents some unique challenges. First doses because of inhibition of cholinergic neu-
of all, a drug must penetrate into the brain. rotransmission. Some of the powerful NMDA
Uptake into the brain can involve active up- receptor antagonists, similar to phencyclidine,
take processes, such as the uptake of certain disrupt normal neurotransmission and cause
vitamins into the brain. This uptake usually is psychotic episodes in some patients that pre-
mediated by transport proteins that bind the vent the drugs from being useful.
drug and facilitate the penetration across the A major concern is the treatment of the pa-
blood-brain barrier. Drugs that do not cross tient, without necessarily focusing on one
into the brain by active uptake must be ade- mechanism of action of a drug. For instance, if
quately lipophilic. Lipophilicity may allow a cooling a patient down improves outcome,
676 Investigative Agents for Use in Neurodegenerative Conditions

why not use a drug that induces hypothermia? damage, and other conditions and may be
Hypothermia is routinely used in open chest caused by temporary interruption of blood
surgery, where patients are mechanically flow to areas of the brain. Infarction produces
cooled to enhance survival. Intracranial pres- a large area of dead tissue that eventually may
sure may increase in patients after stroke. It is form an extensive glial scar. In stroke, infarc-
known that increased intracranial pressure is tion involves necrotic and apoptotic cell death
dangerous in patients suffering from trau- (2,3).The majority of the cell death in the core
matic brain injury. It is routine to monitor of the infarction is necrotic. However, apopto-
intracranial pressure in traumatic brain dam- tic cell death also occurs in the core and is
age patients and to decrease intracranial pres- more prominent in the limit area surrounding
sure by withdrawing cerebrospinal fluids. Yet, the core, sometimes called the penumbra. The
it is not routine to monitor or correct intracra- term limit will be used in this chapter. Penum-
nial pressure in stroke patients. There are bra is a term originally used to refer to an area
drugs available that are known to decrease in- that is not as ischemic as the core and that
tracranial pressure. Yet, they are not used in reperfuses more readily than does the core.
the treatment of stroke. The point here is that The penumbra disappears during reperfusion.
it is the patient that counts. Too often thera- Eventually, the inner part of the penumbra
peutic strategies are neglected because it is may become part of the core of the infarction.
decided that the drug therapy induces an arti- The outer penumbra becomes the limit area
factual effect that is not an intended effect. where apoptosis is prominent. Necrosis is also
For instance, if a drug inhibits excitotoxic seen in the limit area. The point here is that
mechanisms and also induces hypothermia, necrosis must be prevented in order to prevent
the drug may be neglected because the hypo- extensive infarction. However, apoptosis pre-
thermic effect is considered artifactual. Yet, vention may also be important.
such a drug could be a real benefit to patients. Cells die in the brain by two main pro-
It is important to realize that it is the survival cesses, necrotic and apoptotic. However, some
of the patient that is important. authors find other forms of cell death in the
The overall goal of therapeutics with these brain, such as oxytosis. Necrosis is a rapid pro-
drugs is to prevent the death of cells in the cess in which the defense mechanisms of the
brain. Of course it is important to protect neu- cell are overwhelmed. The cell nucleus swells
rons because they do not normally regenerate and ruptures. Cellular mitochondria may
well. However, stem cells in the brain may al- swell. The cytoplasm swells and forms small
low some neuronal regeneration. Endothelial vacuoles. The cell membrane may eventually
cells maintain the blood-brain barrier and rupture. Necrosis may be maximal in the
must be protected if the brain is to survive. brain at about 6-12 h after an insult.
Astrocytes support neuronal activity by deac- Apoptosis is delayed and may be maximal
tivating neurotransmitters, providing trophic at 24-48 h after an insult. However, apoptotic
factors and other activities. Therefore, astro- cells can be seen even within 6 h of an insult,
cytes must be protected if the brain is to sur- but are not common. Apoptosis involves con-
vive. Oligodendrocytes make myelin that is densation of the nucleus. Condensation of the
vital for axonal survival. Therefore, oligoden- cytoplasm occurs with large vacuole forma-
drocytes must be protected. It is obvious that tion. Some mitochondria may condense. Very
all of the cells of the brain are vital to brain uncommonly, some mitochondria swell in ap-
survival and should be protected if possible. optosis. The cell splits up into membrane-
bound apoptotic bodies that can be seen in the
limit areas surrounding the core of an infarc-
2 NECROSIS A N D APOPTOSIS tion. Apoptosis is a programmed form of cell
death that occurs following a small but suffi-
Infarction of the brain is involved in stroke, cient amount of damage to a cell. This initiates
ruptured berry aneurysm, traumatic brain a program that eventually kills the cell.
3 DNA Damage and Repair

3 DNA DAMAGE AND REPAIR repair, nucleotide-excision repair, mismatch


repair, and double-strand break repair. Each
3.1 DNA Damage type of repair process involves slightly differ- -
ent enzymes.
DNA is damaged within minutes of oxygen
Base-excision repair involves removal of a
free-radical generation in the brain. This dam-
damaged base by DNA glycosylase. The dam-
age must be repaired for the cell to survive.
aged area is removed by an endonuclease.
Even neurons need DNA. Although neurons
DNA polymerase beta resynthesizes DNA.
are terminally differentiated, they have very
This is called short-patch base-excision repair.
active protein synthesis to maintain neuro-
However, a long-patch repair process also oc- -
transmission. Without intact DNA, neurons
curs. This involves recognition of the damage
cannot continue normal neurotransmission.
by PCNA (proliferating cell nuclear antigen),
In addition, neurons have only two copies of
which activates DNA polymerases delta and
DNA in the nucleus, unlike the liver and some
epsilon. The new strand is joined to the old
other cells that have many copies of DNA in
strand by Fen 1 (a structure-specific nucle-
the nucleus. Extensive DNA damage leads to
ase).
necrosis. A small, but critical, amount of DNA
Nucleotide-excision repair involves PCNA,
damage leads to apoptosis. Repair of neuronal
DNA polymerase epsilon, and several acces-
DNA is critical to survival of patients suffering
sory proteins, such as RF-C (replication factor
from stroke and similar conditions.
C), RP-A (replication protein A), and Lig I
DNA damage is induced by oxygen radicals,
(DNA ligase I). It could be that these proteins
necrotic events, and apoptotic events. Oxygen
form an aggregate DNA repair machine.
radicals are well known to cause DNA frag-
PCNA is a hollow circular protein that encir-
mentation and other damage to DNA. Necro-
cles DNA. PCNA binds and activates many
sis involves the detachment of histones from
proteins involved in DNA repair. Mismatch re-
DNA and the random cleavage of DNA by en-
pair is less well characterized, but involves
donuclease. Apoptosis involves the cleavage of
DNA polymerase delta.
DNA, with the histones still attached, into nu-
Double-strand breaks, nicks, and similar
cleosome fragments by endonuclease.
DNA damage activate PARP. Once the dam-
DNA damage by oxygen radicals can stim-
age is recognized by PARP, there is a rapid.
ulate DNA repair processes. DNA damage in-
activation of PARP that quickly activates sev-
volved in either necrotic or apoptotic events
eral enzymes involved in DNA repair. PARP
may also stimulate DNA repair processes.
activates transcription factors that regulate
Whether the cell can be rescued from DNA
the transcription of proteins that may be in-
damage depends on how much DNA damage
volved in DNA repair.
has occurred and when the DNA damage oc-
curred. For instance, if necrotic events are al- 3.3 PARP and DNA Repair
ready well under way, it may be too late to
PARP contains two zinc fingers that bind the
reverse the necrosis.
two broken stands of DNA and stabilize the
structure. PARP uses NAD as a substrate to
3.2 DNA Repair
poly(ADP)-ribosylate proteins, including it-
Several enzymes are involved in DNA repair self. Early on, there is a small amount of self-
and are potential targets for drug therapy in poly(ADP)-ribosylation that activates PARP
neurodegeneration (4). DNA damage must by causing it to homodimerize. This dimeriza-
&st be recognized. This recognition depends tion allows the activated PARP to bind to four
on several poorly defined enzymes. Next, the strands of fragmented DNA, stabilize the
damaged DNA must be excised, usually by a structure, and facilitate repair. PARP also
specific endonuclease. Then new DNA must be poly(ADP-ribosylates) endonuclease, which
synthesized by a DNA polymerase. Finally, deactivates endonuclease and protects DNA
the new DNA is joined to the old DNA by DNA from cleavage.
ligase that requires ATP. There are several PARP is composed of three domains (5).
distinct DNA repair processes: base-excision The N-terminal contains the two zinc fingers
Investigative Agents for Use in Neurodegenerative Condit

Figure 11.1. NAD.

and the nuclear location signal. The middle very similar to those found in the bacterial
section contains the automodification area. toxins that are mono(ADP-ribosyl) trsms-
The C-terminal contains the active site that ferases (6).
binds NAD (Fig. 11.1). The active site has a Several amino acids are involved in the ac-
nicotinamide-binding site and an adenine- tive site of PAW: Glu988, Tyr896, Ala8198,
binding site. Lys903, His862, Ser904, Gly863, and Tyr'907
The crystal structure of the active site of (6). A crystal structure for NAD bound to
PARP has been described (5). It is made up of PARP is not available because the complex is
a five-stranded antiparallel beta sheet and a unstable. However, a model system of N'AD
four-stranded mixed beta sheet (Fig. 11.2). bound to diphtheria toxin, a mono(ADP-riibo-
The two beta sheets are connected by two hy- syl) transferase, has yielded a useful cry;jtal
drogen bonds. The beta sheet structure is sup- structure (7). NAD binds with the ribose in a
ported by a surrounding protein structure 3'-endo conformation and the nicotinamidce in
made up of five alpha helices, three 3,, helices, a syn position (Fig. 11.3). Several hydro;gen
and beta sheet excursions. The active site is bonds and hydrophobic interactions occur be-

Figure 11.2. Ribbon representation of the PARP active site. A strongly conserved motif that binds
NAD (black) is shown in gray. This figure is from Ref. 5 and is used with permission.
dlular Energetics

Figure 11.3. Stereo view of atomic interactions of NAD and a model of the PARP site. NAD is shown
in black. The PARP site amino acids are shown in gray. Hydrogen bonds are shown as dashed lines.
This figure is from Ref. 7 and is used with permission.

twe~ en the enzyme and the substrate. The hy- proteins, making them anionic. This estab-
drof;en bonds are as follows: Gly876, Asp770, lishes an electrostatic repulsion from nega-
and Arg878 bond to the adenine; Ser864 or tively charged DNA.
His:562 bonds to the ribose connected to the PARP is a family of enzymes including
adeinine; Asp766, Gln763, and Tyr896 bond to PARP-1, PARP-2, PARP-3, tankyrase, and V-
the phosphates; Gly863 or Ser904 bond to the PARP (8).PAW-1 is perhaps the most impor-
niccjtinarnide; and Tyr907 and Glu988 bond to tant enzyme involved in DNA repair in stroke.
the ribose connected to the nicotinamide. Hy- However, if PARP-1 is deactivated, perhaps
dro]~hobicbonds are as follows: Leu877 and the other enzymes can take its place. The
Ile872 bond to adenine; Tyr907 bonds to nico- PARP inhibitors described so far in the litera-
tina.mide;and T~I-896, which may bond to the ture are PARP-l inhibitors. It is not known
riboise connected to the nicotinamide. Glu988 whether these compounds also inhibit the.
ma) be involved in the catalytic mechanism by other forms of PARP.
polarizing the NAD and the ADP-ribose accep-
tor 1through hydrogen bonding. This polariza-
tion would stabilize the NAD transition state 4 CELLULAR ENERGETICS
and increase the nucleophilicity of the accep-
tor. The NAD transition state involves a ri- During ischemia, oxygen levels diminish, thus
bosf:oxocarbenium ion that leads to cleavage shutting down some mitochondrial functions
in tin S,2 mechanism. and greatly decreasing adenosine 5'-triphos-
I)NA can be stabilized under potentially phate (ATP) levels. When oxygen reperfuses
dam aging conditions by PARP inhibition. into the brain, ATP levels rise to normal levels
Whf?nDNA damage occurs, PARP is activated within about 5 min. ATP is required for cellu-
and binds to DNA, thus stabilizing it. PARP lar energetics, for oxidized glutathione
inhibitors cause PARP to remain bound to (GSSG) reduction, for DNA repair, and for
DNI4, thereby providing long-term stabiliza- many other functions. Therefore, without
tion, even when oxygen radical generation oc- ATP, DNA repair cannot proceed. The cell
C U EI. After the generation of oxygen radicals must turn to other ways to make ATP until
has ceased, the PARP inhibitor can dissociate oxygen returns and mitochondrial function re-
fronI PARP, allowing the DNA to be repaired. turns.
ASter enough DNA repair has occurred, PARP depletes cellular energy resources. It
PAF1P causes the detachment of the repair does this by using NAD as a substrate. When
machinery and of PARP itself from the DNA. DNA damage is severe, such as during isch-
PAF1P does this by poly(ADP)-ribosylating emia and reperfusion, NAD levels can become
680 Investigative Agents for Use in Neurodegenerative Conditions

depleted in the brain within 30 min (9). The 3-(N,N-dimethylamino)benzamide,3,5-


polymers of adenosine 5'-diphosphate (ADP)- dinitrobenzamide, 2-hydroxybenzamide,
ribose have a short half-life because they are 4-hydroxybenzamide, 2-methoxybenzamide,
cleaved by glycohydrolase. This rapid turn- 4-methoxybenzamide, 2-methylbenzamide,
over can deplete NAD. NAD is an adenine- 3-methylbenzamide, 4-methylbenzamide,
containing wmpound, like ATP. As NAD levels and 3-nitrobenzamide. Activity is comparable
decrease so do ATP levels, thus compromising to that of benzamide in 3-acetamidobenz-
cellular energetics. However, NAD is made amide, 3-acryloylaminobenzamide, 3-amino-
into ADP-ribose polymers that can be cleaved benzamide, 3-(2-chloropropionyl)aminobenz-
to make ADP-ribose, which can be used by the amide, 3-(3-chloropropionyl)aminobenzamide,
cell to make ATP (10). and 3-hydroxybenzamide. This suggests that
As ATP levels decrease, cellular calcium the 3 -position of benzamide can be altered
levels increase and activate a number of pro- with either no loss of activity or some gain in
teases, endonucleases, and other enzymes. activity. These 3-position substituents (A)
Caspase enzymes also become activated. may interact with the ribose nucleoside bind-
Caspase-3 rapidly cleaves PARP not bound to ing domain of the active site. Substituents at
DNA, and to a lesser extent DNA-bound the 3 position can improve water solubility of
PARP. When PARP is cleaved, DNA is vulner- the agents, compared to hydrophobic benz-
able to the actions of endonuclease, which is amide. Several benzamide inhibitors of PARP
part of the apoptotic program. are shown in Fig. 11.6 and are good inhibitors
PARP inhibitors can be used to maintain of PARP with significant inhibition at concen-
cellular energetics. They do this by preventing trations of 10 pIVl or less (21).
NAD depletion, which helps prevent ATP de- PARP inhibitors that are based on nicotin-
pletion. In addition, inhibited PARP remains amide have an electron-rich aromatic ring, a
bound to DNA and is less vulnerable to the carbonyl substituent in the anti conformation
actions of caspase-3. This helps prevent necro- that contains a nitrogen and a free hydrogen,
sis and apoptosis. and an aromatic ring substituent (A) such as
hydroxy, methoxy, or amino. The carbonyl
4.1 PARP Inhibitors
group is usually a carboxamide, but can also be
a thiocarbamoyl group. The oxygen in the car-
PARP inhibitors have been synthesized (11) boxamide may serve as an electron donor and
and are shown in Figs. 11.4 and 11.5. Some of the carbon as an electron acceptor in PARP
them have been tested in stroke models with interactions. The carbonyl oxygen should be
good results in terms of preventing infarction in a conformation anti to the 1,Pbond of the
(12-18). Most of the inhibitors are based on aromatic ring (22). The nitrogen of the carbox-
the structure of nicotinamide and therefore amide must not be alkylated because alkyla-
bind to the nicotinamide site of PARP. Several tion abolishes activity. This suggests that a
inhibitors are well known, such as nicotin- hydrogen of the carboxamide nitrogen is in-
amide, benzamide, and 3-aminobenzamide volved in hydrogen bonding to the active site.
(19, 20). However, new quinazolinone, phen- The aromatic ring can be one ring or a polycy-
anthradinone, and other inhibitors are being clic aromatic system. Heterocyclic rings can
investigated. Nicotinamide has a Kiof about also be active.
15 ph4 for PARP (19). Activity is decreased
in 6-aminonicotinamide, isonicotinamide, 1-
methylnicotinamide, 5-methylnicotinamide,
8-methylnicotinamide, and thionicotinamide
(Table 11.1).
Benzamide has a Ki of about 2 pM for
PARP (19). Activity is decreased in 2-acet-
amidobenzamide, 2-aminobenzamide, 4-ami-
nobenzarnide, 2-halobenzamide, 3-halobenz-
amide, 4halobenzamide, 2,6difluombenzamide,
4 Cellular Energetics

Figure 11.4. PARP inhibitors: nicotinamide, 5-methylnicotinamide, 6-aminonicotinamide,picolin-


amide, 3-methoxybenzamide, benzamide, 3-aminobenzamide, 2-aminobenzamide, 4-aminobenz-
amide, coumarin, 3,4-dihydro-5-methylisoquinolinone(PD 1287631, 4-amino-l&naphthalimide,
8-hydroxy-2-methyl-3-hydroquinazolin-4-one, phenanthridinone, and 3-0-alkylbenzamides. This
figure is redrawn from Ref. 33 and is used with permission.

Several inhibitors are known that bind to the biochemical pathways (22). Recent attempts
adenosine site of PARP (19). These inhibitors to make more specific and more potent inhib-
include 5-bromo-2'-deoxyuridine,caffeine, 5- itors of PARP have centered around making
bromouracil, diadenosine-tetraphosphate, 1- conformationally restricted analogs. For in-
methyladenine, 5-nitrouracil, theophylline, stance, the 5-substituted dihydroisoquinolino-
theobromine, thymidine, and other compounds. nes below are restricted to anti conformations
These compounds are not as well studied as the and are PARP inhibitors. However, the 7-sub-
nicotinamide analogs. In addition, it is not stituted dihydroisoquinolinonesare restricted
known whether these compounds can interact to syn conformations and are inactive. 5-Meth-
with the adenosine (A,) receptors that are in- yl-3,4-dihydroisoquinolinone (PD128763) is
volved in modulation of synaptic transmission being investigated for use in stroke and other
and neuroprotective effects. conditions. Several isoquinolinones appear to
Inhibitors based on the structure of nico- be good inhibitors of PARP (21), with signifi-
tinamide or benzamide have been reported to cant inhibition at concentrations of 10 pM or
have toxicity problems arising from the fact less (Fig. 11.7).
that some of them may be antimetabolites for Benzoxazoles have become of interest be-
NAD synthesis or interact with other NAD cause they may have intramolecular hydrogen
Investigative Agents for Use in Neurodegenerative Conditions

Figure
- ,5. PARP inhibitors: 1,5-
dihydroxyisoquinoline, 5-aminoiso-
quinolin-l(2H)-one, 0-(2-hydroxy-3-
piperidinepropy1)pyridine carbonic
acid amidoxime, 6(5H)-phenanthridi- 0
none, 3,4-dihydro-5-[4-(1-piperidinyl)
butoxyl-l(2H)-isoquinoline,2,B-dimeth-
yl-3-hydroquinazolin-4-one,8-methyl-2-
(p-nitrophenyl)-3-hydroquinazolin-4-
one, 5-iodo-6-aminocoumarin. These I
inhibitors are from Ref. 11 and have CH3
been redrawn with permission.

hydroxy group provides more activity than


that of a methoxy group. This may be attrib-
utable to steric constraints in the active site.
The addition of a 2-phenyl to the molecule (C)
enhances activity if electron-withdrawing or
electron-donating substituents are added in
the para position.

R = H, OH, 0CH3, N02, NH2

bonding that may keep them in anti conforma-


tions. Attempts to make benzoxazoles have re-
sulted in quinazolin-4-(3H)-onesynthesis as a
result of rearrangements during synthesis
(23). However, some of the quinazolinones
have been found to be good PARP inhibitors
(Table 11.2). The quinazolinones are re- Benzoxazole
stricted to anti conformations. At least one hy-
drogen must be available on the nitrogen in Thiophenecarboxamides, thienopyridino-
the 3 position or activity is lost. In general, for nes and thienopyrimidinones have been syn-
substituents at the 8 position (X), a methyl or thesized that are sulfur containing analogs of
Table 11.1 Effects of Various Compounds on Poly(ADP-ribose)Polymerase Activity"
Compound K, (fJm Ic60 (a
m-Acetamidoacetophenone -b 930
2-Acetamidobenzamide - 1000
3-Acetamidobenzamide 0.4 -
3-Acetamidobenzamide - l2 -F
8-Acetamidocarsalamc - 1400
3-Acetamidosalicylamidec - 2000
5-Acetamidosalicylamide - 45
Acetophenone' - 2300 -
3-Acryloylaminobenzamide 3.14 -
m-Aminoacetophenone - 1900
2-Aminobenzamide 71 -
2-Aminobenzamide - 100,650
3-Aminobenzamide 1.8-12 -
3-Aminobenzamide - 5.4-33
4-Aminobenzamide 65-75 -
4-Aminobenzamide - 400-1800
6-Amino-1,2-benzopyrone 47 -
6-Amino-1,2-benzopyronec - 850
2-Amino-3-chloro-1,4-naphthoquinonec - 820
4-Amino-1,8-naphthalimidec - 0.18
6-Aminonicotinamide - 1100
5-Aminosalicylamide - 100
A2'pAYpA 50 -
Apigeninc - <1500d
Arachidonic acidc - 44
Benzamide 1.0-39 -
Benzamide - 3.3-22
1,2-Benzopyrone - 47
1,2-Benzopyronec - 2800
1,4-Benzoquinone - 400 .
Benzoyleneureac - 8.1
2-Bromobenzamide - 2900
3-Bromobenzamidec - 55
4-Bromobenzamidec - 2200
5-Bromo-2'-deoxyuridine - 15
3-(3-Bromopropiony1)aminobenzamide 1.73 -
5-Bromouracil - 160
5-Bromouridine - 210
Caffeine 244 -
Caffeine - 1400
Carsalamc - 460
2-Chlorobenzamide - 1000
3-Chlorobenzamide - 22
4-Chlorobenzamide - 300
N-(2-Chloroethy1)-1,s-naphthalimidec - <I800
3-(2-Chloropropionyl)aminobenzamide 1.9-2.0 -
5-ChlorosalicylamideC - 190
5-Chlorouracil - 270
Chlorthenoxazinc - 8.5
4-Chromanonec - 720
Chromone-2-carboxylic acid - 560
Coenzyme Qo - 3900
684 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.1 (Continued)


C;ompounci Ki (ELM) G o (ELM)
Cyclohexanecarboxamide
trans-I-Decalone'
Diadenosine 5',5-pl, p2-diphosphate
Diadenosine 5',5-pl,p4(pl, N6-etheny1)tetraphosphate
Diadenosine 5',5-pl,p4(pl, p2-methy1ene)tetraphosphate
Diadenosine 5',5"'-pl, p4-tetraphosphate
4-Diazoniobenzamide-dGMP
3,5-Dibromosalicylamidec
2,3-Dichloro-1,4-naphthoquinonec
2,6-Difluorobenzamide
10,ll-Dihydrodibenz[b,fl[l,41-oxazepin-1 1-onec
1,5-Dihydroxyisoquinoline
1,3-Dihydroxynaphthalenec
3,5-Dimethoxybenzamidec
3-(N,N-Dimethy1amino)benzamide
3,s-Dinitrobenzamide
Ethidium bromide
Flavonec
2-Fluorobenzamidec
3-Fluorobenzamide
4-Fluorobenzamidec
Formycin B
Harmine hydrochloride
m-Hydroxyacetophenone
2-Hydroxybenzamide
3-Hydroxybenzamide
3-Hydroxybenzamide
4-Hydroxybenzamide
4-Hydroxy-1,2-benzopyronec
1-Hydroxyisoquinoline
4-Hydroxy-2-methylquinolinec
N-Hydroxynaphthalimide sodium salt
4-Hydroxypyridine
4-Hydroxyquinazoline
4-HydroxyquinolineC
Hypoxanthine
1-Indanonec
5-Iodouracil
5-Iodouridine
Isatoic anhydridec
3-Isobutyl-I-methylxanthine
Isoluminolc
Isonicotinamide
Isonicotinate hydrazide
Juglonec
Kynurenic acidc
Lawsonec
Linoleic acidc
Linolenic acidC
y-Linolenic acidc
LuminoF
Menadionec
Menadione sodium bisulfite
4 Cellular Energetics

Table 11.1 (Continued)


Compound Ki ( 4 4 ) Ic50 (M -
2-Mercapto-4(3H)-quinazolinonec - 44
2-Methoxybenzamide - 20
3-Methoxybenzamide 0.6-2.9 -
3-Methoxybenzamide - 3.4-17 r
4-Methoxybenzamide - 1100
1-Methyladenine 226.6 -
2-Methylbenzamide - 1500 .
3-Methylbenzamide - 19
4-Methylbenzamide - 1800
2-Methylchromone - 45
I-Methylnicotinamide - 1700
5-Methylnicotinamide 30-200 -
5-Methylnicotinamide - 70350
8-Methylnicotinamide - 7800
1-Methylnicotinamidechloride - 3800
2-Methyl-4(3H)-quinazolinonec - 5.6
NADH 55 -
NADP 460 -
1,8-Naphthalimidec - 1.4
1,4-Naphthoquinonec - 250
Nicotinamide 5.6-52 -
Nicotinamide - 31-210
3-Nitrobenzamide 9.8 -
3-Nitrobenzamide - 160
2-Nitro-6(5H)-phenanthridinonec - 0.35
3-Nitrophthalhydrazidec - 72
4-Nitrophthalhydrazidec - 510
3-Nitrosalicylamidec - 1600
6-Nitroso-1,2-benzopyrone 40 -
5-Nitrouracilc - 430 ,
Norharman - 4700
Novobiocin - 2200
Oleic acidc - 82
Palmitoleic acidc - 95
6(5H)-Phenanthridinonec - 0.3
Phthalamide - 1000
m-Phthalamidec - 50
Phthalazine - 150
l(2I-I)-Phthalazinonec - 12
Phthalhydrazidec - 30
a-Picolinamide - -100-250
Plumbagin' - 700
PPPA~'PA~'PA 5 10
Pyrazinamide - 130
Pyridoxal 5-phosphatec - 4250
Quinazoline - 2000
Reserpinee - 790
trans-Retinalc - 450
Showdomycin 107.8 -
686 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.1 (Continued)


Com~ound
- - -
Ki (dfl %o (m
a-Tetralonec - 310
Theobromine 15.2 -
Theobromine - 110
Theophylline 29.8 -
Theophylline - 46
Thiobenzamide - 620
Thionicotinamide - 1800
Thiophene-3-carboxamide - -50
Thymidine 13.3-140 -
Thymidine - 43-290
2-Trichloromethyl-4(3H)-quinazolinonec - 2200
Trp-P-1(3-Amino-l,4-dimethyl-5H-pyrido[4,3-blindole) - 220
Trp-P-2 (3-Amino-l-methyl-5H-pyrido[4,3-blindole~c - 2200
Vitamin K,' - 520
Vitamin K,' - 1300
Xanthurenic acidc - 190
ZnC1, - 10-77
"Table modified from Ref. 19 with permission.
*-, not determined.
'2% (final) Me2S0.
dMaximum value estimated under conditions of limited solubility.
'10% (final) Me,SO.

this approach has been neglected in the treat-


ment of neurodegeneration.
NAD glycohydrolase is a member of the
ADP-ribosyl transferase family of enzymes.
The catalytic mechanism of NAD glycohy-
drolase is similar to the PARP mechanism
and involves an oxocarbenium ion interme-
diate of NAD (25). Like the bacterial mono-
(ADP-ribose) transferase toxins, NAD glyco-
Quinazolinone hydrolase has a Rossman fold that binds
NAD in a n extended conformation and may
prevent the synthesis of polymers of ADP-
isoquinolinones and quinazolinones known to ribose. Therefore, NAD glycohydrolase can
inhibit PARP (24). These compounds (Fig. function only in the cleavage of NAD and
11.8) are potent inhibitors of PARP with sig- perhaps the transfer of single ADP-ribose
nificant inhibition found at concentrations of units to other proteins.
10 pM or less. The possible neuroprotective Several inhibitors of NAD glycohydrolase
activities of these compounds has not been re- are known. Nicotinarnide, 3-aminobenzamide,
ported. and gallotannin (26) have been tested in vivo
and were found to be neuroprotective. Novo-
4.2 NAD Clycohydrolase Inhibitors
biocin and meta-iodobenzylguanidine have
ADP-ribose polymers and NAD are catabo- been tested in an in vitro model of traumatic
lized by glycohydrolase enzymes, such as NAD brain injury and were found to be protective
glycohydrolase. Some of the PARP inhibitors, (27). Inhibitors of NAD glycohydrolase include:
such as nicotinamide, also inhibit glycohydro- 3-aminobenzamide, arachidic acid, arachidonic
lase. The inhibition of NAD glycohydrolase acid, benzarnide, bromodeoxyuridine, diethyl-
could be another way to boost cellular energet- amino(benzylidineamino)guanidine, meta-
ics by slowing NAD turnover. Unfortunately, iodobenzylguanidine, isoniazid, novobiocin,
4 Cellular Energetics

Figure 11.6. Benzamide inhibitors


of PARP from Ref. 21.

palmitic acid, palmitoleic acid, stearic acid, ment of pellagra. Before nicotinamide, the
thymidine, theophylline, linoleic acid, vitamin mortality from pellagra was 30% in the United
K2, and vitamin K1 (25, 27,28,29). States. About 10,000 deaths occurred every
year, mostly caused by neurodegeneration. Af-
4.3 NAD Precursors and Cellular Energetics ter the introduction of nicotinamide in 1938
The most potent neuroprotective agent used (301, the mortality from pellagra decreased to
clinically is nicotinamide, used in the treat- nearly 0%. Of course, pellagra is caused by nic-
otinamide, or niacin, deficiency. Both nicotin-
amide and niacin are called vitamin B3. Pella-
gra is a disease of NAD deficiency.
Nicotinamide, but not niacin, is taken up
into the brain by an active uptake process (31)
and is converted into NAD (Fig. 11.9). Niacin
released in the brain from catabolic processes
is converted into nicotinamide as shown. Nic-
otinamide can increase brain levels of NAD by
50% or more (32). By increasing brain NAD
levels, nicotinamide prevents ATP depletion
(9) and protects cellular DNA (32). Therefore,
nicotinamide maintains cellular energetics in
the presence of oxidative stress.
Many compounds have been investigated
that may maintain cellular energetics, espe-
cially in pellagra (Fig. 11.10). All but one of the
compounds found to be active can be con-
Figure 11.7. Isoquinolinone inhibitors of PARP verted into NAD in the body (33). This is im-
from Ref. 21. portant because compounds that make NAD
688 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.2 Selected Quinazolinones Tested for PARP Inhibitiona

Compounda Structure R X

OH
Me
Orne
Me
Orne
Me
Orne
Me
Orne
Me
Orne
Me
Orne
Orne
Me
Orne
Me
OH
OH
OH
Me
OH
"Data are used with permission from Ref. 23 (0 1998 American Chemical Society).
*3AB is 3-aminobenzamide; 3HB is 3-hydroxybenzamide; QN is quinazolin-4(3H)-one;PD128763 is 5-methyl-3,4dihy-
droisoquinolinone.

analogs in the body may be toxic and interfere zymes. The other active compounds can be
with normal biochemical processes. However, converted in the body into nicotinamide by es-
compound (21) may make NAD analogs in the terases, amidases, decarboxylation, and
body and has been reported to be active in methyl oxidation to form carboxyl, N-dealky-
NAD deficiency. Perhaps the NAD analogs lation, and other processes. Tryptophan can
from (21) are not toxic and can substitute for be converted into nicotinamide in the body.
NAD in normal biochemical processes. This The pathway is tryptophan, kynurenine, 3-hy-
seems unlikely, given that the Cposition of the droxykynurenine, 3-hydroxyanthranilic acid,
NAD pyridine ring is involved in hydride l-amino-4-formyl-l,3-butadiene-1,2-dicar-
transfer reactions catalyzed by several en- boxylic acid, quinolinic acid, niacin, and nico-
1 5 NMDA Receptor Antagonists
k
i
I
I
114 0 N H 2 x
11 < ~& C O N ~H ~ ~ ~ ~
,YZ NO2 'Y' NH2

Figure 11.8. Thiophenecarboxam-


ides, thienopyridinones, and thienopy-
rimidinone inhibitors of PARP. For the
thiophenecarboxamides there are three
series of inhibitors: (a) X = S; Y, Z =
CH; (b) X, Z = CH; Y = S; (c) X, Y =
CH; Z = S. For the thienopyridinones
and thienopyrimidinones, R = Me or
Ph. Adapted and redrawn from Ref. 24.

tinamide. Oral NAD is active because it is two subunits, NR1 and NR2, and multiple
cleaved in the gut to make nicotinamide. binding sites for ligands and inhibitors. The
receptors are glutamate receptors. Glutamate
5 NMDA RECEPTOR ANTAGONISTS is released during ischemia such that activa-
tion of NMDA and other excitatory amino acid
NMDA receptors are ligand-gated ion &an- receptors may be involved in damage caused
nels that allow the influx of calcium upon li- by ischemia and reperfusion. The binding sites
gand binding. The receptors contain at least include sites for AMPA, glycine, phencyclid-

CONH2 COOH
1

N Nicotinamide N Niacin

1
CONH2

0 N
I
Nicotinamide
mononucleotide
..
I mononucleotide
Figure 11.9. NAD synthesis pathway
Ri-P Ri-P from nicotinamide or niacin: (1) nicoti-
namidase (E.C.3.5.1.19); (2) nicotinamide
phosphoribosyl transferase, which re-
quires ATP; (3) NMN adenyl transferase,
which requires ATP; (4) nicotinic acid
phosphoribosyl transferase, which re-
quires ATP; (5) NMN adenyl transferase,
which requires ATP; (6)NAD synthetase,
which requires ATP. Ri, ribose; P, phos-
phate; Ad, adenine; NMN, nicotinarnide
Ri-P-P-Ri
mononucleotide. This figure is from Ref.
NAD 33 and is used with permission.
Investigative Agents for Use in Neurodegenerative Conditions

COOH

COOH

aCooH
N

(7)
COOH

n C
N O N H " '

I
glucosiodide
(20)

Figure 11.10. Nicotinamide analogs tested in pellagra or animal models of pellagra. The active
compounds include (1,2,6, 11, 12,13,15,18,and 20). Compounds active in some models or in
pellagra include (7,17,21),pyrazine-2,3-dicarboxylicacid, NAD, pyridyl-3-aldehyde, pyridyl-3-carbi-
nol, tryptophan, and 3-hydroxyanthranilic acid. The inactive compounds are (3,4,5,8,9,10,14,16,
19),3-arninopyridine, thiazole-5-carboxylic acid, 2-methylpyridine, 3-methylpyridine, 2,6-dimethyl-
pyridine-3,5-dicarboxylic acid, pyridine-3,5-dicarboxylicacid, kynurenine, 3-hydroxykynurenine,
and formylkynurenine. This figure is from Ref. 33 and is used with permission.
5 NMDA Receptor Antagonists

COOH
H2N

c COOH
COOH
F

Figure 11.11. 3,4-Diarnino-3-cyclobutene-1,2-diones


redrawn from Ref. 34.

ine, kainic acid, polyamines, and other binding 11.11). These compounds were synthesized
sites. AMPA is ~~-c~-amino-3-hydroxy-5-meth- because it was noticed that several competi-
ylisoxazole-4-propionic acid. Compounds that tive inhibitors of the NMDA receptor had al-
alter glutamate release and thereby alter pha-amino carboxylic acid and phosphonic '

NMDA channel activation are known. Activa- acid functionalities separated by 3-5 carbons.
tion of NMDA receptors is associated with ox- All of the inhibitors shown in Fig. 11.11 have
ygen radical formation and activation of nitric Ki values for inhibition of the NMDA receptor
oxide synthase. of 10 p M or less. In general, nitrogen substitu-
Several NMDA receptor antagonists have ents larger than those shown decrease recep-
been synthesized and tested in stroke models, tor affinity. In addition, substitution on the
epilepsy models, and in clinical trials. Many of second nitrogen decreases affinity.
the antagonists are limited by side effects such A series of N-phosphonoalkyl and N-(phos-
as hemodynamic abnormalities, hypotension, phonoalky1)phenyl-spaced alpha-amino acids
neuronal vacuolation, memory disturbances, have been explored as NMDA receptor antag-
cognitive disturbances, motor dysfunction, onists (35). The compounds are competitive
seizures, hallucinations, unpleasant dreams, inhibitors and are shown in Table 11.3. A
psychotomimetic episodes, and other effects. folded conformation of the inhibitors seems to
This has made the search difficult for NMDA be favored that places the phosphonic acid and
receptor antagonists that can be used as neu- the alpha-carboxylic acid moieties in close
roprotective agents. proximity in the receptor. The phosphonoal-
Many NMDA receptor antagonists have kyl group must be long and flexible enough to
been synthesized that are based on the struc- allow the phosphonic acid to stretch across the
ture of glutamate, NMDA, and AMPA. Several molecule and fit into the acidic binding site of
3,4-diamino-3-cyclobutene-1,2-dionederiva- the receptor. Addition of too much length cre-
tives (34) have been synthesized and found to ates excessive bulk that hinders the fit of the
be good inhibitors of the NMDA receptor (Fig. molecule into the receptor.
692 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.3 N-(Phosphonoalky1)phenyl-Spacedand N-(phosphonoalkyl) Alpha-Amino Acid


Inhibitors of the NMDA Receptor"

I
COOH
HN\ /
H
HOOC, ,NH I
C
I
H
C

A
Structureb Position, Xb n m R % Inhibc Ic,o (rUM)
(A) o 0 0 (C0OH)l H 4
(A) o 0 0 H 27
(A) o 0 1 H 48
(A) 0 0 2 H 0
(A) 0 0 2 (ElZ H 9
(A) 0 1 1 H 21
(A) 0 1 1 CH3 4
(A) m 0 2 H 0
(A) m 0 3 (E)' H 13
(A) m 0 3 H 5
(A) m 1 0 H 21
(A) m 1 1 H 2.4
(A) m 1 1 CH3 31
(A) m 1 1 CH(CH& 0
(A) m 2 1 H 13.7
(A) P 1 1 H 2.3
(B) - 2 0 H 14
(B) - 3 0 H 3
(B) - 4 0 H 17
(B) CH=CH(E)' 1 1 H 1.0
(B) CH=CH(E)' 1 1 CH3 42.4
(B) CH=CH(ZE)' 2 0 H 2.3
(B) S 2 1 H 60
(B) S(0) 2 1 H 4
"Data are adapted from Ref. 35 with permission (0 1992 American Chemical Society).
*Position,Xrefers to, for structure A, the position of the phosphate substituent on the phenyl ring, or for structure B, the
nature of X.
'% Inhib refers to the percentage inhibition at 100 a. (1) The phosphate is replaced by COOH; (2) the geometry of the
double bond is entgegen or a combination of entgegen and zuzammen.

Many benzo[b]quinolizinium cations have Many of these compounds are neuroprotective


been synthesized and found to inhibit the in cell-culture systems. Of course, because
NMDA receptor (36, 37). These compounds they are permanently charged, they are not
tend to have high affinity for the open NMDA expected to penetrate the blood-brain barrier
channel and are uncompetitive inhibitors (Ta- well. However, several uncharged compounds,
ble 11.4). They seem to be selective for the below, have been synthesized that are non-
phencyclidine site of the NMDA receptor. competitive NMDA receptor antagonists and
5 NMDA Receptor Antagonists 693

may be of interest in clinical trails against tion between activity and peptide tertiary
stroke. These compounds are based on the structure. The ability of these peptides to
structures of benzoCblquinolizinium cations modulate the NMDA receptor suggests there-
and dizocilpine, which have been clinically may be endogenous peptides that perform the-
tested against stroke. same function.

A family of peptides has been found in ma- Bis(pheny1)guanidines have been explored
rine snails of the Conus genus that are NMDA as NMDA receptor antagonists (39). These
receptor antagonists by virtue of their interac-compounds are similar to N-l-naphthyl-N1-(3-
tions at the polyamine site (38). These pep- ethylpheny1)-N'-methylguanidine(aptiganel,
tides apparently can cross the blood-brain bar- below) that has been tested in clinical trails for
rier and cause ataxia, respiratory paralysis, traumatic brain damage and stroke. Many of
and death. They are noncompetitive inhibi- these compounds are potent NMDA receptor
tors of polyamine responses at NMDA recep- antagonists, but are also sigma receptor an-
tors. However, the peptides do not produce the tagonists. The sigma receptor is not well un-
same effects as those of other polyarnine inhib-derstood. Some sigma receptor antagonists
itors, such as arcaine, ifenprodil, and 1,lO-dia-
may block calcium entry into cells and prevent
minodecane, which implies that the peptides apoptosis (40). These receptors may modulate
act at a novel polyamine site on the NMDA NO synthase activity and appear to bind
receptor. Conantokin-G is the model peptide neurosteroids. However, the effects of sigma
in this series and is Gly-Glu-Gla-Gla-Leu-Gln- receptor antagonists may be dose related,
Gla-Am-Gln-Gla-Leu-Ile-Arg-Gla-Lys-Ser-An- causing potentiation of NMDA receptor activ-
NH,. The peptide contains several gamma- ity at low doses and inhibition of NMDA recep-
carboxyglutamate (Gla) residues that make it tor activity at high doses (41). Some sigma re-
resistant to peptidases. Conantokin-G has an ceptor antagonists have been found to be
IC,, of 0.2 pM in NMDA receptor assays. neuroprotective. However, several of the bis-
Many peptides were synthesized with one (pheny1)guanidines were found to have higher
amino acid difference compared to that of co- affinity for the NMDA receptor than for the
nantokin-G. Only the peptide with an Ala at sigma receptor (Table 11.5). For R1 substitu-
position 7 instead of Gla had enhanced activity ents, iPr and F do not produce NMDA recep-
(IC,, = 0.05 pM). All other amino acid substi- tor-selective agents. In general, for R2 and R3,
tutions either did not enhance or decreased one or both of the two substituents should be
activity. Although conantokin-G possesses al- SMe or CF, to retain NMDA receptor selectiv-
pha-helicity, there was no apparent correla- ity.
694 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.4 Benzo[b]quinolizinium Cations Found to Inhibit the Phencyclidine Site


of the N D A Receptor"

A\/B

OEt Oet
OEt Oet
OEt Oet
OPr OP~
OEt Oet
OEt Oet
OEt Oet
OEt Oet
OEt Oet
OEt Oet
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
3-C4H30 3-C4H30
C6H5 C6H5
-

"Data are adapted from Refs. 36 and 37 with permission (01994, 1995 American Chemical Society).

urea decreases affinity, which may indicate


the importance of oxygen in hydrogen bonding
or other interactions.
5-Amino-quinoxaline-2,3-diones can be
powerful inhibitors of the AMPA receptor and
the glycine site of the NMDA receptor (43).
Several of the compounds are also anticonvul-
sants. None of them has been tested as a neu-
Indole-2-carboxylates have been found to roprotective agent. For the carboxylic acid de-
inhibit glycine binding to the NMDA receptor rivatives (Table ll.71, shortening of the spacer
(42). At least one of these compounds de- between the amine and the carboxylic acid in-
creased infarct volume after ischemia and creases AMPA affinity. However, large sub-
reperfusion. Several of the analogs are able to stituents on the amino acid side-chain de-
inhibit NMDA-induced convulsions. Binding crease AMPA receptor affinity. N-Methylation
affinity decreases when bulky groups are sub- improves selectivity for the AMPA receptor.
stituted at R2 (Table 11.6). This implies that Esterification decreases affinity for AMPA
steric restrictions to binding may exist. The and NMDAreceptors. The most potent glycine
exception is THP (tetrahydropyranyl), which site (MDL) antagonist is a brominated amino
may be more flexible than phenyl substitu- acid derivative. Among the phosphonic acid
ents, perhaps avoiding steric restrictions to derivatives the nitro-D-phosphoalanine deriv-
binding. Replacement of the urea with thio- ative is a potent anticonvulsant and glycine
6 Nitric Oxide Synthase inhibitors

Table 11.5 Bis(pheny1)guanidinesthat Table 11.6 Indole-2-carboxylateInhibitors


Are Selective for Inhibition of the Glycine Site of the NMDA Receptor"
of the NMDA ReceptoF
R1 I

SMe H
Et Et
Et Srne
Et Srne
Et Srne
CF3 Srne
CF3 Srne
SMe Et
SMe Et
SMe Srne
SMe Srne
SMe Br
0CF3 Et "Adapted from Ref. 42 with permission (0 1999 Amer-
Br Srne ican Chemical Society).
"Adapted from Ref. 39 with permission (63 1997 Amer-
ican Chemical Society).
*These compounds have Kivalues for inhibition of the placed with several other side-chains with re-
NNDA receptor that are at most 10 times lower than their tention of activity, such as methyl, ethyl, pro-
ICbOvalues for inhibition of the sigma receptor. pyl, butyl, pentyl, and hexyl. These side- .
chains must be unbranched, given that
site antagonist. However, more potent glycine branched side-chains may have no activity.
site antagonists are the brominated and the This implies steric restrictions exist in the re-
trifluoromethylated phosphoalanine deriva- ceptor for these side-chains. A variety of fluor-
tives. In general, increasing the size of the R inated hydrocarbon side-chains can be added
substituent tends to decrease activity at the in place of trifluoromethoxy, with retention of
glycine site. activity. These side-chains must be at the
6-position to be active. Perhaps a lipophilic re-
ceptor site exists that can interact only with
6-substituents. Many different substituents
can be placed on the ring nitrogen with reten-
tion of antiseizure activity. It is very possible
Riluzole that many of these side-chains are metaboli-
cally removed upon injection into animals.
Riluzole is an NMDA antagonist with ac-
tions at the pre- and postsynaptic levels. It is 6 NITRIC OXIDE SYNTHASE INHIBITORS
currently being used in amyotrophic lateral
sclerosis patients. Riluzole also inhibits gluta- Nitric oxide synthase (NOS) is a family of en-
mate-induced convulsions. Several riluzole zymes consisting of at least three isoforms, in-
analogs have been synthesized and tested for ducible (iNOS) found in macrophages and
inhibition of glutamate-induced seizures (44). other cells, neuronal (nNOS) found in neu-
The trifluoromethoxy side-chain can be re- rons, and endothelial (eNOS) found in endo-
Found to be Active at AMPA (ICs, in p M ) and Glycine (MDL, ICso in p M l Sites
Table 11.7 5-Amino-quinoxaline-2,3-diones
and Found to Have Anticondant Activity (ESM in mglkg)"
R

Carboxylic Acid Derivatives Phosphonic Acid Derivatives


X R AMPA MDL ESM X R AMPA MDL ESM
(la) NO,

HOOcQN
(lb) NO,
H O O C ~ N H
HOOC ( 1 ~ ) NO,
CNH
HOOC- NH (Id) NO,

(le) NO,
H O O c NH
~
HOOC-NH (10 NO,
---

HOOc+
~NH (lg) NO,

Oh) NO,

.OOYNH
I
H O O c ~ N H
CH300
YNH +
%

HOOC- NH

HOOC-NH
.
--

H O O c ~ ""
HOOC

CNH
HOOC-S

HOOCVO
OI
rD
4'
(18a) NO, HOOCVO

(18b) NO,
H O O c ~ O

"Adapted from Ref. 43 with permission from Elsevier Science.


Investigative Agents for Use in Neurodegenerative Conditions

thelial cells throughout the body. Induction of are important in neurodegeneration. Inhibi-
iNOS depends on exposure to cytokines and tors based on the structure of arginine include
other stimuli and is important in the immune p-methyl-L-arginine,p-nitro-L-arginine and
response and other defense mechanisms. its methyl ester, p-amino-L-arginine, N-6-
Blood flow to inflamed tissues may be con- (iminoethy1)-L-ornithine, and others.
trolled by iNOS. Blood pressure regulation N-Phenylamidines are known to reversibly
and antithrombosis responses involve eNOS. inhibit nNOS (46). Slight structural varia-
Neuromodulation involves nNOS. Both eNOS tions can switch isoform specificity with these
and nNOS are constitutively expressed iso- compounds as seen with the two acetamidine
forms. structures shown below. N-(3-(Aminomethyl)-
NOS is a homodimer and requires dimer- phenyllacetamidine, below, was modified by
ization involving calmodulin for activation. changing the aminomethyl side-chain (Table
However, iNOS contains tightly bound cal- 11.8). Ethylamino, methylaminomethyl, and
modulin, such that exogenous calmodulin dimethylaminomethyl side-chains retain nNOS
binding is not required for activation. The en- specificity. A methanol side-chain produces
zyme contains a cytochrome P450 reductase a n nNOS-specific inhibitor. However, acetyl
domain and an oxygenase, heme protein do- and modified acetyl side-chains abolish
main. There are binding sites for NADPH, activity.
FAD, FMN, and tetrahydrobiopterin. The ox- Modification of the acetamidine functional-
ygenase domain oxidizes arginine with the for- ity also produces nNOS-specific inhibitors

iNOS selective nNOS selective

mation of citrulline and nitric oxide. Activation (Table 11.9). Several alkyl side-chains were
of the enzyme requiresdimerization because the found to be effective, including aminomethyl,
flow of electrons from the redudase occurs to fluoromethyl, 2-pyridyl, 2-furanyl, and 2-thie-
the tram oxygenase. Tetrahydrobiopterin facil- nyl. This may imply that the acetamidine side-
itates dimerization, stabilizes the enzyme, shifts chain is involved in hydrophobic interactions
the iron to a high spin state, and facilitates elec- with the enzyme that can be enhanced by ali-
tron transfer (45).NADPH supplies electrons to phatic and aromatic groups. The 2-furanyl
the reductase. Electron transfer in the reduc- and 2-thienyl groups may be able to bind in the
tase involves FAD and FMN. NOS makes NO hydrophobic pocket created by Pro336,
that is a reactive radical, especially after inter- Val338, and Phe355 in the active site of nNOS.
action with oxygen when peroxynitrite is Thiocitrulline and other citrulline analogs
formed. Peroxynitrite can damage DNA and have been found to be good inhibitors of NOS
other macromolecules. (47,48). The inhibitors reported so far do not
Many inhibitors have been synthesized seem to have isoform specificity. Thiocitrul-
based on the structure of L-arginine. These in- line is the most potent inhibitor in the series.
hibitors are not isoform specific. Specificity However, its N-hydroxy analog and other an-
may be important in the treatment of neuro- alogs, below, are nearly as potent. The inhibi-
degenerative disorders. It is possible that inhi- tors shown inhibit NOS with IC,, values in
bition of nNOS could be very important in the the range of 10 pM. It has been proposed (48)
inhibition of neurodegeneration. However, that the sulfur or imidazole nitrogen binds to
NO can diffuse long distances in the brain. For the oxygenase heme iron. Nearby on the en-
this reason, it is possible that eNOS and iNOS zyme is a cationic site that binds the amino
6 Nitric Oxide Synthase Inhibitors

H2N
ACOOH H2N
ACOOH

H2N

COOH
H2N
hCOOH

ACOOH ACOOH
H2N H2N

acid nitrogen. An anionic binding site may equally well. However, none of the dipeptides
bind the carboxylic acid. An H-bonding site inhibits NOS as potently as S-L-isothiocitrulline
may bind the amino hydrogen. (IC,, = 0.06 pM for nNOS). The ability of these
Several dipeptides have been synthesized dipeptides to inhibit NOS suggests that there
that incorporate isothiocitruline into the may be endogenous peptide regulators of NOS.
peptide (49). Some of these dipeptides are Imidazole-containing amino acids can
selective for inhibition of nNOS and iNOS make good NOS inhibitors, given that imida-
but not eNOS. These peptides include S-methyl- zole ligates heme (50). The inhibitors display
L-isothiocitrullinyl-L-phenylalanine,S-meth- some isoform specificity (Table 11.10) in that
yl-L-isothiocitrullinyl-L-leucine, S-meth- at least two of them inhibit nNOS with affini-
yl-L-isothiocitrullinyl-L-tryptophan(-CHO), ties at least 10 times greater than their affin-
S-methyl-isothiocitrullinyl-L-phenylglycine, ities for eNOS. The inhibitors with odd num-
S-methyl-L-isothiocitrullinyl-L-glycine, S- bers of carbons in the spacer between the
methyl-L-isothiocitrullinyl-glycine, S-methyl- imidazole and amino acid are the most selec-
isothiocitrullinyl-L-tyrosine, and S-methyl-L- tive inhibitors. However, when a phenyl sub-
isothiocitrullinyl-4-nitro-L-phenylalanine. All stituent is added to the imidazole, all isoform
of these dipeptides inhibit nNOS with IC,, specificity is lost. Perhaps hydrophobic inter-
values of about 10 pM,and they inhibit iNOS actions exist between the enzyme and the hy-
Table 11.8 N-PhenylacetamidineInhibitors of NOSa

Ki (cJM) Selectivity
R Isomer Salt
CH,NH, 3 2HC1
CH,NH, 4 2HBr
NH, 3 2HBr
CH,CH,NH, 3 2HC1
CH,NHMe 3 2HBr
CH,NMe, 3 2HBr
2HBr
CH(0H)Me HBr
CH,CO,H HBr
CH,CO,Me HC1
C0,tBu HC1
CH,C(O)-N-morpholinyl HBr
CH,NHC(O)-N-morpholinyl HBr
H HBr
F HCl
Br HCl
NO, ' HCl
CN HCl
NMe, 2HBr
SMe HC1
OMe HC1
OH HBr
C(0)Me HC1
C0,H HC1
C(O)NH, HC1
SO,NH, HBr
J 2HBr

HBr >50 27

NHNH,
C(NH)NH,
NHC(NH)Me
"Data are reprinted from Ref. 46 (O 1998 American Chemical Society).
702 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.9 Modified Amidine Inhibitors of NOSa

Ki (CLM) Selectivity
eNOS/ iNOS/
Compound R R' R" Salt iNOS eNOS nNOS nNOS nNOS

"Data are reprinted from Ref. 46 (O 1998 American Chemical Society).

drocarbon spacer. An odd number of carbons amine. The m i n e may be able to bind in the
in the spacer may provide the optimal hydro- nNOS active site better than in the eNOS ac-
phobic interactions, while keeping the amino tive sites.
acid in the proper position for binding to the Phenyl-2-aminopyridines have been ex-
anionic and cationic sites. The phenyl analogs plored as potential nNOS inhibitors (52).
may be too bulky for binding to the site with These compounds have some selectivity for
the best orientation of the amino acid portion nNOS over eNOS. They point out that the
of the inhibitor. nNOS active site appears to be less sterically
Several nitroarginine dipeptides have been hindered than the eNOS active site. When the
found to be very selective inhibitors of nNOS side-chain in the compound below is quino-
(51).These peptidomimetic agents, below, ap- line, the IC,, values (@ I)inhibition
for NOS
pear to fit much better into the nNOS active are 0.21 nNOS and 0.83 eNOS; for the
site than into the iNOS or eNOS sites. The PhCOCH, side-chain, the values are 0.14
amide side-chain containing compound below nNOS and 0.89 eNOS; for the PhCH,CO
has Ki(a) values as follows: 0.13 nNOS, 25 side-chain the values are 0.14 nNOS and
iNOS, and 200 eNOS; the compound without 0.69 eNOS; for the PhCH,CH2 side-chain
the amide side-chain has Kivalues of 0.54 the values are 0.26 nNOS and 0.45 eNOS,
nNOS, 100 iNOS, and 199 eNOS; the com- demonstrating almost complete loss of iso-
pound without the amide or the carbonyl has form selectivity. For the iBu side-chain the
Ki values of 0.12 nNOS, 39 iNOS, and 314 values are 0.35 nNOS and 0.37 eNOS, dem-
eNOS. Elongation of the m i n e side-chain onstrating no isoform selectivity. For the
tends to decrease potency and isoform selec-
tivity. All of these compounds are very selec-
tive for nNOS. The fact that the amide and
carbonyl can be eliminated with retention of
nNOS inhibitory activity and isoform selectiv-
ity shows that these functionalities, although
not critical to nNOS binding, may be more im-
portant for binding to iNOS and eNOS. In ad-
dition, elimination of the carbonyl converts
the amide nitrogen to a basic, secondary
i
I
p 6 Nitric Oxide Synthase Inhibitors

' Table 11.10 Imidazole Containing Amino Acid Inhibitors of NOSa

K,(rn
Compound iNOS nNOS ENOS
(la) 950 170 500
(lb) 10 2 33
(lc) 35 65 150
(Id) 8 2 50
(le) 40 150 250
(2a) 100 80 50
(2b) 50 100 17
(2c) 120 70 350
"Data are from Ref. 50, used with permission from Elsevier Science.
704 Investigative Agents for Use in Neurodegenerative Conditions

Table 11.11 Pteridine Inhibitors of nNOSa


NH2 R5

A B
Compound R2 R4 R5 R6 R7 G o (P.M)

aDataare from Ref. 53, used with permission (63 1999 American Chemical Society).

iPrNHCOCH, side-chain the values are 0.33 tion, perhaps by increasing affinity for the hy-
nNOS and 0.82 eNOS. Apparently, an aryl or drophobic binding site. Substituents other
carbonyl functionality with sp2 characteris- than hydrogen at R7 may not be beneficial.
tics should be adjacent to the terminal piper- Several imidazoles have been found to
azine to retain isoform selectivity. inhibit NOS, including 1-phenylimidazole,
4-Amino-5,6,7,8-tetrahydropteridinesand 2-phenylimidazole, and 4-phenylimidazole.
2,4-diamino-pteridineshave been synthesized These imidazoles bind heme in NOS and other
and tested as nNOS inhibitors (53). These in- enzymes. A search for isoform-specific inhibi-
hibitors are designed to fitinto the tetrahydro- tors based on an imidazole structure has led to
biopterin site of nNOS (Table 11.11). A bind- the discovery of 1-(trifluoromethylphenyl)im-
ing site model has been proposed for these idazole, N-(4-nitrophenacyl) imidazole, and
compounds. The nitrogen in the 3-position, N-(4-nitrophenylacy1)-2-methyl-imidazole,
the exocyclic nitrogen at the 4-position, and below (54). The nitrophenylacylimidazoles are
M may bind to the heme side-chain. Arg375 selective for nNOS rather than eNOS inhibi-
may bind to the exocyclic nitrogen, R4 and N5. tion. They appear to bind to the tetrahydro-
R6 and R7 may bind to a hydrophobic environ- biopterin site and are competitive inhibitors of
ment made up of Phe470 and Serll2. The tetrahydrobiopterin binding. They are non-
pteridine ring may be involved in 7~ electron competitive inhibitors of arginine binding. It
stacking with Trp457. In general, R2 substitu- appears that electron-withdrawing N-1 sub-
ents other than hydrogen do not enhance ac- stituents enhance activity and nNOS selectiv-
tivity. Perhaps bulky groups in this position ity.
inhibit binding to the heme. Similarly, R5 sub- Some imidazoles are selective inhibitors of
stituents other than hydrogen are not benefi- iNOS and could be useful in the treatment of
cial in nNOS binding, perhaps because of pre- stroke. Polymorphonuclear leukocytes and
vention of binding to Arg375. R6 substituents other inflammatory cells are prominent in the
that are hydrophobic enhance nNOS inhibi- limit area within 24 h or less of ischemia and
6 Nitric Oxide Synthase Inhibitors

inhibitors. The sulfur of the inhibitors may


bind to the heme. Hydrogen bonding may be
possible with the carbonyl oxygen. A hydro-
phobic interaction may be possible with the
propyl or methyl groups of the inhibitors. Of
course, it is not proposed to use antithyroid
drugs in the treatment of neurodegeneration
reperfusion. This inflammatory response might because inhibition of thyroid function would
be attenuated with iNOS inhibitors, and not be recommended in these patients.
might be beneficial to patients. A series of im-
6-Nitrodopamine and 6-nitronorepineph-
idazoles has been found that bind to the heme
rine have been shown to inhibit nNOS with Ki
at the sixth axial position and adopt a
U-shaped conformation in the region of the values of about 50 p M (57). These compounds
arginine active site (55). This binding disrupts appear to be endogenous and are produced by
a protein-protein interaction involving the 7a NOS nitration of dopamine and norepineph-
helix containing Glu371 and inhibits protein rine. It is unclear whether these compounds
dimerization. The crystal structure of the pro- could ever reach sufficient concentrations, un-
tein inhibitor complex has been presented der physiological or disease conditions, to in-
(55).Three inhibitors have been found and are hibit nNOS. The nitrocatecholamines inhibit
shown below. They inhibit iNOS with Ki val- nNOS competitively with respect to arginine
ues of about 1-30 nM and are about 5 times and tetrahydrobiopterin and inhibit dimeriza-
less potent for nNOS inhibition and 1000 tion of the enzyme.
times less potent for eNOS inhibition. Active Suicide inhibitors of NOS are known and
compounds are A: R = H, X = C1; B: R = include w-(1-iminoethyl)-L-ornithine and N43-
COOMe, X = H; and C: R = COEt, X = H. (aminomethyl)benzyl)acetamidine ((58), be-
low). These amidines bind to Glu363 but can-
not donate a proton to the ferric hydroperoxy
intermediate. The hydroperoxy group attacks
and hydroxylates the alpha-meso-heme car-
bon and produces biliverdin Malpha. This
leads to NOS inactivation with loss of biliver-
din from the enzyme. A scheme (below) has
been proposed for other mechanism-based
inhibitors such as N-allyl-L-arginine and p-
monomethyl- L-arginine t h a t involves hy-
droxylation of the guanidino nitrogen, oxida-
tion to produce the nitrosated analog, and
elimination of NO with alkylation of the heme.
These agents are not recommended for use in
Thiouracil antithyroid agents have been patients suffering from neurodegeneration
found to inhibit NOS with modest selectivity because accumulation of abnormal heme deg-
for nNOS inhibition (56). These compounds radation products would be detrimental.
are essentially thiocitrulline analogs and are Isothioureas have been explored as eNOS
competitive inhibitors with respect to arginine inhibitors (59). Bisisothioureas, below, bind to
and tetrahydrobiopterin. 6-Propylthiouracil, the guanidino site of eNOS participating in
6-methyl-2-thiouracil, and S-methylthiouracil hydrogen bonds with Glu363 and Trp358.
were found to be NOS inhibitors with Ki They then rotate into twisted configurations
values of 15, 14, and 60 p M , respectively. to position the second ureido group near the
Dithiouracil, thiobarbituric acid, 5-carbo- heme propionate of the pyrrole D ring for hy-
ethoxythiouracil, 2-mercaptopyridine, 2-mer- drogen bonding. The twisted conformation al-
captothiazoline, 2-mercaptoimidazole, and er- lows the bridge group between the two ureides
gothioneine were found to be poor NOS to bond in nonpolar interactions with Va1338.
Investigative Agents for Use in Neurodegenerative Conditions

The S-ethylthiourea above the H bonds ARL17477 is an nNOS-specific inhibitor. A


with both nitrogens to Glu363 in the active similar compound, BN80933, contains an N-
site. The ethyl and phenyl groups make non- phenyl-thiopheneamidine linked to trolox by a
polar contacts with the protein at Pro336 and piperidine bridge. This compound is even
Val338, respectively. Methylation of either of more bulky than ARL17477 and is also an
the two nitrogens abolishes NOS inhibitory nNOS-specific inhibitor.
activity, demonstrating the importance of hy- Several N-phenylisothioureas have been
drogen bonds with this compound. In addi- shown to be selective nNOS inhibitors (60).
tion, the pocket bordered by Glu363 and The bulk of the S-alkyl substituent is impor-
Trp358 is too narrow to accommodate methyl- tant, with ethyl providing the proper bulk, and
ated nitrogens. H-Bonding in this pocket with smaller or larger groups decreasing nNOS in-
drugs containing N appears to be favored over hibition (Table 11.12). N-Methylation of ei-
either S or 0 . ther isothioruea nitrogen decreases nNOS
Extended chain compounds such as the bis- inhibition. The N-phenyl ring enhances inhi-
isothiourea, below, bind through one isothio- bition. The para substitution with electron-
urea to the chirality-specific pocket of the ar- withdrawing groups decreases iNOS inhibi-
ginine binding site. The molecule extends tion without significantly altering nNOS
along a long access channel that connects from inhibition; the para substitution with elec-
the bulk solvent to the heme and pterin bind- tron-donating groups can decrease nNOS in-
ing sites. The second isothiourea binds to hibition. The bulk of the para substituent is
Glu271 and Asp480. This compound is a com- important with trifluoromethyl providing the
petitive inhibitor of arginine binding and in- optimal bulk and larger groups decreasing in-
hibits electron transfer from the reductase do- hibition. Thepara position of the phenyl ring
main of the enzyme. makes direct contact with the heme propi-
Bulky inhibitors such as ARL17477, below, onates (59). This contact seems to confer iso-
and similar compounds, may bind to the ac- form selectivity.
cess channel because of their bulk. There are Several general comments about NOS in-
amino acid differences between the access hibitors can be made. An inhibitor that inhib-
channels of the isoforms that may be useful in its electron transfer from the reductase or di-
the design of isoform-specific inhibitors. rectly inhibits the reductase domain might

COOH

H
K NH
I
-
NADPH, 02 -NKm
I I
- -'I
citrulline
OH R

heme
--.
heme
6 Nitric Oxide Synthase Inhibitors
f

H
H H
SEt N+H2
CH3S
SCH3

Table 11.12 N-PhenylisothioureaInhibitors of nNOSa

HN A NH-HX

X iNOS ENOS NNOS

-
- - - - - -

"Data adapted from Ref. 60 with permission (63 1997 American Chemical Society).

also inhibit cytochrome P450 reductase and that bind to heme might inhibit cytochrome
similar reductases. This would be detrimental P450 and other heme enzymes, leading to in-
to patients, in that drug metabolism might be hibition of drug metabolism. NOS inhibitors
inhibited by these compounds. NOS inhibitors that inhibit tetrahydrobiopterin binding
708 Investigative Agents for Use in Neurodegenerative Conditions

might inhibit other tetrahydrobiopterin en- 18. A. Y. Sun and J. S. Cheng, Acta Pharmacol.
zymes such as tyrosine hydroxylase. This Sinica, 19, 104-108 (1998).
might lead to drug-induced parkinsonism. 19. M. Banasik and K. Ueda, Mol. Cell. Biochem.,
These concerns will be addressed in future re- 138,185-197 (1994).
search. 20. P. W. Rankin, E. L. Jacobson, R. C. Benjamin, J.
Moss, and M. K. Jacobson, J. Biol. Chem., 264,
4312-4317 (1989).
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CHAPTER TWELVE

Therapeutic and Diagnostic .


Agents for Parkinson's Disease -

JOHN L. NEUMEYER
Ross J. BALDESSARINI
Harvard Medical School
McLean Hospital
Belmont, Massachusetts

School of Pharmacy
The University of North Carolina
1 Chapel Hill, North Carolina

i Contents
1 Introduction, 712
2 Parkinson's Disease. 712
2.1 Pathophysiology, 713
2.2 Etiology, 715
2.2.1 Genetic Factors, 715
2.2.2 Developmental Factors and Oxidation
of Dopamine, 716
2.2.3 Environmental Toxins, 717
2.2.4 Parkinsonism and MPTP, 717
3 Treatments for Parkinson's Disease, 721
3.1 Dopaminergic Treatments, 721
.
3.1.1 L-Dowa Metabolism and Therawv. 721
A " ,

3.1.2 Clinically Used Dopamine D, Receptor


Agonists, 725
3.1.3 Experimental Dopamine D, Receptor
Agonists, 726
3.1.4 Structural Modeling for Dopamine
Agonists, 728
3.1.5 Dopamine-Potentiating Agents, 729
3.1.5.1 Monoamine Oxidase Inhibitors, 729
3.1.5.2 Catechol-0-Methyltransferase
Inhibitors, 731
3.2 Agents Acting on Nondopaminergic Systems,
731
3.2.1 Anticholinergic Agents, 731
3.2.2 Adenosine Antagonists, 733
3.2.3 Glutamate Antagonists, 733
Burger's Medicinal Chemistry and Drug Discovery 3.2.4 Serotonin Agonists, 734
Sixth Edition, Volume 6: Nervous System Agents 4 Diagnostic Agents for Parkinson's Disease, 734
Edited by Donald J. Abraham 5 Future Directions, 736
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 6 Acknowledgments, 736
71 2 Therapeutic and Diagnostic Agents for Parkinson's Disease

1 INTRODUCTION Some cases also show dyscontrol of autonomic


functions mediated by the potentially affected
Parkinson's disease (PD) was first described central noradrenergic sympathetic nervous
by British physician James Parkinson in 1817 system, with losses of norepinephrine neurons
as the "shaking palsy" (1). One of the most of the locus coeruleus (4).
. . There can also be
common neurodegenerative disorders, PD is variable late neuropsychiatric disturbances
characterized by tremor, disturbances of pos- that sometimes progress to a debilitating state
ture, and paucity of volitional movement. The and eventual fatality (2, 5, 6). Dementia is
primary etiology of PD remains unknown, but about six times more frequent in elderly pa-
the neuropathology is marked by progressive tients with PD than without it (5). Major de-
degeneration of monoamine-producing neu- pression also occurs in PD, and psychosis is
rons, particularly the dopamine (DA)-contain- sometimes associated with DA agonist ther-
ing neurons of the nigrostriatal system pro- apy (5-7). Mortality is 2-5-times higher
jecting from cell bodies in the midbrain among PD patients than in age-matched non-
substantia nigra to the extrapyramidal motor affected persons, and life expectancy is greatly
control centers of the caudate-putamen of the reduced (8).
basal ganglia. Modern treatment has been Parkinsonism is a syndrome that repre-
based on rational attempts to replace lost DA sents the clinical outcome of etiologically di-
by giving large doses of its immediate meta- verse conditions. These can include idiopathic
bolic precursor, L-dopa, or substituting for lost degenerative disorders (including idiopathic
DA with synthetic agonists. However, the Lewy body dementia and multiple system at-
pharmacotherapy of the disorder remains pal- rophy with dysautonomia), infections (includ-
liative, and limited in both effectiveness and ing postencephalitic parkinsonism of von
tolerability, especially late in the progression Economo's encephalitis lethargica arising
of the illness. Improved symptomatic and from the influenza e~idemicsof 1917 and fol-
hoped-for curative pharmacotherapy awaits lowing years), effects of varied neurotoxins
better understanding of the fundamental (including heavy metals, certain phenylpyri-
pathogenesis of PD. This chapter summarizes dines, and 2-amino-3-[methylaminol-pro-
the medicinal chemistry and salient neuro- panoic acid [BMAA]), and as adverse effects of
pharmacology of currently available antipar- certain centrally active drugs (particularly
kinsonism drugs and discusses ligands emerg- neuroleptics and other DA D, receptor antag-
ing for use in the neuroradiological diagnosis onists or DA-depleting agents) (9, 10). How-
of PD. ever, the designation PD is currently applied
to the idiopathic disorder, to distinguish it
from other parkinsonian syndromes.
2 PARKINSON'S DISEASE Neuropathologically, PD is a slowly pro-
gressive neurodegenerative disorder of un-
PD affects about 1%of the general population, known cause that selectively affects the extra-
or more than one million persons in North pyramidal DA nigrostriatal pathway. The
America alone (2). Typically, the disorder pre- disease is characterized by gradual destruc-
sents in mid- or late life, with onset ranging tion of DA-containing neurons in the pars
from 40 to 80 years, and most likely at 55-65 compacta component of the pigmented mid-
years; cases of early onset before age 40 are brain substantia nigra, leading to a deficiency
less common, and rare juvenile cases have also of the neurotransmitter in DA nerve termi-
been reported (3). PD presents as a classic tet- nals of the corpus striatum, particularly in the
rad of signs: (1)resting tremor that improves putamen (11). Degenerative changes in the
with voluntary activity, (2) bradykinesia or pigmented nuclei of the noradrenergic locus
slowness of initiating voluntary movements, coeruleus region of the midbrain-pons also are
(3)rigidity of muscle and joint motility, and (4) typical, and remaining catecholamine cells
postural disturbances including falls. These typically acquire fibrillar intraneuronal inclu-
signs vary in their early intensity, combina- sions (Lewy bodies), whose development and
tions, and progression among individuals (2). significance remain unclear (5, 12). The dis-
_
covery of DA deficiency in postmortem brain proteins and intraneuronal molecular compo-
tissue of PD patients a half-century ago, with nents of effector mechanisms, including
then-emerging knowledge of DA biosynthesis adenylyl cyclase and phospholipase C (15, 16).-
and metabolism, led to the rational prediction The inhibitory spiny GABAergic neurons
[ that L-dopa (I),the immediate metabolic pre- send projections by two major pathways
t
"
cursor of DA (2), would be an effective pallia- whose net effect appears to exert balanced reg-
j tive agent in PD (13,14). ulatory influences on the ascending thalamos
cortical circuits that mediate control of volun-
: 2.1 Pathophysiology
tary movement through the descending
The "basal ganglia" of the brain consist of five corticospinal projections to the spinal ventral- -
interconnected subcortical nuclei that span horn motoneurons that innervate skeletal
the telencephalon (forebrain), diencephalon, muscles. A widely accepted, but tentative
and mesencephalon (midbrain). These nuclei model of the basic anatomical connections of
include the corpus neostriatum (caudate and this complex is summarized schematically in
putamen), globus pallidus, thalamus, subtha- Fig. 12.1 (12, 15, 17-20).
lamic nucleus, and midbrain substantia nigra The output pathways from neostriatum are
(pars compacta and pars reticulata). Medium- usually considered to include a direct or stria-
sized spiny neurons that produce the major tonigral pathway consisting of GABAergic
inhibitory amino acid transmitter y-amino- neurons that project directly to the pars re-
butyric acid (GABA) are principal neurons in ticulata of the substantia nigra, as well as a
the caudate-putamen. They receive much of prominent projection to the internal (medial)
the heavy input from descending corticostria- portion of the globus pallidus in human brain.
tal projections mediated by the principal ex- Another indirect or striatopallidal pathway in-
citatory amino acid neurotransmitter glu- volves efferent GABAergic projections from
tamic acid, as well as a prominent dopaminer- striatum that communicate through the ex-
gic input from the midbrain substantia nigra ternal (lateral) globus pallidus to the subtha-
zona compacta. The GABA-producing inhihi- lamic nucleus. This inhibitory influence on the
tory neurons, as well as intrinsic acetylcho- subthalamic nucleus is balanced against an
line-producing interneurons, of the caudate- excitatory glutamatergic input from cerebral
putamen respond to DA input through several cortex. In turn, the subthalamic nucleus ex-
DA receptors. erts an excitatory glutamatergic influence on
DA receptors are grouped into excitatory the substantia nigra reticulata.
Dl-type (Dl and much less prevalent D, recep- Modified by " both of these direct and indi-

tors), and inhibitory D,-type (D, with splice rect descending influences, the internal (me-
variants, and less abundant D, and D,) sub- dial) globus pallidus and pars reticulata send
families of membrane proteins. These pep- inhibitory GABAergic projections to modulate
tides, composed of 387-477 amino acids, are activity of ascending thalamic neurons, partic-
typical of the superfamily of GTP-binding pro- ularly in the ventral (mainly anterior and lat-
tein (G-protein)-associated membrane pro- eral) thalamic nuclei. The thalamic nuclei
teins that include most monoaminergic recep- project ascending glutamatergic excitatory ef-
tors and other physiologically important f e r e n t ~to motor cerebral cortex, thus exerting
membrane proteins. Their structure is charac- a major regulatory influence over the descend-
terized by seven relatively hydrophobic, puta- ing corticospinal motor output pathway that
tive transmembrane regions linked by four controls the cholinergic spinal ventral motor
extracellular and four intracellular loop seg- horn cells innervating skeletal muscle (18).
ments, starting from an extracellular amino DA modulates the activity of local and ef-
terminus, and extending to an intracytoplasmic ferent inhibitory GABAergic neurons as well
carboxy end of the receptor polypeptide chain as acetylcholinergic interneurons of caudate-
(15, 16). The third intracellular loop and car- putamen (12, 15, 17). Excitatory DA Dl-type
boxy-terminus segment vary most among Dl receptors, together with the neuropeptides sub-
and D, receptor subtypes, and probably inter- stance P and dynorphin, are mainly expressed
act critically with excitatory or inhibitory G- by the striatonigral GABAergic neurons in the
Therapeutic and Diagnostic Agents for Parkinson's Diseasc

Circuitry of the Basal Ganglia

Glu
(+)

Glu
(+I

GABA GABA

Figure 12.1. Circuitry of the basal ganglia. Shown are major relationships to the neostriatum
(caudate nucleus-putamen complex) with its prominent dopaminergic innervation (particularly of
putamen in man) from the midbrain substantia nigra zona compacta (SNc), as well as descending
control by corticostriatal glutamatergic projections. Dopamine exerts excitatory effects through D,
receptors on efferent medium spiny neurons that are GABAergic and inhibitory to the substantia
zona reticulata (SNr) and the internal portion of the globus pallidus (GPi), thus limiting a secondary
inhibitory influence of nigrothalamic and pallidothalamic GABA neurons (that also express sub-
stance P [SP] and dynorphin [DYN] peptides) to facilitate the ascending excitatory glutamatergic
(Glu) thalamocortical circuits. This short outflow loop from the neostriatum is paralleled by a long
loop that involves D, dopamine receptors inhibitory to generally excitatory acetylcholinergic (ACh)
interneurons (which are inhibited by GABA neurons) as well as to GABA efferents to the external
portion of globus pallidus (GPe) and co-express enkephalins (ENK). The globus projects GABAergic
neurons that tonically inhibit the excitatory glutamatergic neurons of the subthalamic nucleus
(STN)that stimulate an inhibitory influence of nigra, internal globus pallidus, and pedunculopontine
nucleus on the thalamus (including its ventral lateral nucleus) to yield a net reduction of thalamo-
cortical activation. In Parkinson's disease (PD) the nigrostriatal dopamine projections degenerate
and dopaminergic influences in the neostriatum are initially compromised and eventually lost. Loss
of dopamine in PD leads to reduced influences through both the direct and indirect pathways to result
in a net decrease in thalamocortical stimulation, with clinical bradykinesia. Excessive dopaminergic
stimulation encountered in the treatment of PD increases thalamocortical activation, with clinical
dyskinesias. This traditional model remains tentative and incomplete, and does not include simulta-
neous Dl and D, influences that may occur on some GABAergic neurons in neostriatum. More
inclusive models have been proposed (9).
2 Parkinson's Disease

direct output pathway. In contrast, inhibitory nal development of effective therapeutic and
DA D,-type DA receptors, along with the neu- prophylactic pharmacotherapies. Several po-
ropeptide enkephalin, are predominantly local- tentially convergent hypotheses have been -
ized to striatopallidal GABAergic efferents of proposed regarding the cause of PD. They con-
the indirect output pathway. These relation- sider: (1) genetic factors; (2) neurodevelop-
ships lead to a complex role for DA in the basal mental factors associated with advancing age,
ganglia. By stimulating excitatory Dl recep- including oxidation of DA and dysfunction of '
tors, DA appears to have a net facilitatory ef- oxidative metabolism; and (3) effects of envi-
fect on the direct GABAergic pathway to inter- ronmental or endogenous neurotoxins.
nal (medial) globus pallidus and midbrain, Several neurodegenerative disorders af- -
which can diminish their inhibitory connec- fecting motility are genetically determined.
tions to thalamus, to increase ascending exci- Striking progress in defining the genetic basis
tatory thalamocortical activity. In contrast, of Huntington's chorea greatly increased in-
activation of inhibitory D, receptors in the in- terest in genetic contributions to other neuro-
direct pathway inhibits GABAergic neurons degenerative disorders, including PD (21). Ep-
projecting to external (lateral) globus pallidus, idemiological studies have found that, apart
and reduces its inhibitory influence on the from advancing age, a family history of PD is a
subthalamic nucleus. These effects result in a predictor of increased risk of the disorder, sug-
net disinhibition of an excitatory glutamater- gesting a genetic contribution (22). Recent
gic link from the subthalamic nucleus to mid- studies strongly indicate a genetic contribu-
brain that increases nigral GABAergic inhibi- tion in the disorder, although the majority of
tion of thalamus. The outcome is to decrease cases of PD are considered sporadic, given that
thalamocortical stimulation, opposite to the genetic factors account for only a minority of
effect initiated by DA through the direct path- cases, predominantly those of early onset (23,
way (Fig. 12.1). 24).
In sum, the overall effect of DA is to facili- A specific genetic hypothesis has consid-
tate cortical excitation by thalamocortical ered mutation of the gene for the protein
glutamatergic projections through the direct a-synuclein in an autosomal dominant form of
pathway, but to decrease thalamocortical familial PD. This molecule is a highly con-
stimulation through the indirect pathway. Ac- served, relatively abundant, 140-amino acid.
cordingly, in PD striatal DA deficiency alters polypeptide of unknown function that is ex-
the modulation of excitatory outflow from pressed mainly in presynaptic nerve terminals
ventral thalamus to motor cortex (9, 12, 16). in the brain. It is controlled by a gene in the
Presumably, a balance of Dl- and D,-mediated long-arm (4q) of human chromosome 4 (25).
dopaminergic function would be optimal in re- The gene for a-synuclein can be expressed as
storing the functional losses that follow de- distinct structural variants that have been as-
generation of the DA-producingneurons. Neuro- sociated with some pedigrees involving PD
chemically, striatal DA deficiency seems to (26, 27), but not in a larger number of other
8ccountfor the major motor symptomsof PD, par- families (28, 29) or in sporadic cases (27).
ticularly bradykinesia. The mainstay of phar- Other genetic findings have implicated muta-
macological treatment (8) continues to be re- tions in the gene coding for ubiquitin carboxy-
placement therapy with the a-amino acid, L-3,4- terminal hydrolase in another autosomal
dihydroxyphenylalanjne (L-dopa), the immediate dominant form of PD, and other genetic fac-
biochemical precursor of DA, discussed below, tors associated with autosomal recessive
which should produce nearly physiological ago- forms of the disorder (30). However, these spe-
nism of both D, and D, DA receptors. cific genetically based disorders, collectively,
do not account for the great majority of evi-
2.2 Etiology dently sporadic cases of PD.
Nevertheless, a large proportion of the un-
2.2.1 Genetic Factors. Although the neu- common cases of early-onset PD appear to be
ropathology of PD is well defined, the primary inherited by a mechanism involving abnormal
cause remains unknown, thus limiting ratio- molecular processing of intracellular neuronal
716 Therapeutic and Diagnostic Agents for Parkinson's Disease

proteins by the process of conjugation with the 2.2.2 Developmental Factors and Oxidation
protein ubiquitin required for the orderly deg- of Dopamine. DA itself has also been impli-
radation of intracellular proteins by proteases cated in the disease process of PD through pro-
(23, 24). A specific autosomal dominant ge- duction of chemically reactive products of
netic defect produces a mutant form of the oxidation, including reactive quinones, perox-
protein parkin. Normally, parkin enables ides, and free radicals (33). Toxic effects of
ubiquitin ligase-mediated polyubiquitination these compounds may contribute to the appar-
of an 0-glycosylatedform (aSP22) of the pro- ently normal progressive loss of DA neurons
tein a-synuclein. Because polyubiquitin conju- with maturation and aging, at the rate of
gation is required for normal degradation of about 13%/decade(36,37). Clinical symptoms
a-synuclein by proteasomes, ubiquitin-uncon-
of PD emerge as losses of DA neurons exceed
jugated aSP22 accumulates in neurons, possi-
60-70% (38). However, the significance of this
bly contributing to their degeneration (31).It
trend toward spontaneous, possibly geneti-
remains unclear why such mechanisms might
occur selectively in DA neurons, or whether cally programmed (apoptosis) or degenerative,
they pertain to the more prevalent, nonfarnil- but evidently normal loss of DA neurons with
ial forms of PD. The neuropathology of spon- aging for the pathoetiology of PD is not clear
taneous PD, in contrast to the less common (39,40).
familial forms, is characterized by prominent Among products of the metabolism of DA,
accumulation of Lewy bodies rich in polyubiq- the monoamine oxidase (MA0)-catalyzedoxida-
uitnated aSP22 and other proteins, presum- tion of this and other monoamine neurotrans-
ably through insufficient degradation by pro- mitters generates hydrogen peroxide (Equation
teases that remains unexplained. 1 of Fig. 12.2). The peroxide can undergo a redox
The proposal that an increase of a-synuclein reaction with superoxide in the Haber-Weiss re-
may be responsible for PD has inspired new action (41) to form the extremely cytotoxic free
laboratory models of PD involving transgenic hydroxy ( H a ) radical (Equation 2 of Fig. 12.2).
mice (32) or the fruit fly Drosophila (33) made Moreover, auto-oxidation of DA can yield the
to express the human wild-type a-synuclein correspondingcytotoxic quinone (Fig. 12.2) (42).
and recreate certain features of PD. In both Manganese ion can catalyze oxidation of DA,
models, cytoplasmic inclusions of a-synuclein and the resulting quinones have been implicated
resembling Lewy bodies were detected, but in manganese neurotoxicity, an environmen-
these were fibrillar in structure, as in clinical tally determined form of parkinsonism (43). Ad-
PD, only in the fruit fly model. Mechanisms by ditional evidence for a role of oxidative stress in
which abnormal a-synuclein oligomers might PD includes increased levels of oxidized by-prod-
selectively cause dysfunction and death of DA ucts of nucleic acids such as 8-hydroxy-
neurons remain unclear (34). Possibilities guanosine in cerebrospinal fluid or plasma (44).
considered include abnormal cellular distribu- Auto-oxidation of catecholamines also
tion of DA, with an accumulation of toxic by- leads to formation of the polymeric pigment
products, and an effect of DA on a-synuclein neuromelanin that increases with age and is
oligomerization (31). Support for the second responsible for the dark coloration of DA-pro-
possibility arose from recent screening of a ducing cells in the substantia nigra and the
large number of compounds for effects on norepinephrine neurons of the locus caeruleus
a-synuclein fibrilization; 151169 compounds (42). A physiological role for this polymer is
inhibited the process, and 14 of these were not established, and there is no evidence to
catechols, including L-dopa and DA (35). DA support its involvement either in normal loss
underwent oxidative ligation to a-synuclein of DA neurons with aging or in the pathophys-
and selectively inhibited the conversion of pro- iology of PD.
tofibrils to fibrils, causing accumulation of the Conceivably, the symptoms of PD may result
a-synuclein protofibril. These findings suggest from two processes: a specific disease-related in-
a basis for DA-neuron selectivity and may sult combined with changes attributed to nor-
open a novel line for developing novel thera- mal aging that may include accumulation of
peutic approaches to PD (35). endogenous neurotoxins. Such a two-factor
2 Parkinson's Disease 717

\ /
H o ~ c H 2 c H 2 N H +2O2 + H20 - HO CH2CH0 + NH3 + H202 Equation 1

HO HO
Dopamine 'x,

Quinone -

H202+ [OF] - 02 + [OH- + OH'] Equation 2

Figure 12.2. Toxic derivatives of dopamine. These include hydrogen peroxide, the free hydroxy
radical, and the quinone.

pathophysiology might explain why PD is usu- ronmental or endogenous sources, including


ally a progressive disorder of late onset (45). DA. Compounds present in cigarette smoke or
their metabolites might also inhibit MAO, the
2.2.3 Environmental Toxins. Even in disor- main enzyme responsible for metabolism of
ders with strong familial association, a role of monoamine neurotransmitters including DA,
shared environmental exposures and other in- producing hydrogen peroxide in the process,
directly related factors must be considered. as noted above (53).
Studies of familial but idiopathic forms of PD- Overall, neither neurotoxin nor genetic
like neurodegenerative disorders in the West- models account for the majority of apparently
ern Pacific do not support genetic or infectious spontaneous or sporadic cases of PD (48).
etiologies, but leave open the possibility of Nevertheless, the discovery that a specific
toxic factors (46,471. pyridine, MPTP, can produce a severe, acute
There is some evidence to suggest that envi- parkinson syndrome in humans and some lab-
ronmental toxins may cause some types of PD, oratory species stimulated unprecedented in-
or at least, parkinsonism syndromes (48). This terest in both neurotoxic hypotheses concern-
hypothesis seems consistent with the fad that ing the etiology of PD and in developing a very
PD is now the second most common degenera- useful experimental model for the disorder
tive neuropsychiatricdisorder (after the demen- that has supported a great deal of recent re-
tias), in contrast to its evident rarity in previous search aimed at developing innovative treat-
centuries (48). A striking example of a probably ments for the disease. This compelling model
neurotoxic disorder is the PD-like syndrome of a neurotoxin-induced form of the parkin-
characterized by tremor and bradykinesia as sonism syndrome is described next.
well as dystonia and psychiatric disturbances
found among manganese miners in the Andes 2.2.4 Parkinsonism and MPTP. The ter-
(49).Another example involves a correlation be- tiary amine N-methyl-4-phenyl-1,2,3,6-tetra-
tween a remarkably high incidence of PD and hydropyridine (MPTP, 3, Fig. 12.3) is a potent
use of certain pesticidesin an agricultural region and selective neurotoxin to DA-producing
of Quebec (50). cells of the midbrain (51,54). MPTP exposure
One of the best characterized epidemiolog- induces a form of arki ins on ism in humans
A

ical findings in PD is its lower incidence in and monkeys that is similar in neuropathology
cigarette smokers than in nonsmokers (51, and motor abnormalities to idiopathic PD (55-
52). Chemical components of cigarette smoke, 58). Its significance emerged from a serendip-
including nicotine, may protect against an en- itous series of events. In 1977, a young college
vironmental or endogenous toxin relevant to student developed acute parkinsonian symp-
the neuropathology of PD. For example, car- toms with severe rigidity, bradykinesia, and
bon monoxide in cigarette smoke may detoxify mutism (58). The abrupt and early onset of
potentially neurotoxic free radicals from envi- symptoms was so atypical that the patient ini-
718 Therapeutic and Diagnostic Agents for Parkinson's Disease

tially was thought to have catatonic schizo- electron oxidation of MPTP at the allylic
phrenia. Subsequent diagnosis of parkinson- a-carbon, to give the intermediate, l-methyl-
ism was substantiated by his therapeutic 4-phenyl-2,3-dihydropyridinium species
response to L-dopa. When he admitted having (MPDPt, 7; see Fig. 12.3). This unstable
synthesized and used several illicit drugs, his charged substance undergoes further two-
psychiatrist visited his home and collected electron oxidation to the more stable, reactive
glassware that had been used for chemical species 1-methyl-4-phenylpyridinium(MPP+,
syntheses. 8 ) by auto-oxidation, disproportionation, and
Chemical analysis of the glassware re- enzyme-catalyzed mechanisms (59- 61). In-
vealed several pyridines, including MPTP (3), hibitors of MAO-B can prevent MPTP-in-
formed as by-products in synthesizing MPPP duced parkinsonism in primates (62), further
(N-methyl-4-propionoxy-4-phenylpiperidine), supporting the currently accepted view that
(4) and also known as "designer heroin" or MPP (8)is probably the major toxic metabo-
f

"synthetic heroin." MPPP is also the N-des- lite of MPTP (3)responsible for destruction of
methyl analog of a structurally similar nar- DA neurons, although a role for the unstable
cotic analgesic, alphaprodine (5), and is the dihydropyridinium species MPDP+ (7) has
reverse ester of the analgesic meperidine (De- not been ruled out.
merol, 6). It was unclear initially whether The relationship of MA0 and MPTP has
MPTP or other constituents of the injected neurobiological relevance beyond MPTP neu-
mixture accounted for the neurotoxicity. The rotoxicity. Types A and B MA0 catalyze the
patient continued to abuse drugs, died of an a-carbon oxidative deamination of mono-
overdose, and autopsy revealed degeneration m i n e neurotransmitters and other aromatic
of his substantia nigra, but without the Lewy amines. These genetically dissimilar isozymes
bodies typical of the neuropathology of idio- show differential selectivity for specific sub-
pathic PD (58). strates and inhibitors (63). Most intraneuro-
Other persons exposed to preparations of nal MA0 is mitochondrial and type A, and ox-
MPTP (3) or MPPP (4) were later identified idizes primary amines to aldehydes, which are
after presenting with similar acute parkinso- then converted by aldehyde reductases to al-
nian symptoms. In several patients, MPTP cohols or carboxylic acids, including dihy-
was the principal or sole compound impli- droxyphenylatic acid (DOPAC) from DA. Ad-
cated, supporting the hypothesis that MPTP ditional 3-0-methylation yields the major final
is a parkinsonism-producing neurotoxin. Al- human metabolite of DA, homovanillic acid
though more than 400 people are known to (HVA; see Fig. 12.4).
have self-administered MPTP, only a few have In contrast, MAO-B is found in other cell
developed parkinsonian symptoms, though types, including glia in the nervous system.
the incidence may increase as they age. Both Oxidation of the heterocyclic tertiary-amine
the clinical and neuropathological features of MPTP by MAO-B is an unprecedented reac-
MPTP-induced parkinsonism resemble idio- tion that suggests a novel physiological role
pathic PD more closely than any other model for this enzyme. For example, MAO-B may
elicited by toxins, metals, viruses, genetic ma- regulate the oxidation state of pyridine sys-
nipulation, or other means. Accordingly, un- tems, such as those involvingnucleic acids and
derstanding the molecular pathophysiology of NADH (63).In turn, oxidative systems are im-
MPTP neurotoxicity was aggressively pur- plicated in MPTP neurotoxicity (see below).
sued to clarify neurodegenerative mecha- Interesting, too, is evidence that cigarette
nisms that might also occur in idiopathic PD. smokers have been found to have 40% less
The chemical structure of MPTP suggests postmortem brain MAO-B activity than non-
that the compound should be relatively inert smokers or former smokers (64), as well as a
chemically, given that no reactive functional lower incidence of PD (64, 65). That cigarette
group is present, and that MPTP might un- smokers reportedly have depressed MAO-B
dergo metabolic activation to a more reactive activity (64) may be a potential link to their
derivative. Researchers discovered that brain decreased risk of PD (65). Nicotine is not a
MAO-B (mainly in glial cells) catalyzes a two- potent inhibitor of MAO, and may even in-
2 Parkinson's Disease

I
CH3
MPTP MPPP Alphaprodine Meperidine
(designer heroin) (Nisentil) (Demerol)
(5) (6)

MAO-B

II
CH3
MPPP MPTP
deprenyl
(4) inhibit

Nigrostriatal
cell death *
metabolic changes - uptake
catecholamine
neurons
I
0 N
I
CH3

A I MPP'

\ inhibits )

Figure 12.3. Phenylpiperidine analgesics and metabolic activation of MPTP. In efforts to synthe-
size the meperidine-like analgesic agent MPPP ("designer heroin,") (4), MPTP (3)can be formed. It
is converted selectively by monoamine oxidase type B (MAO-B, inhibited by agents including depre-
nyl (selegiline)and pargyline to MPDP (7),and thence to MPP+ (8)the proposed toxic species that
f

accumulated in dopamine neurons to result in disruption of their cellular respiration and death.
nydroxylase
I T
OH
Me0
OH
NH2 L-Tyrosine 3-Methoxy-4-hydroxy

COOH
OH

HO 3-Methoxy-4-hydroxy
phenylpyruvic acid
OH HO
111
L .l

L-3,4-dihydroxyphenylananine OH
3,4-Dihydroxyphenylpyruvicacid
(L-dopa) ,CHO

OH
3,4-dihydroxyphenylacetaldehyde HO
NH2
3,4-Dihydroxy \
phenylacetic acid I

PI
Dopamine
(3,4-Dihydroxyphenethylamine) OH
3-Methoxytyramine (MTA) OH
NHCH3 Homovanillic acid (HVA)
I
(3-Methoxy-
4-hydroxyphenylacetic acid)

OH

8
Epinephrine
NH2
I

/
HO
OH

Norepinephrine OH Vanillylmandelic acid (VMA)


3-0-Methylnoradrenaline (Normetanephrine)

Figure 12.4. Pathways in the metabolism o f L-dopa (1)and i t s major decarboxylated product dopa-
mine (2). Major (heavy arrows) and minor (light arrows) reactions are indicated. AD, aldehyde
dehydrogenase; AAD, aromatic L-amino acid decarboxylase; COMT, catechol-0-methyltransferase;
DH, dopamine P-hydroxylase; MAO, monoamine oxidase; PNMT, phenylethanolamine-N-methyl-
transferase.
3 Treatments for Parkinson's Disease

crease MPTP neurotoxicity (66). Other com- critical components of most theories of nigral
pounds in cigarette smoke, however, do in- cell degeneration in PD (8). Moreover, discov-
hibit MA0 and cigarette smoke protects ery of the selective ability of MPTP to induce -
against MPTP-induced depletion of striatal nigral cell death has stimulated broad interest .
DA in mice (67). in identifying potential environmental or en-
Extensive investigation indicates that ni- dogenous compounds as potential causative
grostriatal degenerative properties of MPTP agents in PD, even though there is no evidence '
are mediated by the MAO-B-derived metabo- that MPTP itself is involved in idiopathic PD.
lite MPP+ (8). First, MPTP (3) binds selec- Another example of a relevant toxin effect
tively to MAO-B, which is highly concentrated is evidence that chronic, systemic inhibition of -
in glial cells in human substantia nigra and complex I by the lipophilic pesticide rotenone
corpus striatum (681, and is oxidized to MPTP causes highly selective degeneration of nigro-
(3)to MPDP+ (7).Several factors may account striatal DA neurons that can produce hypo-
for selective damage of nigrostriatal DA neu- kinesia and rigidity, as well as accumulation of
rons by MPTP (69; Fig. 12.3). Notably the fibrillar cytoplasmic inclusions that contain
MPP+ (3) produced from MPTP (3) is selec- ubiquitin and a-synuclein (75). These findings
tively accumulated by DA transporters into ni- lend additional support to the view that envi-
gral DA cells and striatal DA nerve terminals ronmental toxic factors may contribute to risk
(69). Within the DA nigral cells, MPP+ binds of PD.
to neuromelanin and may be gradually re-
leased in a depot-like fashion, maintaining
3 TREATMENTS FOR PARKINSON'S
toxic intracellular concentrations that inhibit
DISEASE
mitochondrial respiration in DA neurons.
MPP can also displace DA from presynaptic
f

3.1 Dopaminergic Treatments


vesicles into the cytoplasm, and oxidative by-
products of the DA displaced may contribute Available pharmacotherapy for PD continues
further to degeneration of DA neurons. An- to be palliative or symptomatic, involving par-
other critical mechanism is that MPP con-f

tial compensation the DA deficiency in neo-


centrates in neuronal mitochondria, where it striatum, usually by direct stimulation of DA
selectively inhibits complex I of the electron receptors, or by enhancing its synthesis or de-.
transport chain, inhibiting NADH oxidation creasing its catabolism. No treatment has
and eventually depleting the nigrostriatal cell been proved to stop or even slow the progres-
of ATP (70, 71). Depletion of ATP is probably sive neurodegeneration in PD (11, 76). How-
the main mechanism of nigrostriatal cell death ever, evidence of a lesser rate of loss of DA
induced by MPP' derived from MPTP (72). neurons has recently been reported during 4
The serendipitous discovery and subse- years of treatment with the direct DA agonist
quent scientific investigation of the mecha- pramipexole (see 1 7 in Fig. 12.5) compared to
nism of parkinsonism produced by MPTP L-dopa, which are discussed in the following
greatly stimulated study of the p&hogenesis sections (77). Encouraged by the discovery of
of idiopathic PD, and drew specific attention parkinsonism produced by MPTP, and of the
to intraneuronal oxidative metabolism. One ability of MAO-B inhibitors to prevent it, se-
result is growing evidence for a functional de- lective MAO-B inhibitors or antioxidants were
fect in the mitochondrial respiratory biochem- hypothesized to slow progression of idiopathic
istry in idiopathic PD, including a specific de- PD. Clinical evidence, however, has not been
ficiency of NADH-coenzyme Q1 reductase, encouraging regarding the effectiveness of
reflected in a 30-40% lower mitochondrial such treatments nor for their ability to limit
complex I activity in the substantia nigra of the progression of idiopathic PD (11,78, 79).
postmortem brains of PD patients compared
to normal controls (73, 74). In general, mito- 3.1.1 L-Dopa Metabolism and Therapy.
chondrial dysfunction and oxidative metabo- Nearly 40 years after its introduction, levo-
lism (including oxidation of DA to electro- dopa or L-dopa (1; Fig. 12.4) remains an effec-
philic quinone-type species; see Fig. 12.2) are tive pharmacotherapy in PD (8,11,13,80,81).
Therapeutic and Diagnostic Agents for Parkinson's Disease

Brornocriptine (Parlodel) Pergolide (Permax)


(11) (12)

Cabergoline (Dostinex) (14a) Lergotrile, R = CH2CN, X = CI


(13) (14b) Pergolide, R = CH2SCH3,X = H

Lisuride Ropinirole (Requip)


(15) (16)

Pramipexole (Mirapex)
(17 )

Figure 12.5. Representative D, partial agonists.


3 Treatments for Parkinson's Disease

Piribedil
(18)

(20) Apomorphine, R = CH3


(21) R(-) N-mpropylnorapomorphine (NPA),
R = nC3H7

Figure 12.5. (Continued.)

Despite controversy regarding long-term effi- example of a rationally predicted and logically
cacy, adverse effects, and even potential neu- pursued clinical treatment in a neurological
rotoxicity of this amino acid precursor of DA, disorder, based on neurochemical pathology
most PD patients derive a substantial benefit and basic pharmacological theory (13,141.The
from L-dopa throughout their illness. More- effectiveness of L-dopa treatment requires its
over, L-dopa increases life expectancy among penetration into the central nervous system
patients with PD, particularly if instituted (CNS) and local decarboxylation to DA. DA
early in the course of PD (82). does not cross the blood-brain diffusion bar-
In 1960 Ehringer and Hornykiewicz as- rier because its amino moiety is protonated
sayed DA in the brains of patients dying with under physiological conditions (pK, 10.61,
PD and found that DA levels in the corpora making it excessively hydrophilic (86). How-
striata of many of these patients averaged only ever, its precursor amino acid L-dopa is less
20% of normal (83). The signs of illness in PD basic (pK, 8.72) and polar at physiological pH,
patients resembled behavioral changes in rats and more able to penetrate the CNS, in part
treated with reserpine or other amine-deplet- facilitated by transport into brain with other
ing agents. These findings led Birkmeyer and aromatic and neutral aliphatic amino acids
Hornykiewicz to administer high oral doses of (86-88).
racemic dopa to PD patients in Vienna in 1960 L-Dopa is normally a trace intermediary
(84).Subsequent clinical trials led by Barbeau metabolite in the biosynthesis of catechol-
in Montreal in the early 1960s and by Cotzias amines, formed from L-tyrosinein a rate-lim-
in New York in the late 1960s confirmed this iting hydroxylation step by tyrosine hydroxy-
effect of racemic dopa (85). Barbeau in Mon- lase, a phosphorylation-activated cytoplasmic
treal, and later Cotzias, also demonstrated the mono-oxygenase. L-Dopa is readily decar-
greater potency and safety of the physiological boxyated by the cytoplasmic enzyme L-aro-
levo enantiomer (80,81). matic amino acid decarboxylase ("dopa decar-
Development of L-dopa (1;Larodopa; Fig. boxylase") to form DA (2). The effects
12.4) as a therapeutic agent in PD is a rare observed after systemic administration of L-
724 Therapeutic and Diagnostic Agents for Parkinson's Disease

dopa have been attributed to its peripheral creasing decarboxylase activity, with more
and cerebral metabolites, mainly DA, with peripheral conversion of the amino acid to DA
much less conversion to norepinephrine by
0-hydroxylation, or epinephrine formed by N-
-
to make less L - ~ O available
D ~ to the CNS. How-
ever, blockade of peripheral decarboxylation
methylation of norepinephrine by phenyleth- with carbidopa minimizes this effect of
anolamine-N-methyltransferase(86, 87) (Fig. pyridoxine.
12.4). A small amount of L-dopa is O-methyl- DA itself is relatively rapidly metabolized
ated to L-3-0-methyldopa (L-3-methoxyty- to its principal inactive excretion products of
rosine), which accumulates in the CNS be- MA0 (largely by MAO-A in mitochondria of
cause of its long half-life. However, most aminergic nerve terminals) and by extraneu-
exogenous L-dopa is rapidly decarboxyated to ronal catechol-0-methyltransferase (COMT).
DA in peripheral tissues, including liver, Tissue concentrations of the methyl-donor co-
heart, lung, and kidney. Because only about factor of methylpherases, S-adenosyl-L-methi-
1%of an administered dose reaches the brain, onine (SAMe), can be depleted with large
L-dopa, by itself, has very limited dose effec- doses of L-dopa (90). The main by-products of
tiveness (89). In humans, appreciable quanti- DA are deaminated 3,4-dihydroxyphenylac-
ties of L-dopa enter the brain only when ad- etic acid (DOPAC)and deaminated, 3-0-meth-
ministered by itself in doses (3-6 g daily) high ylated homovanillic acid (HVA, 3-methoxy-4-
enough to overcome losses caused by periph- hydroxyphenylacetic acid; see Fig. 12.4).
eral metabolism. A common adverse effect of L-dopa therapy
Inhibition of peripheral decarboxylase ac- is nausea and vomiting, possibly because of a
tivity by coadministration of L-dopa with a hy- combination of gastrointestinal irritation as
drophilic, peripheral decarboxylase inhibitor well as stimulation by DA (and perhaps
(see Fig. 12.8 below) such as carbidopa (9; Lo- L-dopa) of the chemoreceptor trigger zone
dosyn; combined with levodopa in Sinemet (CTZ) in the area postrema of the brainstem,
and Sinemet-SR) or benserazide (10; com- an emesis-inducing center. The blood-brain
bined with levodopa in Prolopa) markedly in- barrier is poorly developed in area postrema,
creases the proportion of L-dopa that reaches making the CTZ accessible to circulating
the brain, where it can be converted to DA by emetics. An important advantage of combin-
widely available aromatic amino acid decar- ing L-dopa with a peripheral decarboxylase in-
boxylase and replace its deficiency associated hibitor. in association with the 75-80% reduc-
with PD. Doses of L-dopa required are corre- tion of the required doses of L-dopa, is less risk
spondingly much lower (typically only 0.2-1.2 of emesis or other adverse effects associated
glday), and most commonly attained with 251 with peripheral formation of excess DA. These
100 mg doses of standard preparations of can include activation of peripheral adrener-
carbidopa/levodopa, or 15/200 mg of SR prod- gic and DA receptors, in part by releasing en-
ucts, although preparations with other dosage dogenous adrenergic catecholamines (88),
ratios are available (20). Patients with PD are with a variety of cardiovascular effects. Theo-
typically started on one of the combination retically, vasoconstriction and hypertension
products, either alone or with other adjunctive might occur by stimulation of peripheral a-ad-
agents discussed below. The extended-release renoceptors, tachycardia by stimulation of
preparations should theoretically provide cardiac P-adrenoceptors, and direct renal and
more sustained benefits with less "wearing mesenteric vasodilatation by DA. However,
off' of benefit after several hours, but the bio- such effects are rarely encountered clinically
availability of these products is variable. In with the use of a peripheral decarboxylase in-
general, tissue uptake of L-dopa is highly de- hibitor with L-dopa (20).
pendent on competition with other aromatic After about 5 years, at least half of L-dopa-
and neutral aliphatic amino acids, and can be treated PD patients develop fluctuating motor
decreased substantially by a protein meal. responses, and nearly three-quarters do so by
Pyridoxine (vitamin B,) is the cofactor for 15 years (90). These fluctuations include "off'
aromatic amino acid decarboxylase. It can re- periods of immobility, and "on" periods with
verse the therapeutic effects of L-dopa by in- abnormal involuntary movements or dyskine-
sias (see Fig. 12.1). This "on-off' phenomenon been developed for clinical application, though
may reflect progression of the disease with apomorphine has some Dl as well as potent D,
more severe striatal nerve terminal degenera- agonist effects (110).
tion and further loss of DA, along with in- Bromocriptine (Parlodel, 11; Fig. 12.5) is
creased sensitivity of its receptors. an ergot alkaloid-peptide that acts as a weak
Psychiatric disturbances such as hypersex- partial agonist (or antagonist) at Dl-type and
uality, mania, visual hallucinations, and para- a partial agonist at D,-type DA receptors, with f

noid psychosis also are quite common adverse moderate intrinsic activitv." It was the first di-

responses to treatment with L-dopa or direct rect DA agonist to be employed in the treat-
DA agonists. These psychiatric disturbances ment of PD, after its development as a prolac- -
tin inhibitor (101, 111, 112). Bromocriptine
are widely proposed to reflect excessive stimu-
inhibits prolactin release from anterior pitu-
lation of DA receptors in mesolimbic or meso-
itary mammotrophic cells that express D, DA
cortical DA systems. They can greatly com-
receptors selectively. These receptors respond
plicate clinical management of depression com-
to DA produced in the arcuate nucleus of the
monly associated with PD, and of dementia
hypothalamus and released at the median em-
that sometimes arises in late stages of the dis-
inence into the hypophysioportal blood ves-
ease. Modern antidepressants usually are well
sels, and carried to the pituitary to act as a
tolerated, with inconsistent and probably mi- prolactin-inhibitory hormone. Bromocriptine
nor risk of worsening bradykinesia with sero-
is an effective prolactin inhibitor at low doses
tonin-enhancing antidepressants (91). Use of (typically 1-5 mgtday), for which it is used to
antipsychotic drugs, however, is limited to
treat hyperprolactinemia associated with pi-
those with minimal risk of worsening bradyki-
tuitary adenomas, or to suppress prolactin
nesia and other aspects of extrapyramidal mo-
output in prolactin-sensitive metastatic carci-
tor dysfunction (7). Clozapine is best toler-
noma of the breast. The partial-agonist acts as
ated; quetiapine and low doses of olanzapine
an agonist at pituitary D, receptors that are
are sometimes tolerated; and the new atypical
normally in a high sensitivity state. At higher
antipsychotic agent ziprasidone has not been
doses (typically 10-20 mglday), bromocriptine
evaluated in PD patients with psychotic reac-
and other D, partial-agonist ergolines act as
tions, although the chemically related risperi-
D, agonists with antiparkinson, and perhaps
done and older neuroleptic D, antagonists are
mood-elevating, effects. This agonism evi-
not tolerated by PD patients (7,92-95). dently reflects the supersensitized status of
denervated DA receptors in PD (94, 113).
3.1.2 Clinically Used Dopamine D, Recep- The peptide component of bromocriptine
tor Agonists. The nigrostriatal neurodegen- evidently is not necessary for its dopaminergic
eration underlying PD reduces the number of activity, and pergolide (Permax, 12; see Fig.
striatal nerve terminals available to decarbox- 12.5) was the first nonpeptide ergoline used
ylate L-dopa to DA, but also increases sensitiv- successfully in the treatment of PD, as well to
ity of DA receptors as well as loss of the inac- inhibit release of prolactin from the pituitary
tivation of DA by neuronal reuptake at DA (96, 103, 107, 108, 111). Pergolide shows
transporters virtually expressed only by DA greater agonist effects at both D,- and Dl-type
neurons and their terminals. Drugs that act DA receptors than does bromocriptine. Sev-
directly to stimulate DA receptors do not re- eral additional experimental ergolines have
quire functioning DA nerve terminals or en- been developed with a range of D, agonist or
dogenous synthesis of DA, and can be particu- partial-agonist actions, including cabergoline
larly useful in managing late-stage PD. (13),lergotrile (14a), pergolide (14b), and lis-
Several agents with direct DA-agonist activity uride (15) (11,95,96, 101, 104, 105,109).
have been used in the treatment of PD (20, Other small molecules are direct D, ago-
96-109). All are primarily agonists or partial nists or partial agonists, and are effective in
agonists of the D, family of DA receptors. No the treatment of PD. They include ropinirole
agents with selective Dl agonist activity, or hydrochloride (Requip 16), and pramipexole
well-balanced Dl and D, agonist actions have dihydrochloride (Mirapex, 17) (11, 102, 103,
726 Therapeutic and Diagnostic Agents for Parkinson's Disease

107, 108),as well as piribedil(18)(98)and the peripheral and central dopaminergic effects,
experimental agent R-PNU-95666-E (19) (99, including nausea, hypotension, and agitation
100) (Fig. 12.5). In contrast to the ergolines, also are encountered with ropinirole and
these compounds are more selective in their pramipexole. They also can produce paradoxi-
interactions with DA receptors, and have cal somnolence as well as edema, and have
much less effect at nondopaminergic sites. been associated with uncommon narcolepsy-
Currently, ropinirole (16) and pramipexole like sleep attacks during the daytime, with po-
(17)are among the most commonly prescribed tential risk during driving (114).
direct DA agonists for PD in the United States R-(-)-apomorphine (20; Fig. 12.5) is an
(20). They were introduced primarily for use acid-rearrangement product of morphine em-
in advanced stages of PD to limit fluctuations ployed in experimental neuropharmacology
in response to L-dopa therapy and as a "res- since the late nineteenth century (110, 115).
cue" therapy when L-dopa became less effec- Apomorphine is an agonist for both D, and Dl
tive. However, their relative tolerability, cou- DA receptors. With a pK, of about 9, it is
pled with clinically unresolved concern that mostly protonated at physiological pH, but
L-dopa therapy might contribute to additional sufficiently lipophilic to cross the blood-brain
toxic damage to DA neurons through forma- barrier readily. Apomorphine hydrochloride
tion of reactive oxidized by-products, has led was resurrected as a useful adjunct in the
to their growing use as a first-line treatment therapy of PD a decade ago (1161, following
option, sometimes before L-dopa is added. An years of neglect after promising early observa-
additional advantage of these agents is that tions (85, 117). Lack of oral bioavailability,
they have a relatively prolonged dopaminergic short duration of action, and potent central
action, to provide more sustained clinical ben- emetic action discouraged its clinical use. Nev-
efit with less risk of fluctuation than with L- ertheless, in 1993, apomorphine received reg-
dopa, even as modified by cotreatment with ulatory approval in the UK for control of
inhibitors of its peripheral metabolism by de- refractory motor dysfunction and wide fluctu-
carboxylase and COMT. This impression is ations in responses ("on-off' syndrome) to L-
supported by controlled comparisons of the dopa or DA agonists (118-120). Improved mo-
two forms of treatment (101-103). A recent tility in response to an acute challenge dose of
study in patients initially treated with apomorphine can also predict responsiveness
pramipexole (17) demonstrated a reduction in to L-dopa treatment (121-123). Apomorphine
loss of striatal (1231)-/3-CIT(54, see Fig. 12.11) can be administered subcutaneously by inter-
a marker of DA neuron degeneration, com- mittent self-administration with a small self-
pared with those initially treated with L-dopa injector (Penject), or continuous infusion with
during a 46-month period (77). a portable minipump (115, 120). Catechol-di-
The direct DA agonists generally produce ester and methylenedioxy aporphine prodrugs
similar adverse effects, including initial nau- limit first-pass metabolic inactivation, while
sea and vomiting, postural hypotension, and retaining much of the activity of catecholapor-
fatigue. These effects are more likely with the phines (124). The 11-monohydroxy congener
ergolines, which are started in low doses and of the potent DA agonist R-(-)-N-n-propyl-
increased slowly, as tolerated, whereas ropini- norapomorphine (2 I), R-(-)-N-n-propyl-1 l-
role and pramipexole can usually be dosed hydroxynoraporphine (22; Fig. 12.5), retains
more rapidly to clinically effective levels. Ad- the critical free hydroxyl group analogous to
ditional risks include psychotic reactions the meta-3-hydroxy substituent of DA, has po-
when the DA agonists are given alone or with tent dopaminergic activity, and is orally bio-
L-dopa. These reactions include hallucina- available (124-127).
tions, delusions, and confusion, suggesting de-
lirium, which is most likely to occur in elderly 3.1.3 Experimental Dopamine D, Receptor
PD patients with mild dementia. Treatment is Agonists. The opposing actions of the direct
similar to psychotic reactions to L-dopa ther- and indirect pathways in the basal ganglia (see
apy, and usually includes use of low doses of Fig. 12.1) suggest that coordinated movement
clozapine or quetiapine (6, 7, 91-94). Adverse requires neurotransmission to be activated in
3 Treatments for Parkinson's Disease

(24) X = R = H: SKF-38393
(25) X = CI, R = H: SKF-81297
(26) X = Br, R = CH2CH=CH2: Br-APB
(27) X = CI, R = CH2CH=CH2: SKF-82958, CI-APB

Dihydrexidine Dinapsoline
(28) (29)
-7

Figure 12.6. Representative experimental Dl agonists. These agents have unproved or untested
clinical utility in the treatment of Parkinson's disease.

the direct pathway and attenuated in the indi- first selective Dl partial agonists such as
rect pathway. DA in the striatum may achieve the benzergoline CY-208-243 (23; Fig. 12.6)
such neuromodulation by stirnulatory actions and the phenylbenzazepine SKF-38393 (24)
at Dl-type receptors and inhibitory actions at showed that these drugs were either short-act-
D,-type receptors. Consistent with a role for ing or lacking in efficacy (11,128, 129). Other
the Dl receptor as a regulator of the direct phenylbenzazepines are also short-acting Dl
output pathway, stimulation of Dl receptors partial agonists (25-27). It was later hypothe-
represents a plausible pharmacotherapeutic sized that adequate testing of D, agonist util-
approach in PD. Initial clinical trials with the ity in PD required a full, not a partial, agonist.
728 Therapeutic and ~iagnosticAgents for Parkinson's Disease

The benzophenanthridine dihydrexidine (28) zures, but an analog, A-77636 (32), showed
was the first full-efficacy Dl agonist to be de- antiparkinson effects without inducing sei-
veloped, though it also has some D,-type activ- zures in MPTP-treated marmosets (144).
ity (130, 131). In MPTP-lesioned monkeys, However, A-77636 showed rapid desensitiza-
dihydrexidine essentially eliminates all par- tion to its beneficial effects (1451, possibly re-
kinsonian signs, and this effect was fully lated to its prolonged action (>20 h) (142).
blocked by the Dl antagonist SCH-23390 but
not by the D, antagonist remoxipride, consis-
tent with a Dl mechanism of action (132). 3.1.4 Structural Modeling for Dopamine
Moreover, continuous administration of dihy- Agonists. Rational molecular design of DA
drexidine to rats for 2 weeks produced mini- agonists for treating PD is limited by a lack of
mal or no changes in either Dl receptor den- validated three-dimensional models of inter-
sity or Dl receptor-mediated DA-stimulated actions of DA with critical amino acid residues
adenylyl cyclase activity, suggesting that tol- at DA binding sites within DA receptor pep-
erance should not develop to its antiparkinson tide chains. Moreover, structural models that
effects. In PD patients, however, dihydrexi- would differentiate the known DA Dl-type
dine has a narrow therapeutic index and (Dl, D,) or D,-type (D,, D,, D,) receptors are
dose-limiting adverse effects including flush- also lacking, and the physiology of the low-
ing, hypotension, and tachycardia after single abundance subtypes, including D,, D,, and D,
intravenous doses (133). receptors, remains highly tentative, particu-
The Dl receptor pharmacophore model de- larly at the level of motor control (15). Devel-
veloped for dihydrexidine subsequently was opment of selective DA receptor agents con-
used to design novel molecular structures as tinues to be guided by quantitative structure-
full-efficacy Dl agonists (134). One such com- activity relationships (QSAFt) based on lead
pound is dinapsoline (29) (135). Numerous molecules, discovery of which in turn remains
other analogs have since been produced with highly empirical, based largely on affhities to
structural elements of both dihydrexidine and receptor subtypes in brain tissue or expressed
dinapsoline (29). For example, the dihydrexi- in genetically transfected cultured cells, all la-
dine isostere A-86929 (30a) and its diacetyl beled with receptor-selective radioligands (15,
prodrug ABT-431 (30b) are full Dl agonists 146).
with sustained antiparkinson effects in Because the side-chain of DA possesses un-
MPTP-lesioned monkeys (136). In patients limited flexibility and unrestricted rotation
with PD, ABT-431 was highly effective against about the p-carbon-phenyl bond, little infor-
bradykinesia, but produced dyskinesias (137). mation can be obtained concerning conforma-
Several full-efficacy R-(+)-phenylbenzaz- tional requirements for activation of DA re-
epine Dl agonists have been developed based ceptors using the endogenous ligand itself.
on SKF-38393 (24), including SKF-81297 (25; Accordingly, compounds in which the catechol
Fig. 12.6) and its 6-halo derivatives, 6-Br-APB ring and the aminoethyl side-chain of DA are
(26) and 6-CI-APB (SKF-82958, 27) (138, held in rigid conformation have been synthe-
139). In MPTP-lesioned monkeys, 6-Cl-APB sized. Several groups of such heterocyclic
(27) produced antiparkinson effects (140),but agents have contributed important insights
its utility was limited by very brief action (<1 into SAFt requirements of DA agonists. Nota-
h; 141) and severe adverse effects (142).More- bly, aporphines, aminotetrahydronaphtha-
over, SKI?-81297 (25) and dihydrexidine (28) lenes (aminotetralins),and aminobenzoquino-
(141) showed beneficial results only in mon- lines have yielded D,-like agonists, and the
keys with severe parkinsonism, supporting phenylbenzazepines and isochromans have
the suggestion that Dl agonists may be most provided Dl-like agents (146, 147).
useful in late stages of PD, if tolerable agents Structural models of the DA-agonist R-(-)-
with prolonged action can be developed (143). enantiomers of apomorphine (20) and its more
Several isochromans are also full Dl ago- potent congener, N-n-propylnorapomorphine
nists. The first compound in this series to be (21; Fig. 12.5) have been proposed, based on
tested, A-68930 (31; Fig. 12.61, produced sei- their X-ray crystal structure (148). Such anal-
3 Treatments for Parkinson's Disease

HO
/
NH2

1
:

I HO
/
NH2

1
:
H

HO
0

/
r N H 2

'i

OH 1- /
trans, a-rotamer trans, p-rotamer cis, a-rotamer . -

Figure 12.7. Rotameric forms of dopamine, a flexible p-phenethylamine.

yses show that these tetracyclics contain mo- 3.1.5 Dopamine-Potentiating Agents. Sev-
lecular features in common with DA in its eral agents have been used in the treatment of
trans-a-rotamer conformation (Fig. 12.7). PD that limit the metabolism of cat-
Experimentation with rigid dopaminomi- echolamines. They include the MA0 inhibitor
metic agents strongly suggests that the pre- selegiline (37) and several inhibitors of
ferred conformation of D2-like DA agonists COMT. Because active neuronal transport
models DA in its extended trans-a-conforma- ("reuptake") mediated by the DA transporter
tion. The trans-a-rotameric conformation of is the principal means of inactivating DA in
DA is also likely to be an important determi- the synaptic region (151),it is also plausible to
nant of agonist activation of Dl-type recep- expect that DA transport-inhibiting agents
tors, based largely on consideration of a series might also potentiate DA available in remain-
of phenylbenzazepines that also contain the ing dopaminergic neurons in early PD, and in
elements of DA within a rigid heterocyclic sys- potentiating DA produced from L-dopa. Al-
tem (149) (Fig. 12.6). though stimulant agents have some beneficial
Computational chemistry methods such as effects in mild PD, they are rarely used cur-
comparative molecular field analysis (CoMFA) rently and evidently have not been evaluated
also have been applied to elucidate quantita- as a means of potentiating L-dopa (114).
tive three-dimensional structure-activity re- 3.1.5.1 Monoamine Oxidase Inhibitors.
quirements (3D-QSAR) for activation of DA Among MA0 inhibitors, those selective for the
receptors. One such analysis considered 16 MAO-A in monoaminergic nerve terminals
structurally diverse, prototypical template Dl might be expected to potentiate DA. These in-
and D2 DA agonists (150). Interactions of ago- clude the long-acting, irreversible, nonselec-
nists with DA receptors were best described by tive MAO-IVB inhibitors phenelzine (Nardil;
a pharmacophore consisting of one protonated 33; Fig. 12.8) and tranylcypromine (Parnate;
nitrogen (at physiological pH) and at least one 34) (136,152). There are also short-acting, re-
electronegative center able to participate in versible inhibitors selective for MAO-A, which
hydrogen bonding (e.g., catechol, critically po- include the antidepressant moclobemide
sitioned hydroxy, or equivalent electronega- (Manerix, 35 and the experimental agent bro-
tive moieties). The pharmacophore maps for faromine 36; Fig. 12.8) (153). Presumably be-
Dl- and D2-type receptors differed primarily cause of their short and reversible actions,
in requiring a higher position of the amino- they have less risk of inducing hypertensive
nitrogen atom above the plane of the electro- crises when combined with indirect sympatho-
negative hydrogen bonding group Dl receptor mimetic amines that release endogenous cat-
activity. These analyses indicate that the cat- echolamines, though they have some risk of
ionic nitrogen moiety is more important than inducing cerebral intoxication when given
the rotameric conformation of the electroneg- with serotonin-potentiating agents including
ative hydroxy or other hydrogen-bonding serotonin (5-hyroxytryptamine) reuptake in-
groups in determining pharmacophore selec- hibitor antidepressants, meperidine, and
tivity for Dl and D2 receptors. other agents (136,152). Combinations of long-
730 Therapeutic and Diagnostic Agents for Parkinson's Disease

M A 0 inhibitors

Phenelzine (Nardil) Tranylcypromine (Parnate) Moclobemide (Manerix)


(33) (34) (35)

Brofaromine Selegiline (R(-)-Deprenyl,Eldepryl)


(36) (37)
Aromatic amino acid decarboxylase inhibitors (peripheral)

L(-)-Carbidopa(Lodosyn) Benserazide
(9) (10)
COMT inhibitors

NO2
Entacapone (Comtan) Rolcapone (Tasmar)
(38) (39)
Figure 12.8. Dopamine potentiating or protective agents. These include MA0 inhibitors (only
selegiline is used clinically to treat PD),inhibitors of the peripheral decarboxylation of L-dopa, and
inhibitors of the 0-methylation of dopamine and L-dopa.

acting MAO-A/B inhibitors like phenelzine to neurotoxic by-products (see Fig. 12.3).
and tranylcypromine with L-dopa are contra- Probably by protecting DA, selegiline can in-
indicated because of the risk of inducing hy- crease the potency and duration of action of
pertensive crises and delirium (20). L-dopa, and do so safely provided that doses
Selegiline hydrochloride (Eldepryl; L-de- are kept low (153, 154). However, at doses
prenyl; R-(-1-N,2-dimethyl-N-2-propynyl- above 20 mg/day, selegiline has an inhibitory
phenethylamine, 37; Fig. 12.81, at low doses effect on both MAO-A and MAO-B. In addi-
(a10 mglday), is a selective inhibitor of mainly tion, it can be converted to methamphetamine
nonneuronal MAO-B, which oxidizes MPTP or similar metabolic by-products, inhibit neu-
3 Treatments for Parkinson's Disease

ronal transport of monoamines, and release fective, and with clinical monitoring of hepatic
DA (153). In this way, selegiline resembles tra- functioning (156-159). Other adverse effects
ditional stimulants that release DA and other of these agents include severe diarrhea and
monoamines (114). It had also been hoped risk of dyskinesias and psychosis in PD p a
that use of an MAO-B inhibitor like selegiline tients when combined with L-dopa (160).
might prevent formation of neurotoxic oxida-
r
tion products of DA or perhaps MPTP-like
compounds and slow the progressive neurode- 3.2 Agents Acting on Nondopaminergic
generation in PD, but evidence for such a neu- Systems
-
roprotective effect of this agent or of antioxi-
dants including vitamin E is lacking, and 3.2.1 Anticholinergic Agents. Cholinergic
selegiline has only limited clinical benefits in interneurons in the striatum exert mainly ex-
early or mild PD (75, 76, 155). citatory effects on GABAergic output from the
3.1.5.2 Catechol-0-Methyltransferase In- striatum (see Fig. 12.1). Drugs that increase
hibitors. The peripheral metabolism of L-dopa cholinergic neurotransmission (e.g., the cho-
given alone leads to very limited access of the linesterase inhibitor physostigmine and the
amino acid to the CNS. It is rapidly decarboxy- direct agonist carbachol) have long been
lated by L-aromatic amino acid decarboxylase known to aggravate parkinsonism in humans,
and 3-0-methylated by COMT. In addition to whereas centrally active muscarinic antago-
potentiating L-dopa with peripheral decarbox- nists (such as the belladonna alkaloids, includ-
ylase inhibitors including carbidopa and ing atropine), have moderately beneficial ef-
benserazide, there are also inhibitors of fects (20, 161-164). Accordingly, before the
COMT. This methyl transferase, with its discovery of L-dopa, drug therapy for parkin-
methyl-donor cofactor S-adenosyl-L-methio- sonism depended primarily on the limited ef-
nine ( W e ) ,converts dopa and catecholamines ficacy of the natural belladonna alkaloids and
preferentially to their m-methoxy derivatives newer synthetic antimuscarinic alkaloids, as
(see Fig, 12.4). These include 3-0-methyl-dopa well as antihistamines that also exert central
and 3-0-methyldopamine (3-methoxytyra- antimuscarinic actions (Fig. 12.9). Synthetic
mine, 3-methoxy-4-hydroxyphenethylamine), central anticholinergic agents include benz-
as well as the 3-0-methylated, deaminated tropine mesylate (40; Cogentin and others),
compound homovanillic acid (HVA),the major biperidin (41; Akineton), diphenhydramine
metabolite of DA in humans. Treatment with (42; Benadryl and others), ethopropazine (43;
L-dopa can reduce tissue concentrations of Parsidol), orphenadrine (44; Disipal and oth-
SAMe (87), with uncertain consequences that ers), procyclidine (45; Kemadrin), and tri-
should be limited by cotreatment with a hexylphenidyl (46; Artane and others). Such
COMT-inhibitor. COMT acts in both periph- drugs continue to be used to control parkin-
ery and CNS, though the use of COMT inhib- sonism and other adverse extrapyramidal
itors to potentiate L-dopa is most effective in neurological effects of the potent D,-receptor
peripheral tissues (20, 140, 156-158). antagonist neuroleptic antipsychotic agents,
COMT inhibitors in current clinical use in- for which they are quite effective (20,91).
clude entacapone (Corntan; 38) and tolcapone In contrast, central antimuscarinic agents
(Tasmar; 39; Fig. 12.8). Although these drugs have limited therapeutic benefit in PD. They
lack beneficial effects on PD themselves, they also exert a range of undesirable adverse ef-
potentiate L-dopa and prolong its actions by fects because of their blockade of peripheral
inhibiting the metabolic inactivation of L-dopa parasympathetic function. These include dry
and DA. Entacapone is more widely used, acts mouth, impaired visual accommodation, con-
only in the periphery, and is relatively short- stipation, urinary retention, and tachycardia.
acting (-2 h). Tolcapone is longer acting, but Adverse CNS effects include delirium of vary-
has about 2% risk of elevating hepatic ing severity, marked by confusion, memory
transaminases, and has been associated with impairment, and psychotic symptoms. Despite
several cases of hepatic failure, leading to its their relatively unfavorable benefitlrisk ratio,
preferred use when other options are not ef- these agents are still sometimes employed in
Therapeutic and Diagnostic Agents for Parkinson's Disease

Benztropine mesylate (Cogentin) Biperiden (Akineton)


(40) (41)

CHO- CH2CH2- N
,
, CH3
S N-CH2-CH-N
/ CH3
\
I CH3
CH3

Diphenhydramine (Benadryl) Ethopropazine (Parsidol)


(42) (43)
A

Orphenadrine (Disipal) Procyclidine (Kemdrin)


(44) (45)

C N-CH2CH2-C- OH
C
0
I

Trihexyphenidyl (Artane)
(46)

12.9. Agents with central antimuscarinic activity sometimes used to treat idiopathic or
leptic drug-induced parkinsonism.
3 Treatments for Parkinson's Disease

Amantadine (Symmetrel) Memantine


(48) (49)

Riluzole Sarizotan (EMD 128130)


(50) (51)
Figure 12.10. Agents acting on nondopaminergic systems. These include agents that act on aden-
osine, glutamate, and serotonin systems.

the treatment of PD in combination with L- ger systems (173) and reduce the binding af-
dopa, particularly to help control tremor (163, finity of DA for D, receptors (173). An A.,,
164). antagonist presumably would block these A.,,
receptor-mediated inhibitory effects on DA
3.2.2 Adenosine Antagonists. KW 6002 neurotransmission and perhaps provide bene-
(46; Fig. 12.10) is a potent and selective antag- fit in PD. Activation of A.,, receptors also stim-
onist at adenosine AZAreceptors (165, 166) ulates release of acetylcholine in striatum
currently in clinical trials for treatment of PD (174). Because muscarinic acetylcholine re-
after improving motor disability in primate ceptor antagonists can ameliorate some signs
models of PD (167, 168). The adenosine A, of PD, A,. receptor antagonists may exert ad-
receptor is one of four cloned adenosine recep- ditional benefits in PD by reducing striatal
tors that are members of the seven-transmem- cholinergic neurotransmission (171).
brane, G-protein-coupled receptor superfam-
ily. AZAreceptor mRNA is highly concentrated 3.2.3 Glutamate Antagonists. Amantadine
in the striatum, nucleus accumbens, and olfac- (Symadine, Symmetrel, 48; Fig. 12.10) is an
tory tubercle, and colocalizes with D, receptor adamantane with an unusual cagelike struc-
mRNA in these brain regions (169).Activation ture, originally developed as an antiviral
of A, receptors inhibits GABA release in stri- agent. Amantadine, as a primary amine with a
atum and reduces GABA-mediated inhibition pK, of 10.8, is mainly in the protonated form
of striatal medium spiny output neurons at physiological pH, but it can enter the brain
(170). Thus, antagonism of A.,, receptors is because of its unusual structure that not only
expected to increase GABA-mediated inhibi- increases its lipophilicity, but also prevents its
tion of the medium spiny output neurons to catabolism by oxidative enzymes so that most
help compensate for the loss of DA Dl recep- of it is excreted in the urine unchanged.
tor-stimulated GABA release and D, receptor- Amantadine has some ability to release DA
mediated inhibition of these neurons in PD and norepinephrine from intraneuronal stor-
(171) (see Fig. 12.1). Adenosine A, receptors age sites and block reuptake of DA, and was
also oppose the actions of Dl and D, receptors initially considered a DA-potentiating agent
on gene expression (172) and second-messen- for use in mild PD (172, 173, 175-177). How-
734 Therapeutic and Diagnostic Agents for Parkinson's Disease

ever, in addition, amantadine and its conge- kinsonism-like catalepsy induced by haloperi-
ner, memantine (1-amino-3,5-dimethylada- do1 (189), 5-HT,, receptor activation might
mantane, 49; Fig. 12.10) have some activity as also counteract losses of nigrostriatal DA neu-
NMDA (and possibly AMPA) glutamate recep- rotransmission in PD (188). Moreover, in pa-
tor antagonists that might also provide neuro- tients with advanced PD, intact striatal5-HT
protective effects (178). Both have been used terminals are an important site of decarboxyl-
to treat PD (20,178). Amantadine has moder- ation of exogenous L-dopa to DA (190). A
ately beneficial effects early in PD, can en- 5-HT,, agonist might act at striatal seroto-
hance the effects of L-dopa, and perhaps limit nergic terminals to limit release of DA pro-
the severity of dyskinesias induced by L-dopa duced by L-dopa treatment and released from
therapy (179). Also, memantine has been used 5-HT terminals as a "false transmitter" (85).
as a spasmolytic agent in the treatment of Sarizotan (EMD-128130, 51; Fig. 12.10) is
both PD and dementia (180). The potential an arninomethylchroman derivative with po-
that such agents might afford long-term neu- tent central 5-HT,, agonist activity. Given by
roprotective effects that might include slow- itself to MPTP-lesioned monkeys, sarizotan
ing the progression of PD remains speculative. had no effect on the severity of motor deficits
Riluzole is a benzothiazolamine (50) with or on beneficial responses to L-dopa, but it re-
sodium channel blocking activity that inter- duced L-dopa-induced choreiform dyskinesias
feres with glutamatergic neurotransmission by more than 90% (187). It is in clinical trials
by blocking glutamate release in the subtha- for the treatment of PD and of dyskinesias
larnic nucleus, an area of increased neuronal resulting from L-dopa therapy. The lack of in-
activity in PD (181). It is currently given to teraction of sarizotan with L-dopa in MPTP-
patients with amyotrophic lateral sclerosis lesioned monkeys (187) is unsupportive of
(ALS) in an attempt to slow the progression of concern that it might limit release of DA from
this degenerative disorder of motor neurons of 5-HT terminals. Although sarizotan also has
the spinal anterior horn by inhibiting gluta- weak DA D, receptor affinity (10 times less
mate neurotoxicity (182). In the MPTP-le- than its 5-HT,, affinity), its beneficial effects
sioned monkey model of PD, riluzole delayed in parkinsonian monkeys seem specific to
appearance of parkinsonian motor abnormal- 5-HT,, agonism, in that they were reversed by
ities by a mechanism not involving decreased a selective 5-HT,, antagonist (187).
formation of MPP', the neurotoxic metabolite
ofMPTP (183,184). Recently, riluzole was as-
sessed for safety, tolerability, and efficacy in 4 DIAGNOSTIC AGENTS FOR
treatment of PD patients who had L-dopa-in- PARKINSON'S DISEASE
duced dyskinesias (185). Riluzole was effective
in lessening dyskinesias in these patients, was Even for an experienced clinical neurologist,
well tolerated, did not interfere with L-dopa, diagnosis of PD can be difficult to confirm,
and is undergoing further trials in PD. especially in the early stages of this disease.
Signs of PD vary markedly among patients
3.2.4 Serotonin Agonists. Dysfunction of and in the same person over time; disability
neurotransmission mediated by 5-hydroxy- can fluctuate dramatically, and progression
tryptamine (5-HT; serotonin) occurs in the of the disorder is unpredictable. In addition,
basal ganglia of patients with PD, and exces- a number of conditions mimic PD disease,
sive serotonergic transmission may contribute and vary in their responses to antiparkinson
to dyskinesias associated with dopaminergic drugs (191). Given these difficulties, brain
treatments (186). 5-HT,, receptors are ex- imaging techniques are increasingly applied
pressed presynaptically on 5-HT terminals, to both diagnostic and neuropharmacologi-
where they limit serotonin release as autore- cal studies of brain function in PD patients.
ceptors (187). Their activation should de- Positron emission tomography (PET) and
crease 5-HT release and perhaps alleviate do- single photon emission computed tomogra-
paminergic dyskinesias in PD (188). Because phy (SPECT) are sensitive methods em-
5-HT,, receptor stimulation can reverse par- ployed in such studies.
4 Diagnostic Agents for Parkinson's Disease

Cocaine
(53)

(1231)-p-~~~ (Iz3!)-FP-CIT(loflupane)
DOPAScan DATScan

Figure 12.11. Radioligands for dopamine neurons. These include [lsF]-labeled dopa and nonhydro-
lyzable, long-acting phenyltropane analogs of cocaine, which bind selectively to the dopamine trans-
porter proteins and are highly specific markers of dopamine neur,ons. These agents are useful for
imaging with [lsF] for PET and [lZ3I]for SPECT.

Spatial resolution is greater with PET, but is rapidly hydrolyzed at its benzoyl ester func-
SPECT technology is less expensive and more tion, making it an impractical candidate for
widely accessible in many clinical settings. In use in imaging (193). However, linking the
addition, positron-emitting nuclides used in phenyl ring of cocaine directly to the tropane
PET imaging have very short half-lives (llC, system yields nonhydrolyzable, long-acting
20 min; 18F,109 min) and usually require an phenyltropanes. Many such compounds have
on-site cyclotron for their production. SPECT proved to be potent stimulants and some have
nuclides have longer half-lives (1231,13 h; high affmity and varying selectivity for DA
""Tc, 6 h), often can be supplied commer- transporters in the brain. Some compounds of
cially, and [99mTc]-labeledradioligands can be this type have been prepared as clinically use-
f prepared locally as needed. Specifically, quan- ful radiopharmaceuticals (Fig. 12.11).
titative assessment of nigrostriatal presynap- The first such agent was p-[1231]phenyl-
tic DA nerve terminal function by PET using labeled 2-P-carbomethoxy-3P-(4-iodophenyl)-
[18F]-labeled L-6-fluorodopa ([l8F1dopa, 52; tropane (54 [1231]p-CITor RTI-55; Dopa-
Fig. 12.11) has proved useful for the early di- Scan), although this agent requires about 8 h
agnosis of PD (192). for peak uptake before imaging, thus limiting
Additional radioligands have recently been its practicability (77, 191, 194). However, the
developed for probing the DA transporter pro- radioiodinated N-3-fluoropropyl analog of
teins that are highly characteristic gene prod- P-CIT [N-3-fluoropropyl-2-P-carbomethoxy-
ucts of DA neurons and nerve terminals in the 3P-(4-iodopheny1)-tropane,(55),[12311FP-CIT
basal ganglia. Cocaine (53; Fig. 12.11) binds to or [1231]ioflupane(DATScan)] has the advan-
the DA transporter (DAT) and other mono- tage of more favorable kinetics for clinical use
amine transporters, but radiolabeled cocaine because patients can be imaged 1-2 h after
736 Therapeutic and Diagnostic Agents for Parkinson's Disease

injection of the radioligand (195). Moreover, a leads discussed above, and by gradual progress
radioligand suitable for PET imaging is ob- toward a better molecular understanding of
tained by replacing the fluorine atom with the primary pathoetiology of the disease. In all
[lsF] in FP-CIT (196). [1231]-FP-CITis also of these efforts, medicinal chemists working in
being studied in patients with PD and other collaboration with basic and clinical biomedi-
neuropsychiatric disorders, and is commer- cal research colleagues will continue to play a
cially available for clinical application. central role.

5 FUTURE DIRECTIONS 6 ACKNOWLEDGMENTS

Research related to PD has been directed to- We thank the Branfman Family Foundation,
ward developing more effective and better-tol- the Bruce J. Anderson Foundation, and the
erated new treatments, largely guided by the McLean Private Donors Neuropharmacology
central role of DA in the pathophysiology of Research Fund for financial support, as well as
the disorder. However, recent research has in- Susan Trofinow and Drs. Xiao-Hui Gu and
creasingly included efforts to clarify the Wennan Xiong for assistance in preparing the
pathophysiology of PD and to define its pri- manuscript.
mary causes, which remain obscure. Research
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CHAPTER THIRTEEN

Alzheimer's Disease:
Search for Therapeutics
RZESZOTARSKI
W. JANUSZ
Food and Drug Administration
Rockville, Maryland

Contents
1 Introduction, 744
2 Epidemiology, 745
3 Etiology, 745
3.1 Genetic Determinants, 745
3.1.1 Presenilins 1 and 2, 745
3.1.2 Amyloid Precursor Protein (APP),746
3.2 Genetic Risk Factors, 746
3.2.1 Apolipoprotein E W O E ) , 746
3.2.2 Susceptibility Locus on Chromosome
10, 747
3.2.3 Susceptibility Locus on Chromosome
12,747
3.2.4 Tau Protein, 748
3.3 Nongenetic Risk Factors, 748
3.3.1 Traumatic Head Injury (THI), 748
3.3.2 Hypercholesterolemia and High
Density Lipoprotein (HDL)
Cholesterol, 749
4 Prevalent Hypothesis: Amyloid Cascadecum-
Cholesterol Et Inflammation, 749
4.1 Inhibitors of Ap Production, 752
4.1.1 a-Secretase Inhibitors, 752
4.1.2 0-Secretase Inhibitors, 753
4.1.3 y-Secretase Inhibitors, 754
4.2 Statins, 756
4.3 Compounds Affecting Fibril Formation, 758
4.4 Inhibitors of Ap Aggregation, 758
4.5 Accelerators of Ap Fibril Disaggregation, 760
4.6 Ap Catabolism and Removal, 760
4.7 Modulators of Ap Neurotoxicity, 760
4.8 APP Gene-Knockdown Agents, 761
4.9 a-Secretase Shift, 761
5 Attenuation of Cholinergic Transmission, 761
5.1 Acetylcholine Esterase Inhibitors, 761
Burger's Medicinal Chemistry and Drug Discovery 5.2 Muscarinic Acetylcholine Receptor Agonists
Sixth Edition, Volume 6: Nervous System Agents and Antagonists, 762
Edited by Donald J. Abraham 5.3 Nicotinic Acetylcholine Receptor Agonists,
ISBN 0-471-27401-1 O 2003John Wiley & Sons, Inc. 764
Alzheimer's Disease: Search for Therapeutics

6 Modulation of AMPA Responses, 765 10 Inhibitors of Apoptosis, 766


7 Estrogens and Androgens, 765 11 Anti-Inflammatory Agents, 767
8 Immunotherapy, 766 12 Antioxidants, 767
9 Immunosuppression, 766 13 Conclusions and Perspective, 768

1 INTRODUCTION The disease propagation to limbic and neocor-


tical sites represents stages I11 and IV (incipi-
Alois Alzheimer (1864-1915) was the first to ent AD) and V and VI (fully developed AD). A
describe the specific unique pattern of neuro- longitudinal MRI study of presymptomatic
pathologic changes in the brain of a victim of representatives of families with known auto-
what we now call Alzheimer's disease (AD) (1). somal dominant mutations leading to AD il-
Emil Kraepelin (1855-1926) named the dis- lustrated in real time the points of origin and
ease after him but to this day the precise def- the progress of the disease (10). By the use of
inition of AD, the most common (50-70%) voxel compression mapping of serial MRI im-
form of dementia in the elderly, is far from ages over the period of 5-8 years, the study
complete. Clinically, AD overlaps with many reveals progressive atrophy in presymptom-
other conditions leading to dementia, ad- atic individuals with posterior cingulate and
vanced age in particular, making accurate di- neocortical temporoparietal cortical losses,
agnosis difficult if not impossible (2-5). Even and medial temporal-lobe atrophy. A shorter
at necropsy, macroscopic examination of AD 3-year longitudinal study of normal elderly
brains again shows an extensive overlap . with has shown the predictive value of MRI guided
changes encountered in normal aging (6). 2-[18F]fluoro-2-deoxy-~-glucose/positron-
Thus, at present, AD can be diagnosed posi- emission tomography (11).In that study the
tively only at necropsy on microscopic exami- baseline metabolic reduction in the entorhinal
nation using silver impregnation stains, amy- cortex predicted future longitudinal memory
loidophilic dyes, or antibodies for visualization and temporal neocortex metabolic reductions.
(6).Characteristic, but not unique to AD, is Patients who eventually declined into a mild
the observed presence and abundance of (1) cognitive impairment (MCI) and AD showed
so-called intracellular neurofibrillary tangles memory impairement and hypometabolism in
(NFT) and (2) extracellular amyloid in the
temporal neocortex and hippocampus.
form of meningeal vascular amyloid, cortical
microvascular amyloid, and senile (neuritic)
It is established from early studies that in
plaques (SP) in the affected parts of dissected patients with diagnosed AD the widespread
brain. At present, SP, extracellular spherical atrophy includes the primary motor and sen-
abnormalities of about 0.2 mm diameter con- sory cortices and cerebellum. The cholinergic
sisting of a core of amyloid P-peptides (AP) of innervation in these parts of brain is dis-
various densities surrounded by dystrophic rupted; choline acetyl transferase, high a n -
neurites, are at the center of AD research.~he ity nicotinic acetylcholine receptor (nAChR)
highest accumulation of the NFTs and SPs is binding, and choline transporter sites' de-
observed in the hippocampus and the associa- creased (12-15). The observed deposition of
tive regions of the cortex and the formation of fibrils of the misfolded into P-sheet AP in the
the latter precedes the formation of the SP places AD in the group of over 20 clinically
former. The concentration of AP was shown by defined amyloidoses. The short-term memory
Greengard et al. to correlate with the severity impairment represents the earliest observable
of cognitive decline (7). symptom of the disease. Further impairment
Earlier, six stages of AD propagation were of memory interferes with the determination
proposed based on severity of NFT pathology of visuospatial orientation and causes severe
(8,9). The initial involvement of transentorhi- mood alterations and depression combined
nal subdivision of the hippocampal cortex rep- with language disturbance, and loss of both
resents stages I and I1 (clinically silent cases). judgment and reasoning ability (16, 17). The
3 Etiology 745

average duration of AD is 6-10 years, and in- genetic etiology, reflecting perhaps the effects
tercurrent infection is the most common cause of several genes, is classified as sporadic or
of death (6). late-onset AD (SAD or LOAD). When the age-
at clinical onset is considered, over 90% of AD
develops after the age of 65 (21).By definition,
2 EPIDEMIOLOGY
in all FAD, LOAD, and SAD groups the patho-
logical changes observed postmortem are assoy
Given the available demographics, AD should
ciated with the formation of SP and NFT in
be one of the most thoroughly researched dis-
the affected neurons (22). That association
eases. Regretfully, this is not the case. An au-
lends credence to Kdizuka,s (23) hypothesis-
thor may be tempted to paraphrase Charles
of protein precipitation as the common etiol-
Maurice de Talleyrand-PBrigord (1754-1838):
ogy of neurodegenerative disorders.
"You will kindly observe, ladies and gentle-
men, that I neither condemn nor defend, I 3.1 Genetic Determinants
merely narrate." According to Brookmeyer et
At present it has been postulated that between
al. (18, 19) the estimated prevalence of AD in
30-50 and 95% of the population risk for de-
the United States in 1999 was 2.44 million
velopment of AD may be attributed to genetic
with the range of 1.15 to 4.78 million. Over the
factors (21,24).However, when the autosomal
next 50 years the incidence of AD is expected
dominant mutation cases of high penetrance
to triple from about 420,000 new cases in 1999
are considered, that percentage drops to less
to 1.32 million per year. Assuming no success-
than 5% (21). The most comprehensive and
ful intervention, the prevalence of AD could be
current lists of all mutations that may be con-
expected to rise over the next 50 years by a
sidered as AD genetic determinants or risk
factor of about 3.7 to 8.94 million with the
factors are maintained by Online Mendelian
range of 4.55 to 15.81 million in the United
Inheritance in Man (OMIM) (25) and Alzhei-
States alone. With the exception of early-onset
mer Disease Mutation Database (ADMB) (26).
familial AD (FAD) the disease is age.+ correlated
and its incidence grows exponentially with
3.1 .I Presenilins 1 and 2. Mutations in the
age. In part, because of their increased longev-
genes coding for the membrane proteins pre-
ity (294), women represent and will continue
senilin 1 (PSI) and presenilin 2 (PS2) are as-
to represent the majority (68% in 1997) of the
sociated with the early-onset FAD (27).Muta-
affected population. If one adds the year 2000
tions in the PSI gene on chromosome 14 are
U.S. census figures to the population of the
responsible for 30-50% of early-onset FAD
European Union (EU-15)and Japan, the prev-
and AD with the onset before the age of 55
alence of AD in "the major pharmaceutical
years. Some mutations in the PS2 gene on
markets" for that year could be estimated as
chromosome1 have also been observed but are
close to 8.7 million (20).
not as highly penetrant as those of PSI. It
appears that intracellular binding of the amy-
3 ETIOLOGY loid precursor protein (APP) to either PSI or
PS2 leading to cell-cell adhesion (28) repre-
Although a few genetic determinants and a sents a part of their normal function. The pre-
number of genetic and nongenetic (called in- senilins and their mutated forms participate
terchangeably medical, metabolic, lifestyle, in APP processing leading to production,
environmental, etc.) risk factors are recog- among others, of 4-kDa P-amyloid peptide
nized, or suspected as causative, the etiology (AP) of varied, predominantly 40-42 (39-43
of AD remains unclear. Only a small percent- overall) amino acid (aa) lengths (29). It was
age of AD cases can be segregated within fam- postulated that the PSI mutations represent a
ilies as early-onset (<60 years of age) or late- "gain-in-function" effect and contribute to or
onset (>60 years of age) FAD representing the are responsible for an aberrant increase in
autosomal dominant mutation cases of high production of amyloidogenic (having greater
penetrance and therefore considered a genetic tendency to misfold into a p-sheet and to form
disease. The prevailing rest, lacking the clear amyloid fibrils aggregating into amyloid) AP of
Alzheimer's Disease: Search for Therapeutics

42-aa length (30). PSI and PS2 may also affect cells appears to involve the static cell-sub-
other intracellular pathways linked to cell strate adhesion and/or neurite outgrowth
death (27). At present at least 35 to 50 differ- (381, synaptogenesis, synaptic plasticity, and
ent, mostly missense, and two splicing defect promotion of neuronal cell survival (39). APP
mutations in PSI and two in PS2 have been and an APP-binding protein FE65 are in-
identified in AD patients (21, 31). The PSI, volved in the regulation of cell movement (40).
PS2, and APP mutations linked to FAD were Exposure of cortical neurons to monoclonal
reported to increase secretion of AP (299). antibody, which binds to the extracellular do-
main of APP (human, rat, or mouse), leads to
3.1.2 Amyloid Precursor Protein (APP). neurite degeneration followed by caspase-de-
Mutations in localized on the chromosome 21 pendent apoptosis (41). One wonders whether
gene for APP have also been connected to a the AD-associated neuronal cell death is at-
limited number of early-onset FAD cases (32). tributable to aberrant processing of APP over-
At least 16 homologous amyloid-like proteins producing neurotoxic AP aggregates or to APP
(APLP) and APP species have been isolated deprivation.
and characterized (32). From the identified
major APP isoforms of 695, 751, and 770 aa, 3.2 Genetic Risk Factors
the 695-aa form is expressed preferentially in
the neuronal tissue. Alternative splicing of 3.2.1 Apolipoprotein E (APOE). Although
APP provides a total of eight isoforms, with the APP and PSI mutations represent a clear
lengths of 677, 695, 696, 714, 733, 751, 752, autosomal-dominant Mandelian trait of high
and 770 amino acids (33).Seventeen single-aa penetrance, their participation in all AD cases
and one two-aa (Swedish APP,7,Nm67,,) is minuscule (<5%). The case of PS2 remains
mutations of APP have been identified so far far from being clarified but its participation is
(25).APP, a type 1 cell surface glycoprotein, is negligible. Nevertheless, the determined mu-
produced in many cells and processed through tations provide, after expression in cell and
the secretory or endosomal-lysosomal path- animals, useful tools for in vitro and in vivo
ways (34). Processing of APP is carried out by studies.
the proteolytic enzymes named secretases. The polymorphism of the ApoE gene is con-
When the cleavage takes place in the presence sidered a major, best-documented, genetic
of distinct PSI or PS2 mutations regulating susceptibility risk factor for the late-onset AD
the y-secretases cleavage sites, it may lead to (21). The last decade observed the emergence
an increase in the production of amyloidogenic of ApoE as a dominating factor in aging-re-
AD42 (Apl-42). Under "normal" conditions, lated diseases like cardiovascular disease
in the brains of nondemented elderly individ- (0) or dementia and longevity in general
uals, Ap42 is actually the ubiquitous form (42). Besides being synthesized in liver (90%of
(37). Although AP42 is considered "amyloido- ApoE in circulation), lung, ovary, muscle,
genic," one should keep in mind that it is AP42 spleen, and kidneys, ApoE is also synthesized
that is a major component of the SPs that are in the central nervous system (CNS) by glia,
of diffused "preamyloid" nature and present macrophages, and neurons (43). ApoE Ad its
in the old but otherwise AD-free individuals low density lipoprotein (LDL) receptors are
(296). It is the AP40 that dominates in the employed in transport and metabolism of lip-
more compact, dense, "mature" SP, consid- ids, and in neural tissue repair after injury.
ered by some to be of greater inflammatory Located on chromosome 19, the ApoE gene
potential at a 1 : l O ratio of AP42IAp40 (35-37). occurs in three natural allelic variants ( ~ 2E,3,
The diffuse, "preamyloid" SPs that can be ob- 84).The mature protein of 34.2 kDa is secreted
served throughout the brains of normal, aged in mono- or disialylated form but most of the
individuals are therefore considered an age- sialyl
- is removed in circulation. The most
related phenomenon (6).The question of why, ubiquitous allele, ~ 3 is, found in approxi-
when, and how the diffuse SPs mature into the mately 78% of the Caucasian population (44).
dense AD-characteristic SPs remains unan- The presence of the ~4allele (allelic frequency
swered. The normal function of intact APP in ~4 = 0.15) is considered a major genetic risk
3 Etiology

factor for the late-onset FAD, SAD (45),CVD, Ap deposition. The model thus confirmed a
and longevity. The e4 heterozygous individu- critical and isoform-specific role for ApoE in
als have a three- to fourfold increased risk of (1)AP trafficking and (2) SP formation. Con-
AD, which doubles for the e4 homozygotes versely or additionally the binding of ApoE
(19). The 82 allele (allelicfrequency e2 = 0.08) isoforms to tau may affect phosphorylation of
seems to indicate the opposite (46). that protein and lead to NFT formation (52, ,
The allelic frequency varies in different 55). The connection between ApoE isoforms,
populations, with race being only one factor their serum concentration, high intake of di-
(47). The evident North-South allelic gradient etary cholesterol, and/or high cholesterol .
-
in Europe (30-35% of Scandinavians are e4 blood levels and an increased risk of AD, car-
carriers) might have a greater impact on lon- diovascular disease, and longevity is visible
gevity than the Mediterranean diet of red and rational but remains to be proved (47).
wine, olive oil, and feta cheese (47-49). Pa- The reports of observably lower incidence
tients carrying at least one e4 allele were re- of SAD among the patients prescribed statins
ported to have an increased density of SP and (56),the differentiated cholesterol response to
AP deposition. The exact role of polymorphism statin treatment dependent on the allele
of this 299-aa, 34-kDa protein is unknown and present (571, and the surprising response of e4
probably very complex. The structural differ- carriers with CVD to statin in a myocardial
ences are relatively small. The most ubiqui- infarction survival study (58) emphasize the
tous isoform ApoE3 has cysteine (Cys) and ar- need for large enrollment studies of these
ginine (Arg) in positions 112 and 158, links. An additional link between the ApoE
respectively. In the most common variant of allele and AD comes from the increased CSF
ApoE2, the amino acid Arg15' is replaced by cortisol as a function of ApoE genotype (59).
Cys. InApoE4 Argreplaces the Cys112residue. The highest levels of cortisol that may contrib-
ApoE binds to the usual AD suspects, AP and ute to neuronal degeneration were observed in
the microtubule-associated protein tau, and e4/e4 individuals with AD.
has been localized in the SP. The purified,
nonlipidated e4 isoform was reported to have 3.2.2 Susceptibility Locus on Chromosome
higher affinity than e3 to AP (50), suggesting 10. As mentioned above 95% of AD cases show
it may act as a pathological chaperone (51,52) no clear pattern of inheritance and out of that
stabilizing the P-sheet structure of AP fibrils, group only 50% carry ApoE e4 allele(s).A two-
and impairing AP clearance. The more recent stage genomewide screen, used to locate addi-
data on binding of ApoE isoforms and AP sug- tional genetic susceptibility risk factors (60,
gest that the native lipid-associated 83 isoform 61), located additional AD locus on chromo-
binds to Ap with two- to threefold higher af- some 10. From the presented evidence the
finity than that of lipid-associated e4 (53). chromosome 10 locus modifies risk of AD not
These findings may indicate that perhaps linked to the presence of ApoE genotype (60).
ApoE is involved in the clearance or routing It appears that the locus increases the risk of
out of Ap from the CNS and that the presence AD by elevating AP42 in carriers, as might be
of e4 impairs the process, thus leading to its evidenced by its high blood levels (61).
accumulation. Either alone or in complex with
Ap, ApoE seems to have no effect on APP pro- 3.2.3 Susceptibility Locus on Chromosome
cessing (52). A critical and isoform-specific 12. Another genomic screen of families with
role of ApoE in SP formation has been demon- LOAD (62) revealed AD susceptibility locus on
strated in a mouse model (54). In that model of chromosome 12 also not linked to the presence
FAD, APPV717Ftransgenic mice expressing of ApoE e4 allele. The a2-macroglobulin and
mouse, human, or no ApoE, the neuritic de- lipoprotein receptor related protein (LRP)
generation was virtually absent in ApoEP'- genes present on this chromosome were ini-
mice, although significant AP deposition was tially considered as suspects (63).
observed. When the mice expressing ApoE4 It has been proposed that a genetic varia-
were compared with those expressing ApoE3, tion in a transcriptional factor LBP-lc/CP2/
the former showed a 10-fold greater fibrillar LSF gene and not the LRP gene is the suscep-
Alzheimer's Disease: Search for Therapeutics

tibility factor for LOAD (63). The search is far ceptibility factor, the ApoE genotype, has been
from over and one can expect additional loci to implicated as a modulator of the environmen-
be discovered as the result of genomewide tdmetabolic risk factors, such as head injury,
screening. stroke, hypertension, arteriosclerosis, and
thrombosis, serum cholesterol, or estrogen re-
3.2.4 Tau Protein. Intracellular NFTs, con- placement therapy to mention a few (68). The
sisting mostly of paired helical filaments putative environmental risk factors, consid-
(PHFs), occurring in the selected populations ered among the others, are diet (high choles-
of nerve cells before degeneration carry the terol andlor high caloric intake), smoking, al-
subunit protein: the microtubule-associated cohol consumption, depression, chronic or
protein tau in the hyperphosphorylated, insol- oxidative stress, and the like, affecting the
uble form (64). A number of familial neurode- vascular or endocrine equilibrium (69). What
generatory diseases grouped into the so-called is hoped for is to establish a link between a
"frontotemporal dementia and parkinsonism genetic susceptibility factor, or the lack of it,
linked to chromosome 17" (FTDP-17) show and an environmental trigger (e.g., head in-
tau protein pathology indistinguishable from jury) (66). The overwhelming number of fac-
that of AD (64). Although no pathogenic mu- tors, which appear to contribute to AD, en-
tations in tau protein have yet been associated couraged attempts to formulate a unified
with the AD, the abundance of NFTs corre- hypothesis including or explaining all of them.
lates with the degree of neurodegeneration Particularly of interest is the unifymg hypoth-
(65). The prevailing opinion at present is that esis of Heininger (70-73), which advances the
the presence of NFTs in AD manifests a concept of AD as a metabolic disease. The ge-
"downstream" response to the pathological netic and environmental/metabolic factors,
events initiated by that disease. In transgenic according to the hypothesis, could contribute
mice expressing the Swedish mutation of APP to the deterioration of homeostasis of the cal-
(APP695,,5N,N,,,,), the Ap amyloidosis in- cium ion-energy-redox triangle and disrupt
duces the initial stage of tau accumulation the cerebral reserve capacity under metabolic
(66). Nevertheless, given the large number of stress. The brain in AD would then attempt to
neurodegenerative disorders with tau pathol- adapt to energetic stress by releasing soluble
ogy, the mechanism of NFT formation is sub- Ap as an agent mediating the metabolic switch
ject to detailed studies (67). that preserves glucose for anabolic needs and
promoting the oxidative use of ketone bodies.
3.3 Nongenetic Risk Factors
From that point of view, AD should be consid-
Although a much higher percentage (30-50 to ered as a progeroid systemic disease and all
95%) of genetic risk factors has been postu- the factors leading to it as progeroid factors
lated, the genetic determinants of high pen- (73).
etrance listed above and linked to FAD repre- Factors for which the anecdotal threshold
sent only a small (<5%) percentage of total has been crossed are briefly discussed below.
clinical manifestations of AD. FAD, LOAD, Unsurprisingly, they link to the ApoE genotype.
SAD, and the process of aging show many sim-
ilarities, whereas the differences appear to be 3.3.1 Traumatic Head Injury (THI). A num-
of a quantitative, chronological, and kinetic ber of studies suggest a likely link between a
nature. It is highly unlikely that AD pathology risk of developing AD and THI acting as an
can originate in response to environmental environmental trigger (74). It is evident in the
challenge alone. The elucidation of interde- pig model of a brain injury that even a mild
pendency between genetic and nongenetic risk trauma with full recovery leads to the accumu-
factors implicated in AD should benefit from lation of Ap and formation of neurofilament
the completion of long-term, multicenter, inclusions (75). Similarly, an overexpression
large-enrollment clinical studies, planned or of APP was observed in the brains of gunshot
under way at the present, and from exhaustive survivors (76) and in head-injured sheep (77).
epidemiological investigations. For example, Regretfully, studies involving large groups of
the already mentioned notorious genetic sus- participants, like the MIRAGE (78) and the
4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation 749

Rotterdam (79) studies, provide contradictory provide an atlas of therapeutic targets of op-
results. The presence of ApoE s4 allele(s) is portunity a la arachidonic acid cascade. The
associated with worse neurological impair- amyloid cascade hypothesis (29, 87) is so
ment in head injury or stroke patients, sug- widely circulated and accepted that it leads
gesting that ApoE4 might actually impair neu- one to recall a classic Russian proverb: "Ha
ral tissue repair (80). 6e3n~nsen mona conosefi" ("In birdless field, ,
even . . ."). It has also awakened a vocal oppo-
3.3.2 Hypercholesterolemia and High Den- sition rejecting /3-amyloidocentrism and the
sity Lipoprotein (HDL) Cholesterol. In the be- Church of Holy Amyloid (CHA) (88).Proposed _ -
ginning, the relationship between ApoE geno- by Hardy and Allsop (89), and modified ever
type, total serum cholesterol, its high and low since, it may be coarsely summarized (Figs.
density lipoprotein fractions, and AD was the 13.1 and 13.2) as follows.
subject of narrow epidemiological studies in APP is expressed in neurons and glia,
old and very old. A small Finnish study in- where it is synthesized and cotranslationally
ferred that, independent of genetic status, inserted into the endoplasmic reticulum (ER)
high serum cholesterol represents an indepen- (90). Of all the APP mutations identified, most
dent risk factor (81). The conclusion of the of them take place in the immediate vicinity of
equally modest in size PAQUID study sug- the N- and C-terminal of the AP fragment or in
gested that, independent of genetic and other the middle of its @-turnarea (Fig. 13.1).
risk factors, elevated high density lipoprotein Two distinct paths carry out the proteolysis
cholesterol (HDLC) significantly reduced the ofAPP. Both appear to be regulated by numer-
risk of dementia of AD and vascular type (82). ous factors including stimulation of acetylcho-
The same study reported that age, low HDLC, line, serotonin, glutamate, and neuropeptide
the presence of apoE4 allele, low education, receptors (91, 92). The dominant, nonamyloi-
and low wine consumption were significantly dogenic a-pathway involving a-secretase,
associated with AD. Studies of patients taking cleaves APP between Lysl6 and Leu 17 of the
cholesterol level-lowering 3-hydroxy-3-meth- Ap domain in the extracellular space, and pro-
ylglutaryl coenzyme A reductase inhibitors duces a soluble APPa fragment (sAPPa) and
(statins)confirmed its, perhaps pivotal, role in aC-terminal fragment (aCTF). aCTF (also
the pathophysiology of AD (56, 83, 84). The known as C88 for 88 aa) is in turn cleaved by
reports indicated that the patients on statins y-secretases to produce fragments p3 (from its
did show a reduction in AD incidence (56,831. 3-kDa molecular weight, synonymous with
Epidemiological observations are begin- some Apx-40 and Apx-42). Most (90%) of the
ning to be confirmed in vitro. For example, in APP is processed that way. One should keep in
APP751-transfected HEK 293 cells the ele- mind that the activity of y-secretase indicates
vated, by various means, level of cholesterol a relatively distance-specific [from the trans-
caused a dramatic reduction in secretion of the membrane domain (TM)], not aa-specific, (93)
soluble APP fragment sAPPa (84). At the cel- enzyme.
lular level it is by now proved that cholesterol The second amyloidogenic p-pathway em-
depletion (by 70%) in cultured neurons by ploys p-secretase [beta-site APP cleaving en-
combination of lovastatin treatment and zyme (BACEl), Asp2, memapsin21, which is
methyl-p-cyclodextrinextraction reduces pro- largely present in the distal Golgi membrane
duction of Ap below detectable levels (85) by (94). p-Secretase is responsible for cleaving
shifting the APP processing to a-secretase APP at the N-terminus of AP between Asp1
(86). and Met-1. Thus, the generated soluble
APPP fragment (sAPPp) leaves the scene,
4 PREVALENT HYPOTHESIS: AMYLOID whereas the membrane-bound PC-terminal
CASCADECUM-CHOLESTEROL ET fragment (PCTF or C99) is in turn cleaved by
INFLAMMATION y-secretases to produce Ap of 40- or 42-aa
length. The y-secretase cleavage of C99 leaves
The delineation of the AD pathogenic cascade, an unstable CTFy of 57- to 59-aa residues (95).
leading to neuronal death by apoptosis, should Both AP40 and AP42 are produced in normal
75 0 Alzheimer's Disease: Search for Therapeutics

Extracellular I transmembrane

p-secretase a-secretase
I y-secretase(s?)

[ Mutation sites KLVFF (Ap16-20) - aggregatmn domain

Figure 13.1. Human AP domain of APP: processing and mutation sites.

and SAD individuals but in different propor- ported to be significantly lower in the CSF and
tions (37). The ratios differ, with AP401AP42 plasma of AD patients (99). The sites of pro-
ratio of 10 in SAD. In nondemented geriatric duction of AD of various lengths and its
controls Ap42 was dominant. The soluble Ap N-truncated fragments were the subject of nu-
are present in cerebrospinal fluid (CSF) of nor- merous investigations. According to Green-
mal and AD individuals at similar levels field et al. (go), APP translocated into the lu-
(10-8-10p10 M ) (96). Their serum and CSF men of ER forms N-truncated Apx-42, which
levels were suggested (971, but do not appear stays in the ER in an insoluble form. The un-
to be indicative of the presence of AD (98). processed APP moves through the Golgi appa-
Naturally occurring antibodies to AP were re- ratus (GA) to the trans-Golgi Network (TGN)

I psecretase
I a-secretase
I Y-secretase

Y-secretase path
CTFB / c&xI

Figure 13.2. Amyloid cascade.


4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation 75 1

where AP40, AP42, and their N-truncated teristic of being processed in the transmem-
APx-40 and Apx-42 peptides are generated. brane domain (108, 110-113). That discovery
The unprocessed APP, PCTF (C99),and solu- presents the seekers of y-secretase inhibitors
ble AP are packaged for release into post-TGN with a predicament of selectivity, how to pre- -
secretory vesicles. When released they can vent processing of APP without affecting the
travel to the surface of neuronal cells, where fate of Notch. -F
a-secretase generates the bulk of sAPPa One of the remaining questions is how the
(loo),secreted together with AP40, AP42, and Aps, generated inside the cell, pass through or
the N-truncated fragments. The unprocessed detach from the cell membrane and leave for
APP and the a- and P-CTFs can be internal- extracellular space where the SPs are formed.
ized to the endosome or lysosome and re- To that effect, an ATP-binding cassette (ABC)
turned to TGN for additional processing. That transporter, a p-glycoprotein (p-gp), was pro-
pathway was confirmed when production of posed as an Ap efflux pump (114). Equally im-
Ap40 and AP42 was abolished by preventing portant is the question of degradation of the
C99 from leaving ER (101). generated AP. One of the candidate enzymes
The M P a fragment was reported to have was reported to be neprilysin, one of the major
neurotrophic and neuroprotective (against endopeptidases in the brain (115) and the fast-
glucose deprivation and glutamate toxicity) est to degrade both Ap40 and AP42 (116). In
properties, to stimulate neurite outgrowth, the brains of neprilysin-deficient mice the ele-
and to regulate synaptogenesis (39, 102). The vated Ap located in the same order and regions
memory-enhancing properties of sAPPa were as reported for humans (hippocampus > cor-
reported in normal and amnestic mice (103). tex > thalamus/striatum > cerebellum).
Recently, the sAF'Pa fragments originating Once secreted, the Ap may aggregate sponta-
from APP751 and APP695 were identified as neously, with more hydrophobic AP42 showing
ligands for the class A scavenger receptor (SR- greater rate of assembly (96,117).The length of
A), suggesting a possible way for their clear- AP is not the only determinant of the rate of
ance (104). Evidently, the Kunitz-type pro- aggregation. The studies of a pathogenic muta-
tease inhibitor (KPI) domain present on tion of APP, the "Arctic" mutation (E693G1,
sAPPa originating from APP751 is not re- was reported to produce AP, which forms proto-
quired for binding. fibrils at a much greater rate than does the wild-
The biological activity, if any, of sAF'PP is so type (118).To form the core of SP after being
far unknown. The role or contribution of generated through proteolytic cleavage of APP,
N-truncated AP (p3, for example) to AD is the AP have to undergo a continuous process of
subject of a hotly contested debate, entitled the structural transformation (117, 119). The re-
shorter amyloid cascade hypothesis (87,105). leased AP initially stay in solution as a random
A mutation in either APP or PSI or even coil or a-helix (120, 121). The transition from
PS2 (29) alters the way APP is processed, ei- random coil or a-helix to p-sheet conformation
ther in favor of increasing the ratio of amyloi- begins the process of oligomerization and fibril
dogenic AP42 (which predominates in the im- formation, with AP42 assembling more readily
mature, diffused SPs) or simply increasing the than AH0 (122). A stable AP dimer appears to
production of AP4O. Indeed, some FAD-linked be the building block of the AP filament. The
mutations in PSl(A9) lead to formation of growth of the fibrils proceeds by the addition of
higher levels of AP42 in TGN-to-plasma mem- Ap dimers and tetramers (123). The amyloid
brane transport vesicles (106). Presenilin is fibrils thus formed are straight, unbranching fi-
necessary for production of AP as it complexes bers of 70-120 A in diameter and of indetermi-
with the CTFs (C99 and C83) (107). The evi- nate length (124).
dence exists of a physical interaction between The in vitro studies of that process using
PSI and Notch receptors, Notch being a pro- synthetic Ap40 at low pH suggested a kinetic
teinlike APP, a large single-transmembrane model in which (1) a nucleation step is re-
protein important in development and differ- quired, (2)nuclei are produced from seeds and
entiation of adult self-renewing cells (108, from AP micelles, and (3) fibril elongation is
109). Both proteins have an atypical charac- achieved by irreversible binding of AP mono-
Alzheimer's Disease: Search for Therapeutics

mers to the fibril ends (125). Concentration of rectly in contact with Ap, the astrocytosis was
Ap appears as a critical parameter for micelle evidently doubling the number of apoptotic
and fibril formation. Either AB monomer or cells (132).
dimer polymerization models could be used to The presence of reactive microglia, macro-
determine the rate of fibril formation under phage-like phagocytic cells, associated with
given
- conditions (126). The maximum rate of the mature, neuritic SP is one of the charac-
formation was given as t , , for AP42 of approx- teristics of AD. The presence of these main
imately 18 min and for AP40 as approximately inflammatory response cells in AD represents
6 h. ApoE and antioxidants decreased the final the foundation of the inflammation hypothe-
-
amount of fibril formed in a dose-dependent sis. The question whether reactive microglia
way, although only ApoE extended the time to are there to help or to harm is still open. An-
other question is whether they appear at the
proceed to equilibrium (126). These findings
beginning or at the end of development of AD
are in agreement with the observation that
(133). It is the fibrillar AP that induce strong
free radicals, some perhaps generated by the cellular activation in primary cell culture
A0 fragments (127), appear to promote AP (134).Small aggregates of fibrillar AP and sol-
fibril formation (126). As always, there are uble AP, despite minor differences in interac-
also reports that Ap does not form spontane- tion with microglia, do not show a great degree
ously free radicals (128). The other problem of degradation after internalization (96).
with the fibrillogenesis models is that a num- Some of the fibrillar AP might be initially de-
ber of Apx-40142 N-terminal fragments have graded by microglia but the degradation stops
been reported in the SPs and they appear to after 3 days. The soluble AP is released rapidly
aggregate much faster than do the full-length after internalization and very little is de-
Ap (129). The identified pyroglutamyl N-ter- graded. Almost accepted is the hypothesis that
mind fragments AP3pE and APllpE, by ag- the neurotoxicity of Ap is not linked to its mo-
gregating faster and being more resistant to nomeric forms or insoluble amyloid precipi-
proteolysis than the full-length AP, would tate but to its soluble intermediate oligomers
make perfect seeds for amyloid formation of full-length AP and its fragments (131, 135,
(130). From in vitro assays a number of com- 136).
pounds have been identified to affect that con- All the above-described events happen in
tinuous process of assembly. A conclusion was the environment sensitive to cholesterol levels
also drawn that the processes of fibril assem- linked to or influenced by the genetic risk fac-
bly and disassembly appear to be distinct tor ApoE. The presence of the ApoE4 allele,
(119). The process of AP fibrillogenesis is still ~ 4 1 in
~ 4particular, indeed correlates with the
waiting for its Melvin Calvin to unravel it. degree of Ap deposition (119,137-139).
Secreted AP and their fragments in various
oligomeric forms are considered to be, to a dif- 4.1 lnhibitors of AP Production
ferent degree, cytotoxic and to induce apopto-
sis in neuronal cells (131). 4.1 .I a-Secretase Inhibitors. Proteolysis of
The transformation of immature, diffuse APP by a-secretase takes place at the cell sur-
SPs composed almost exclusively from amyloi- face, manifesting an end to its processing by
dogenic AP42 into the mature, neuritic SPs is the cell (100). Inhibition of a-secretase would
poorly understood. It appears to be a continu- serve no purpose in AD but, as one of three
ous process, with numerous intermediates ob- enzymes or groups of enzymes processing
servable in the postmortem brains. The con- APP, it deserves attention. Although not iso-
struction and composition of mature, neuritic lated as yet, it appears to belong to a group of
SPs are fairly complex processes, in which the zinc metalloproteases and to be closely re-
core consists mainly of AP40/42 and Apx-40142 lated, by inhibition profile, to angiotensin-con-
fragments and is surrounded by dystrophic verting enzyme (ACE) secretase and to colla-
neurites, activated microglia, and reactive as- genase (100, 140). Some of the investigated
trocytes (96). In neuronal cultures condi- (140) a-secretase inhibitors, such as batima-
tioned by AP-treated astrocytes, but not di- stat (1)and marimastat (21, initially devel-
4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation

(2)

0
fH3k
H
CH3
H cHT
CONHOH CONHOH
(4)

NHCH3

CONHOH

HO
(5)

Figure 13.3. Inhibitors of a-secretase.

oped as antineoplastic agents, and their ana- produced no profound phenotypic defects with
logs can be seen in Fig. 13.3. simultaneous reduction of Ap (142). The fact
that the knockout mice developed normally
4.1.2 p-Secretase inhibitors. p-Secretase, and showed no consistent differences with
also known as memapsin 2 or p-site APP their wild-type littermates makes p-secretase
cleaving enzyme (BACE1) [BACE2 was a perfect target of opportunity for the develop-
mapped to Down syndrome (14111, the pri- ment of AD therapeutics. The observed ab-
mary membrane-anchored aspartic protease sence of astrocytic BACE immunoreactivity in
in mammalian brain, does not appear to be of young transgenic Tg2576 mice (143) and the
importance in mammals (142). The loss of consecutive expression at later stages as a pos-
p-secretase activity in BACE knockout mice sible result of astrocytes activation should en-
Alzheimer's Disease: Search for Therapeutics

I phr.r HNfi
HOOC COOH
R = H (OM99-1) (6)

Figure 13.4. Inhibitors of 0-secretase.

courage vigorous pursuit of that enzyme. The 13.111 was found to be a perfect substrate for
accumulated knowledge and experience with recombinant memapsin 2 (144). X-ray crystal-
the approved peptidomimetic HIV protease in- lography studies of (7) bound to memapsin 2
hibitor drugs is available. Yet, despite the en- permitted the design of inhibitors of lower mo-
couraging experiments with the knockout lecular weight (145).The most potent of them
mice, the trepidation persists that there might (8-11,Fig. 13.4) have Ki values between 2 and
be a role for p-secretase in normal physiology 10 nM.
and that the selectivity against other pro-
teases might be difficult to attain. 4.1.3 y-Secretase Inhibitors. PSI-associ-
The first reported p-secretase inhibitors, ated y-secretases participating in processing
OM991 and OM992 (144) (6 and 7, Fig. 13.4), of APP are also needed for proteolysis of an-
were designed by use of the template of the other transmembrane protein, Notchl (146,
Swedish mutant APP. The Swedish mutation 147). Both proteins appear to be competitive
site of p-secretase action [SEVNLDAEFR in- substrates: APP, or rather its C99 fragment,
stead of SEVKMDAEFR wild-type (see Fig. for APs and Notchl for a signaling molecule
4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation

Figure 13.5. Inhibitors of y-secretase.

Notch C-terminal domain (NICD) (148). The clear translocation but to preserve Notchl
dipeptide aldehyde (12, Fig. 13.5) (149) served signaling (156).This was further confirmed in
as a lead to a group of inhibitors, with one fetal thymus organ cultures, where they inter-
compound (13)showing 10-fold improvement fered in T-cell development, indicating loss or
in IC,, values (150).A study of difluoro ketone reduction of Notchl function (109). An aspar-
peptidomimetics developed from a lead (14) tyl protease transition state mimic, L-685,458
provided a valuable insight into the mecha- (17) was reported to be a potent (IC,, = 17
nism of the action of y-secretases (151-153). nM) inhibitor of y-secretase (157). One of the
At a micromolar level these compounds calpain inhibitors, MDL28170 (18), was re-
blocked the formation of AP40 and AP42 and ported to block production of AP40 but not
increased formation of AP42 at a subinhibi- AP42 (158). The search has been recently en-
tory level (152,153).A similar group of dipep- hanced by introduction of a y-secretase assay
tide aldehydes (15) confirmed the findings based on detection of the elusive and unstable
(154). A group of fenchylamine sulfonamides CTFy (95).
(16) was reported to inhibit y-secretases at mi- The first group of y-secretase inhibitors
cromolar concentrations in HEK293 cells free of interfering with Notch processing (19-
transfected with the double-mutant form of 21, Fig. 13.6) or endoproteolysis of presenilins
human APP (155). reduced AP40 and AP42 in favor of C99 and
The first peptidomimetic y-secretase inhib- C83 CTFs arising, respectively, from P- and
itors and aspartate mutations in PSI were re- a-secretase action (159). Their design was
ported to impair Notchl proteolysis and nu- based on observations that (1)disruption of
Alzheimer's Disease: Search for Therapeutics

Figure 13.6. Inhibitors of y-


secretase.

the chymotrypsin-like activity of the protea- CoA) reductase] are prescribed chronically to
some correlates with the inhibition of AP se- the elderly (162). The initial success of statins
cretion (160) and (2) that the serine-protease was impressive and the FDA approved six of
inhibitor AEBSF modulates AP recovery them (22-27, Fig. 13.7) (163).Although all ap-
(161). At 100 pit4 concentration, compounds proved statins have been associated with a
(19),(20), and (21) achieved 70-80% inhibi- very low incidence of rhabdomyolysis, only
tion of total Ap40142 recovered. one, cerivastatin (271, was withdrawn from
the U.S. market because of it (164, 165). The
4.2 Statins ability of statins to reduce the levels of Aps in
Developed to control elevated low density li- uitro and in uiuo was reported (85, 86, 166,
poprotein cholesterol, statins [the inhibitors 167) but at doses exceeding the approved hu-
of 3-hydroxy-3-methylglutaryl-CoA (HMG- man dosage. A cyclohexylalanine-based statin
4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation

NaOOC

HO
(22) Lovastatin [mevacor] (1 987) (23) Pravastatin sodium [pravachol] (1991)

(24) Simvastatin [zocor](1991) (25)Atorvastatin calcium [lipitor](1996)


F

COONa

CH3

(26) Fluvastatin [lescol](l993) (27) Cerivastin sodium [baycol] (1997-2001)

Figure 13.7. Statins.

(28, Fig. 13.8) was trawled out from the patent justice, the cited study did not show any differ-
literature along a lipophilic tetraline (29) as ence in total cholesterol and HDL cholesterol
an inhibitor of AP formation in cell culture either.
(155). A small study of age- and gender- The actual mechanism of how the statins
matched asymptomatic Japanese patients, ei- affect AD remains unknown. For amyloid cas-
ther on pravastatin or simvastatin or na'ive for cade enthusiasts, it is possible that the re-
an unknown length of time, did not show any ported reduction in the AD prevalence in pa-
observable difference in serum A@ levels tients on statins (56, 83) reflects the
(168). One should remember that the AP lev- cumulative effect of small but effective de-
els in serum or CSF are not considered the creases in Ap production over a long period of
best measure of therapeutic progress. To do chronic administration. The explanation of
Alzheimer's Disease: Search for Therapeutics

experimentally observed shift, favoring ecule will self-assemble or complex with simi-
y-secretase processing of APP, attributed to larly attractive molecules. Aggregation (self-
lowering of membrane cholesterol, might be assembly) of APs and their neurotoxicity are
the peculiar nature of y-secretase (84). The intimately linked but may be affected by the
y-secretase site of APP processing belongs to a different groups of compounds. If the SPs are
very limited number of intrarnembrane pro- responsible for initiation of neurodegenera-
teolytic cleavage sites, requiring perhaps a tion, prevention of formation of AP fibrils, or
cholesterol-rich environment such as a lipid their disassembly, should have a therapeutic
raft domain (84, 169). Fluorescence micros- effect. If the SPs are just the deposits of assem-
copy studies of PC-12 and SH-SY5Y cell lines bled AP and cellular debris, taking them apart
exposed to exogenous Ap revealed an inverse might do the opposite (173). The division of
correlation between membrane cholesterol
compounds affecting the AP fibril formation
level and AP cell surface binding and subse-
into inhibitors of AP aggregation (self-assem-
quent cell death (170). At present the debate
bly) and accelerators of AP disaggregation is
continues (171a,b) while the clinical trials of
spurious, but practiced by many.
statins for AD indication proceed (172). New,
safer, and significantly superior statins, which
reduce total cholesterol, low density lipopro- 4.4 Inhibitors of AD Aggregation
tein cholesterol, and apolipoprotein B, and in- To inhibit AP aggregation into amyloid is to
crease high density lipoprotein cholesterol prevent misfolding of soluble AP. Once the
more effectively than the presently available misfolding took place the aggregation is only a
five, might be in the NDA pipeline (http:// matter of time and far more difficult to control
www.ndapipe1ine.com). Their effectiveness to (174). So far only nicotine (30, Fig. 13.9) and
reduce the incidence of AD may be hoped to melatonin (31)appear to be affecting the con-
similarly improve. formation of soluble Ap (175-177). Antioxi-
dants, such as antituberculosis antibiotic ri-
4.3 Compounds Affecting Fibril Formation
fampicin (32) or a-tocopherol, were reported
At physiological pH Ap carries seven positive to inhibit aggregation and neurotoxicity of Ap
and seven negative charges in addition to two in vitro (178-180). A monoamine oxidase in-
hydrophobic domains (123). That kind of mol- hibitor, selegiline (33, Fig. 13.9), may also be
4 Prevalent Hypothesis: Amyloid Cascadecum-Cholesterol Et Inflammation

CH3

NH
0

HO\\"' (34) (PPI 433), Y = OH


H (35) (PPI 457),Y = NH2

Figure 13.9. Inhibitors of Ap aggregation and accelerators of A@fibril disaggregation.

considered to belong to that group. The role of basement membrane, were reported to inhibit
ApoE as antioxidant and fibril formation in- AP fibril formation by inducing a random coil
hibitor is still under investigation. It appears structure (183, 184). Like ApoA-I, laminin
that it has a biphasic effect that inhibits fibril binds AD with high nanomolar affinity.
formation at lower concentrations, while ac- The review by Findeis (185) and the work
celerating at higher micromolar AP concentra- of Bohrmann et al. (117) start a very diversi-
tions (126, 181). A constituent of high density fied list of compounds affecting aggregation of
lipoprotein complexes, apolipoprotein A-I AP in vitro at micromolar concentrations.
(ApoA-I),has a higher affinity to ApoE than to Given the high affinity of Ap for itself it was
AD, which it binds in a saturable, specific, and used as a lead to a number of D-aa analogs,
reversible manner with K, of 6 nM (182). providing stable compounds such as (34) and
Laminin and entactin, the components of (35) (186).
Alzheimer's Disease: Search for Therapeutics

4.5 Accelerators of AP Fibril Disaggregation levels were constant in all brain areas and
were not decreased with AD. That observation
Once an AP fibril is formed and becomes a
led to the conclusion that the lower levels of -
component of SP, it may be impossible to dis-
NEP mRNA observed in hippocampus and the
aggregate it and to return it to its original ran-
temporal gyrus were not related to neuronal
dom coil conformation. Although the process
loss but were preordained. Both areas are the
of assembly of AP fibril appears distinct from
high SP areas of AD brain. In the NEP gene-"
the process of disassembly, the same or similar
disrupted mice, the degradation of exogenous
groups of compounds may affect them both.
and endogenous AP was affected in a gene
The simplest of disaggregation agents 2,4-di-
dose-dependent manner (115). The highest -
nitrophenol and 3-nitrophenol were shown to
levels of AB in NEP-deficient mice were in
cause, at micromolar concentrations, com-
hippocampus and cortex and the lowest in cer-
plete disaggregation and to block neurotoxic-
ebellum, reflecting the AD pattern. Immuno-
ity of AP to rat hippocampal neurons in cul-
histochemical localization of NEP in postmor-
ture (187). In vivo, coinjection of these
tem human brain tissues indicated the same
nitrophenols with AP into rat hippocampus re-
pattern (193). The hippocampus and the asso-
duced (86 +- 17%) the volume of amyloid de-
ciation cortices, the sites most affected in AD,
posits. According to the authors, the hydro-
showed the lowest NEP immunoreactivity
phobic interaction of CTF nonpolar aa
compared to that of the primary somatosen-
sequences responsible for fibril formation is
disrupted by the hydrophobicity of nitrophe- sory and visual cortices. The question remains
whether the observed downregulation of NEP
noles.
activity reflects aging or is particular to AD.
The N-methylated congeners of hydropho-
The upregulation of NEP activity in the af-
bic core domain Ap16-22 (36, Fig. 13.9) were
fected areas of Ap deposition without affecting
reported to inhibit fibrillogenesis and also dis-
the NEP involved in the metabolism of numer-
assemble preformed fibrils (188).
ous regulatory peptides of the nervous, cardio-
vascular, inflammatory, or immune systems
4.6 AP Catabolism and Removal
presents another question. Another metalo-
One assumes that even a slight shift in the protease, endothelinanverting enzyme (ECE-I),
anabolic-catabolic steady state of AP produc- was identified with similar properties of de-
tion and removal, persisting over a prolonged grading Ap (194).
period of time, will eventually produce a Learning and memory deficits developed
pathological change. The hypothesis that the with aging in AP overproducing SAMPB mice
differential vulnerability of distinct parts of have been reversed with intracerebroventric-
brain to Ap deposition and neuronal destruc- ular (i.c.v.) or even i.v. injections of AP anti-
tion is based on altered metabolism of Ap was sense phosphorothiolate oligonucleotide (195).
behind the extensive search for the specific en-
4.7 Modulators of Aj3 Neurotoxicity
dopeptidase catabolizing Ap. Howell et al.
(189)reported extensive catabolism of AP by a APs, soluble as either random coil or a-helix,
neutral endopeptidase that leaves the APP in- do not show any neurotoxicity (196, 197),
tact. A thermolysin-like zinc metalloendopep- which appears to be related to the degree of
tidase, neprilysin (NEP) (1901, was deter- their aggregation (198). The inhibition of var-
mined to be involved in Ap degradation by the ious cholinergic neurotransmitter functions
use of multiple radiolabeled synthetic AP42 by AD takes place at the very low concentra-
injected into rat hippocampus (191). Catabo- tions below the neurotoxic treshold. The
lism of endogenous AP42 was arrested by in- fibrils of AP are toxic to cultured neuronal
fusion of NEP inhibitor and led to pathological cells and lead to their death, probably by ob-
deposition. NEP mRNA levels were measured served rapid production of hydrogen peroxide
in the brain and peripheral organs of AD and and lipid peroxidation (199). Oxidative stress
control cases (192). Simultaneously measured appears to be a proximal event in the AD (200)
were levels of the mRNA for the neuronal and the oxidative damage appears to be the
marker microtubule-associated protein 2. Its greatest in the beginning of the disease and
5 Attenuation of Cholinergic Transmission

decreases with the disease progression and favor of p-secretase in AD. Whether the in-
formation of SP and NFT (201). crease in production of AP40 and/or AP42 is
The recognition sequence of AP leading to achieved at the expense of the a-secretase pro-
aggregation consists of residues 16 to 20, that cess is also unknown. In addition, the process-.
is, KLVFF (135). The residue itself had no ef- ing of APP in human neurons appears to differ
fect on aggregation kinetics and only some ef- considerably from rodent CNS primary neu-
fect on Ap neurotoxicity. Coupling of the rec- ron cultures and continuously dividing celf
ognition sequence with a disrupting lysine types (34). Different sites of a-, P-, and y-secre-
hexamer (KLVFF-KKKKKK)dramatically ac- tase activity require codistribution of APP,
celerated AP aggregation, thus generating in- with respective secretases to affect the relative-
soluble AP precipitate, and significantly im- utilization (209). The removal of APP from
compartments with p-secretase activity to com-
proved protection against AP neurotoxicity
partments with a-secretase activity should in-
(135, 136). The inference from these findings
crease the release of sAPPa and, it is hoped,
is that the insoluble AP aggregate is not the decrease the release of APs (210-212). Phor-
molecule to be blamed for toxicity but, rather, bol esters acting by activation of protein ki-
a soluble intermediate oligomer generated in nase C (PKC) enhance the release of sAPPa
the process (136). from cortical synaptosomes (213, 214). The
The observation that the N-terminal part observation that muscarinic agents may act in
of AP is not associated with the fibril forma- a similar manner (215) provides for collateral
tion and remains outside of the fibril core (202, efficacy of acetylcholine esterase inhibitors. A
203) led to generation of specific monoclonal phosphatidylinositol 3-kinase inhibitor wort-
antibodies (mAbs) against that part of Ap mannin decreased release of both Ap and
(204-206). Used on PC12 cells the mAbs were sAPPa in N2a neuroblastoma cells expressing
shown to disaggregate Ap fibrils, maintain AP either wild-type APP or the Swedish FAD mu-
solubility, and prevent neurotoxic effects tant variant (209). Testosterone was reported
(207). to increase the secretion of sAPPa without af-
fecting the total amount of cellular APP (216).
4.8 APP Gene-Knockdown Agents
5 ATTENUATION OF CHOLlNERGlC
Gene knockdown, unlike gene knockout, per- TRANSMISSION
mits fine-tuning of gene expression. So far
only site-directed antisense oligonucleotides, A failing cholinergic transmission may be at-
directed at the AP region of APP, were tried in tenuated either by (1)prevention of ACh de-
a strain of mice spontaneously overexpressing struction, (2)supplementation of diminishing
APP (208). Administered by i.c.v. injection,
amounts of ACh released with exogenous, or
with or without antibody, the antisense phos-
(3) blocking of feedback mechanism regulat-
phorothiolated oligonucleotides directed at ing the release or synthesis of ACh.
the midregion of Ap reversed deficits in learn-
ing and memory. Given alone, these oligonu- 5.1 Acetylcholine Esterase Inhibitors
cleotides reduced APP levels by 43-68% in the
arnygdala, septum, and hippocampus. It has Acetylcholine esterase inhibitors are the first
been further proved that the phosphorothio- and so far the only group of drugs approved for
lated oligonucleotides can cross the blood- AD indication. With the advancing destruc-
brain barrier, and can be given in effective tion of the cholinergic network, the overall
doses by i.v. route (195). quantity of ACh released decreases below the
level necessary for transmission. Inhibition of
acetylcholine esterase (AChE) may prolong
4.9 aSecretase Shift
the life of Ach in the synapse, modulating the
The a-secretase-processing route is dominant strength and the duration of the signal. The
under normal conditions and it is unknown U.S. FDA has so far approved four AChE in-
whether and how that process is impaired in hibitors. The first on the market, tacrine hy-
Alzheimer's Disease: Search for Therapeutics

(37)Tacrine (cognex) (1993) (38) Donepezil (aricept)(1 997) '5

-
COOH

HBr

-
HOOC
(39) Rivastigmine tartrate (exelon)(2000) (40) Galantamine hydrobromide (reminyl)(2001)

Figure 13.10. Approved acetylcholine esterase inhibitors.

drochloride (Cognex, 37, Fig. 13.10), was ap- ceptors, if any are left, thus reducing the re-
proved in 1993. It did inhibit the AChE and lease of endogenous ACh. Because of their
butylcholine esterase but the hepatotoxicity nonselective site of action their use eventually
limited its use. Donepezil hydrochloride ( h i - leads to M3 AChR stimulation and untoward
cept, 38) approved in 1997, has a longer half- gastrointestinal effects (nausea and vomit-
life time that permits once-a-day dosing and ing). They do provide some improvement
lower hepatoxicity. Rivastigmine tartrate (Ex- when prescribed to patients with early to mild
elon, 39), approved in 2000, has a similar pro- AD. Their clinical benefits in advanced AD re-
file. Galantamine hydrobromide (Reminyl, main to be proved and seem doubtful. Thus,
40), initially extracted from daffodils, was ap- given the substantial investment in taking
proved in 2001. All four AChE inhibitors have these drugs to the market, the extended pre-
shown in well-controlled trials a statistically and postapproval search for collateral efficacy
significant improvement of at least three of these drugs, such as in affecting APP pro-
points on the Alzheimer's Disease Assessment cessing or allosteric sensitization of nicotinic
Scale, measuring independently the cognitive receptors, seems justified (218-221).
(ADAS-Cog) and noncognitive function. The
ADAS-Cog part of the scale scores between 0
5.2 Muscarinic Acetylcholine Receptor
and 70 points, with zero meaning the patient
Agonists and Antagonists
made no errors at all and 70 meaning the pa-
tient is profoundly demented. The normal in- An MI-selective agonist would be preferred
dividuals will usually make some errors, scor- for two reasons: (1)to activate M1 receptors in
ing between 5 and 10. One can therefore the affected areas and (2)to activate a-secre-
conclude that the relief provided by this group tase, shifting the processing of APP from pro-
of drugs is modest. Thus, the results obtained duction of AP, as M1 muscarinic agonists are
by the approved AChE inhibitors are compa- reported to do (222, 223). The problem with
rable to those produced by the porcine brain- the muscarinic agents is their selectivity. A
derived hydrolysate, marketed outside the muscarinic agonist could be selective to a
United States as Cerebrolysin (217). point in a functional assay and completely
The future of therapy with these drugs is in nonselective in a binding study. Every known
question. Although they prevent ACh from muscarinic agonist tried in preclinical studies
rapid hydrolysis, eventually the saved ACh ac- possessed an agonist, partial agonist, and an-
tivates the presynaptic autoinhibitory M2 re- tagonist portfolio that was impossible to un-
5 Attenuation of Cholinergic Transmission

Figure 13.11. MI-selective agonists, M1/M2 agonist/antagonist, and M2 antagonists.

tangle and was thus dose limiting. Many of properties, provided that the compound could
them, such as sabcomeline (SB-202026, 41, be made CNS selective. Otherwise, the M2
Fig 13.111, milameline (RU35926, 42), xa- AChR in the cardiovascular system would be
nomeline (LY246708, 43), or talsaclidine affected. A number of compounds claim to pos-
(WAL 2014,44), have been tried in the clinic sess that combination. For example, L-687,306
and failed. The reasons for failure were insuf- (45) and L-689,660 (46) were reported to be
ficient efficacy (lack of statistically significant M1 agonists and M2 antagonists in functional
improvement of cognitive functions) and side studies (225) and nonselective in binding stud-
effects. Even the most selective M1 agonist ies (221).
talsaclidine was withdrawn from clinical stud- The antagonists SCH72788 (47) and
ies, thus placing the muscarinic approach to SCH57790 (48) were reported to have greater
AD in doubt (224). affmity to M2 versus M1 AchR, and improved
Even more desired would be a combination performance in rodent models of cognition
of an M1-selective agonist with M2 antagonist (226,227).
Alzheimer's Disease: Search for Therapeutics

5.3 Nicotinic Acetylcholine Receptor


Agonists
Alfred Dunhill's book, The Gentle Art of
Smoking, can be found only in the old book-
stores, although the legend that smoking to-
bacco provides some degree of protection from
AD persists (http://www.forest-on-smoking.
-
org.uWfactsheets/factsalzheim.htm). It is rec-
ognized that nicotine and therefore the nico-
tinic ACh receptors
- (nAChRs) are involved in
attention, verbal learning, spatial memory,
and psycho-motor speed (228). The loss of nic-
otinic rather than mACh receptors is evident
from imaging and postmortem autoradio-
graphic and histochemical studies (229, 230).
The first to go are nAChR in the upper cortical
layers of the frontal cortex and in the temporal
cortex (229). That reduction is far more pro-
nounced than the loss of muscarinic acetylcho-
line receptors (mAChR), including M2 recep-
tors (230). Particularly affected in AD appear
to be neurons with high affinity nAChR of
a4p2 subtype, whereas the low affinity a7 ho-
mopentamer nAChR appears to be left intact
(231). Epidemiological studies of the smoking Figure 13.12. CNS-selective nicotinic agonists.
population are hampered by the fact that the
smokers, as perfect citizens, expire ahead of
their cohort and the survivors may therefore 235). Thus, given the remarkable heterogene-
belong to a more select group than their non- ity of nAChR [17 known subunits forming
smoking peers. The Rotterdam Study, a popu- multiple functional homopentamers and het-
lation-based follow-up study of elderly ini- eropentamers (236)l and their importance in
tially free of dementia concluded that the the CNS, one may hope these adverse affects
smokers have a higher risk of dementia and might be "designed out." From a family of nic-
AD (232). Of interest is the finding of that otinic agonists based on marine animal toxin
study that the smoking carriers of ApoE 84 anabaseine (49, Fig. 13.12),a selective agonist
allele had no increased risk, only the carriers of a7 nAChR, GTS-21(50), was developed and
of the other two "good" allelic forms. The ef- tested (231). Its 4-hydroxy metabolite was
fect of smoking may, of course, be explained shown to be equally efficacious on human and
away as being more than just a delivery of nic- on rat a7 receptors. On the other hand, MR-
otine. 2403 (51) was equipotent with nicotine in
What is truly frightening is the report that CNS, although it was 15-30 times less potent
nicotine alone, acting through nicotinic ace- in peripheral (237). In human nAChR sub-
tylcholine receptors (nAChR), stimulates an- types expressed in Xenopus oocytes MR-2403
giogenesis and promotes tumor growth and (51) was reported to be a selective agonist of
atherosclerosis at concentrations that are human a4P2 nAChR (238). Its close analog,
pathophysiologically relevant (233). TC-2559 (521, demonstrated CNS selectivity
Nevertheless. collateral functions for nico- by improving cognition without affecting loco-
tine have been found to (1) promote an motor activity (239). One way to compensate
a-secretase shift, leading to release of neuro- for the loss is the search for allosterically po-
tropic and neuroprotective sAPPa, and (2) tentiating ligands (APL) of nAChRs, which in-
prevent Ap and CTFp neurotoxicity (234, crease the probability of channel opening in-
7 Estrogens and Androgens

Figure 13.13. Modulators of AMPA responses.

duced by Ach and nicotinic agonists, and also potentiation in hippocampus in vivo (250).
decrease the receptor desensitization (230). The mechanism of action of far more potent
LY392098 and LY404187 was suggested to be
different from that of Ampakines, in that the
6 MODULATION OF AMPA RESPONSES
magnitude of the enhancement is time depen-
dent, increasing with continued agonist expo-
Episodic, short-term memory is the first to go
sure (246).In either case, despite the frequent
with the progression of AD and other neuro-
forward-looking statements, compounds like
degenerative diseases (240). Compounds such
the AChE inhibitors are nothing more than
as aniracetam (53,Fig. 13.131, piracetam (54)
palliatives free of disease-modifying proper-
or S18986-1 (55) (2411, CX516 (56) (242),
ties.
CX509 (57) (2431, or CX614 (58) (2441, and
LY392098 (59) (245) or LY404187 (60) (246)
positively modulate a-amino-3-hydroxy-5- 7 ESTROGENS AND ANDROGENS
methyl-4-isoxazole propionic acid (AMPA) re-
ceptors. In addition S18986-1 enhances The belief that estrogen, and especially the
AMPA-mediated release of noradrenaline postmenopausal estrogen replacement ther-
(247). The term nootropic agents is often ap- apy (ERT), may reduce the risk of AD is very
plied to these compounds and one group was strong. The idea was advanced by many short-
even registered as Ampakines (241, 248). term, open-label studies but rejected by the
Compounds such as aniracetam, piracetam, or well-controlled, long-term studies (251-254).
S18986-1 positively modulate the AMPA re- The discrepancy between the in vitro promises
ceptors by suppressing the desensitization and the in vivo hopes is glaring (255,256). In
process (249). The Ampakines also facilitate cultured neurons 17P-estradiolreduced secre-
the induction of NMDA-dependent, long-term tion of AP40142 (257)and protected them from
Alzheimer's Disease: Search for Therapeutics

Ap toxicity (258), providing a molecular basis fected. Peripheral administration of AP anti-


for the claim of ERT as an AD-preventive mea- bodies suggests their ability to cross the blood-
sure. Regretfully, longer-term ERT studies brain barrier and reduce the amyloid burden
provided negative results (252). The use of es- (268). What is of interest is that the antibodies.
trogen for treatment of mild to moderate AD, trigger microglia to clear amyloid deposits
in women who had hysterectomy, for a period through cell-mediated phagocytosis, some-
of over 1 year also did not slow the disease thing they do not do alone (96). The synthetic:
progression (253). The results of the Rotter- aged, and fibrillar Ap42 (AN-1792) was used
dam Study (254) did not support the hypothe- with adjuvant as an immunization tool in clin-
sis that a longer reproductive period reduces ical trials (269). When some of the patients (5-
the risk of dementia. The awaited results of of 360) showed brain inflammation, the trial
truly long term studies will hopefully provide was prudently suspended (297).
an answer, although prognosis is not optimis- Given the fact that the Ap42 does cross the
tic (259). blood-brain barrier in both directions, and
Like the estrogen levels, so the total testos- may begin to form fibrils, immunization with a
terone level and the bioavailable testosterone nontoxic, nonammmyloidogenic, homologous
level, in particular, decline in both sexes with peptide K6Apl-30-NH2 was suggested as a
age. Testosterone supplementation was re- safer approach (270). A remarkable (89 and
ported to protect orchiectomized, aging male 81%) reduction of cortical and hippocampal
rats from osteoporosis (260), increase nerve brain amyloid burden was reported. Another
growth factor levels in rat brain (261), or im- approach reported was the production of
prove depression in aging men (262). The highly specific antibodies locking the epitope
treatment of N2a cells and rat primary cere- EFRH of AD (271). One should remember
brocortical neurons with testosterone in- that, unlike transgenic mice, the AD patients
creased secretion of SAPPLY and diminished usually (298)do not show elevated levels of AP
the release of Aps (263). In a similar manner, in either blood or CSF (a measure of success)
treatment of GT1-7 rat hypothalamic cells and that their immune response may not
with testosterone stimulated the a-secretory match the expectations (272).
pathway by increasing the secretion of SAPPLY,
without affecting the total amount of cellular
9 IMMUNOSUPPRESSION
APP (216). In a group of six men treated for
adenocarcinoma of the prostate with hor-
Given the evidence presented, the AD mani-
monal suppressants, the precipitous drop in
fests itself with the reactive microglia cluster-
their levels of testosterone and estradiol cor-
ingand attacking SPs (273). The SP stimulate
related with the increase of Ap40 plasma lev-
the microglia to become not only reactive but
els (264). The therapeutic implications of ob-
also neurotoxic (274). Whether an immuno-
servations like these remain uncertain.
suppressive therapy aimed at the inflamma-
tory glia endogenous to the CNS has a chance
of success remains an open question. Neuro-
8 IMMUNOTHERAPY
immunophilin ligands like cyclosporin A or
FK-506 (tacrolimus) prevented overexpres-
Very low levels of autoantibodies to AD were
sion of APP and Ap and stimulated release of
detected in the elderly, although they do not
neuroprotedive SAPPLY (275).
appear to be indicative of either the presence
of AD or protection against developing that
disease (265). In PDAPP transgenic mice over- 10 INHIBITORS OF APOPTOSIS
expressing APP,,,,, immunization with
Ap42 was reported to provide, depending on A large family of cysteine proteases has been
the time of immunization, protection from de- identified as responsible for apoptosis of neu-
velopment of AD-like neuropathologies or re- ronal cells. Activation of caspase-3 in CNS was
duction of their extent and progression (266, observed in stroke, spinal cord trauma, head
267). The overall levels of AP were not af- injury, and AD and proposed as a target of
12 Antioxidants

therapeutic intervention (276). The inhibition


of neuronal loss in animal models of stroke
and head injury by peptide-based inhibitors of
caspase may provide leads for future systemi-
cally active agents. However, to do that the CH3
etiologic role of caspase in AD must be further
investigated and proved (277). (61 P

11 ANTI-INFLAMMATORY AGENTS

A comparison of positron emission tomogra-


phy (PET) and MRI scans of AD patients and
normal individuals suggests activation of mi-
croglia in the early stages of the disease (278).
The Cl1 tracer indicated increased binding in
areas, which are known to be affected by the
disease. Over a period of 12-24 months, the
repeated MRI scans correlated the areas of the
highest binding with the areas of highest rate
of atrophy. In a mouse model of AD, ibuprofen
suppressed plaque pathology in mice fed chow
containing 375 ppm for 6 months (279). Nu-
merous studies of risk and progress of AD
among the users of anti-inflammatory drugs
suggested a time of use-related decrease of
risk (2801, but could not prove their therapeu- Figure 13.14. Anti-inflammatory agents in IND
tic usefulness (281). The selection of the right trials for AD indication.
anti-inflammatory agent might be needed. At
least two of the approved nonsteroidal anti-
degradation in vitro and in vivo (284) and cat-
inflammatories (NSAIDs), ibuprofen (61, Fig.
alyzes P-sheet aggregation in a transgenic
13.14) and naproxen (62), and one cyclooxy-
mouse (285).
genase (COX)-2 inhibitor, rofecoxib (63), are
listed in IND trials for AD indication. So far
the NSAIDs, steroids, or even antimalarials do 12 ANTIOXIDANTS
not seem to work as therapeutics after the AD
has been diagnosed. In a small, well-controlled Evidence of selective oxidative damage, result-
study the antimalarial hydroxychloroquine ing from redox imbalance, involving neurons
showed no difference in the disease progress tied to AD is accumulating. The advanced gly-
between the treated and the placebo groups cation end products, nitration, lipid peroxida-
(282). tion adduction products, carbonyl-modified
A proteinase inhibitor characteristic of neurofilament protein, and free carbonyls be-
acute-phase inflammation, al-antichymo- long to the list (200). The question remains
trypsin (ACT) has been identified in SP and whether the oxidative damage is caused by AP,
reported to be elevated in AD patients (283). known to possess oxidative and hydrolytic
The level of ACT depended on ApoE genotype properties (286, 287), or by other factors,
and was the highest in &3/&3 homozygotes and whereas AP is released as an antioxidant in
correlated with cognitive impairment and du- response to oxidative stress (200). As in other
ration of the disease. The ~4 genotypes have groups of potential AD therapeutics there is a
shown a lower level of ACT and no correlation noticeable difference between their behavior
with impairment or duration. One should in vitro and in vivo. A number of potential
keep in mind that the same ACT inhibits Ap antioxidants are or have been in clinical trials
Alzheimer's Disease: Search for Therapeutics

as potential therapeutics: vitamin E (288), es- the percentage of forward-looking statements


trogen (251-254), ginkgo biloba (2891, selegi- appearing simultaneously: that numerical
line (290), idebenone (291), acetyl-L-carnitine growth is still to convert into a feasible hy-
(292), or melatonin. So far the results are less pothesis and a successful line of therapeutics.
than promising. This will not be achieved by reviewing each
other's reviews. An expensive, aggressive ap-
13 CONCLUSIONS A N D PERSPECTIVE proach, in which every hypothesis, every leafl,
no matter how anecdotal, should be pursued
When faced with a disease. science has a num- to exhaustion by the pharmaceutical stalwarts
ber of options. It can look for means to prevent and the boutiques alike. Otherwise, the prom-
or delay the onset, reverse the damage (cure), ised "bulging pipeline" of AD drugs will re-
or at least slow down the progress of disease. main empty save for spinach (293).
When the opportunities to do so do not present
themselves, it can look for means to improve
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CHAPTER FOURTEEN

Cognition Enhancers
CMK N. EID, J R . .

YONG-JIN
WU
Division of Central Nervous System Chemistry
Bristol-Myers Squibb Pharmaceutical Research Institute
Wallingford, Connecticut

GENE G. KINNEY
Department of Neuroscience
Merck Research Laboratories
West Point, Pennsylvania

Contents
1 Introduction, 780
1.1 Dementia, 780
2 Assessing Cognition, 780
2.1 Animal Models of Cognition, 780
2.2 Measurements of Human Cognition, 781
3 Cognition-Enhancing Therapies, 781
3.1 Therapeutic Approaches, 781
3.2 Clinically Approved Agents, 781
3.2.1 Acetylcholinesterase Inhibitors (AChEI),
781
3.3 Exploratory Approaches, 781
4 Ion Channel Modulation of Neurotransmission,
782
4.1 GABAA/BzReceptor Complex, 782
4.1.1 Physiology and Pharmacology of the
GABAA/BzReceptor Complex, 782
4.1.2 Pharmacophore Model for the GABAJ
Bz Receptor Complex, 784
4.1.3 Structure-Activity Relationships with
GABAA/BzRInverse Agonists, 786
4.1.3.1 P-Carbolines and
Pyridodiindoles, 786
4.1.3.2 Imidazobenzodiazepines, 790
4.1.3.3 Pyrazoloquinolinones, 790
4.1.3.4 Miscellaneous Chemotypes, 792
4.1.4 Cognition-Enhancement Experiments,
794
4.1.5 Future Direction, 796
4.2 Nicotinic Acetylcholine Receptor, 797
Burger's Medicinal Chemistry and Drug Discovery 4.2.1 Physiology and Pharmacology of the
Sixth Edition, Volume 6: Nervous System Agents nACh Receptor, 797
Edited by Donald J. Abraham 4.2.2 Structure-Activity Relationships for
ISBN 0-471-27401-1 0 2003 John Wiley & Sons,Inc. nAChR Agonists, 798
779
Cognition Enhancers

4.2.2.1 Nicotine Derivatives, 798 4.3.2.2 Other Chemotypes, 816


4.2.2.2 Epibatidine Derivatives, 806 4.3.3 Future Direction, 816
4.2.2.3 Anabaseine Derivatives, 808 4.4 Potassium M-Channel, 817
4.2.3 nACh Receptor Pharmacophore Model, 4.4.1 Physiology and Pharmacology, 817
809 4.4.2 Structure-Activity Relationships for
4.2.4 Future Direction, 811 M-Channel Blockers, 818
4.3 5-HT, Receptor, 811 4.4.3 Cognition-Enhancement Experiments, r
4.3.1 Physiology and Pharmacology of the 819
5-HT, Receptor, 811 4.4.4 Future Direction, 820
4.3.2 Structure-Activity Relationships for
5 Conclusion, 820
5HT,r Antagonists, 813
6 Web Sites for Further Reading, 821
4.3.2.1 Imidazolyl Indolyl Derivatives,
813

1 INTRODUCTION cognition have been estimated (10). Further-


more, protocols for behavioral assays that are
1 .I Dementia commonly employed, such as passive avoid-
ance (11)or the Morris water maze (12), can
The average life expectancy has increased in
vary widely between investigators, often pro-
modern times, and with it so has the per-
viding contradictory results (10). This vari-
centage of the world's population reaching
ability has precluded all but the most general-
old age. The elderly are a t increased risk to
suffer from dementia, which has the clinical ized comparisons of the efficacy for different
features of impairments in cognition, mem- cognitive-enhancing compounds in animal
ory, language, and visuospatial skills. The models.
need for effective treatments in Alzheimer's Another major obstacle in developing effec-
disease (AD), age-associated memory im- tive therapeutic strategies for cognitive en-
pairment (AAMI), multi-infarct dementia hancement is a lack of knowledge about how
(MID), vascular dementia, and Parkinso- complex processes like learning and memory
nian dementia is fast becoming acute (1, 2). occur. Preclinical studies have revealed func-
Although successful intervention has been tional properties of neuronal plasticity that
achieved for a few reversible cognitive defi- have intuitive appeal as potential substrates
cits, such as those induced by nutritional de- for memory encoding. The best studied of
ficiencies (3), depression (4), acute drug tox- these is long-term potentiation (LTP) (13,14).
icity (5-7), and some metabolic disorders (8, LTP is a long-lasting, use-dependent increase
9), formidable challenges remain. in synaptic strength that was first described in
the hippocampus, a brain region critical for
the formation of new long-term memories in
2 ASSESSING COGNITION humans (15). It has been hypothesized that
the plasticity that occurs during LTP may pro-
2.1 Animal Models of Cognition vide a molecular basis for learning and mem-
Although there are several accepted methods ory. As such, electrophysiological tests to de-
for assessing cognitive function in humans, termine the effects of drugs on LTP have often
this presents a more complex problem pre- been used as a way to identify cognitive en-
clinically. Experimental paradigms vary enor- hancers. However, despite decades of dedi-
mously. Different animal species are used, cated research, the relationship between LTP
such as nonhuman primates, rodents, and pi- and learning or memory is still actively de-
geons. Substrains in any given species (espe- bated (16-20). For this reason, and because
cially mice) often provide conflicting results, this topic has been widely reviewed (21),stud-
as can the age of the animal. Nearly 100 be- ies assessing LTP will not be considered in this
havioral tasks used to assess various aspects of chapter.
3 Cognition-Enhancing Therapies

2.2 Measurements of Human Cognition these neurotransmitter levels have been the
focus of intense research.
Animal studies are used routinely for predict-
ing the efficacy of cognitive-enhancing phar-
3.2 Clinically Approved Agents
maceutics in humans, but this has its limita-
tions. For example, every marketed agent for Palliative treatment of Alzheimer's disease,
the treatment of dementia has been shown to the most common cause of dementia, has b e 9
enhance cognition in some animal model, but the primary focus of research in cognitive en-
the converse is not always true. Many agents hancement. However, despite these efforts, ef-
that produce positive effects in animal models fective pharmacological interventions remain
fail in clinical trials (22, 23). Increasing the elusive. The most fruitful pharmacological
predictiveness of preclinical behavioral tests strategy pursued in AD research to date has
would greatly improve the development of ef- focused on the relief of cognitive and memory
fective treatments for dementia. Presently, deficits that are attributed to cholinergic dys-
there is no single behavioral test or animal function.
model that increases the likelihood of identi-
fying an effective cognitive-enhancing com- 3.2.1 Acetylcholinesterase Inhibitors (AChEI).
pound in humans, although strategies have There is substantial rationale for exploring
been proposed for achieving this goal (24). cholinomimetic therapies for the treatment of
A fundamental problem with attempting to the symptoms of dementia (3238). Central
quantify cognitive function is that cognition is cholinergic depletion is a hallmark of AD and
multifaceted. This is especially evident in the experimentally induced cholinergic dysfunc-
preclinical setting, where the individual ele- tion produces cognitive deficits both preclini-
ments of attention, learning, and memory can- cally and clinically (39). Acetylcholinesterase
not be adequately measured in a single behav- (AChE)inhibitors suppress the normal break-
ioral test. However, more extensive tests have down of acetylcholine from the synaptic cleft,
become somewhat standardized to measure thereby increasing the overall level of ACh
cognition in humans. The Mini-Mental State available to the relevant postsynaptic recep-
Examination [MMSE (2511 and the cognitive tors. As such, AChE inhibitors represent a
subscale of the Alzheimer's Disease Assess- valid approach in the development of cogni-
ment Scale [ADAS-Cog (26, 2711 are used in tive-enhancing compounds. Indeed, acetylcho-
virtually all clinical evaluations of cognitive linesterase inhibitors, such as tacrine (I),
enhancers. Use of these protocols allows rea- (Cognex; Warner-Lambert Co.), donepezil(2),
sonable comparisons to be made between (Aricept, E2020; Eisai Co. Ltd.), rivastigmine
drugs. (31, (Exelon, Novartis), and galantamine (4),
(Reminyl; Janssen) are the only U.S. FDA-ap-
proved drugs currently marketed in the
3 COGNITION-ENHANCING THERAPIES United States for the symptomatic treatment
of AD (Fig. 14.1). It should be noted, however,
3.1 Therapeutic Approaches that tacrine is no longer widely used because
of the recent advent of safer AChE inhibitors
Alzheimer's disease is the best known age-re-
(e.g., Aricept). The evidence to date indicates
lated disorder for which the primary symptom
that these agents provide only short-term re-
is dementia. Advances have been made in un-
lief, in part by slowing the progression of the
derstanding the etiology of AD, but much re-
disease (40- 43).
mains to be discovered. Clearly, there are doc-
umented neuropathological changes in the
3.3 Exploratory Approaches
brain. For example, there is a broad spectrum
of neurotransmitter dysfunction, where ace- Many other pharmacological approaches are
tylcholine (ACh),serotonin [5-hydroxytrypta- currently being examined to reduce the cogni-
mine (5-HT)], norepinephrine, dopamine tive impairments seen in AD or in other de-
(DA), and glutamate levels are reduced (28- mentia. These approaches include agents that
31). Understandably, therapies that affect act at glutamate receptors [e.g., AMPAkines
Cognition Enhancers

0
I .
(1)tacrine (2) donepezil

Figure 14.1. Acetylcholinester-


ase inhibitors on the market in the
' \

United States. (3) rivastigmine (4) galantamine

(44-46), NMDA receptor modulators (47-50)], agonists; (3) serotonin subtype 3 receptor (5-
monoarnine oxidase B (MA0 B) inhibitors HT,R) antagonists; and (4) potassium M-
(51-55), antioxidants (52, 56-59), nootropics channel inhibitors.
(41, 60), lipid-lowering agents (e.g., statins)
(611, insulin (62), anti-inflammatory agents 4.1 CABAA/Bz Receptor Complex
(63-671, and estrogen supplementation (63,
65,66,68,69). Because several other reviews
are available that compare these therapeutic 4.1.1 Physiology and Pharmacology of the
approaches (70-77), the remainder of the CABAA/Bz Receptor Complex. The neuro-
present chapter focuses on ion channel mod- transmitter y-aminobutyric acid (GABA) and
ulation approaches to cognition enhance- its associated receptors constitute the major
ment. inhibitory pathway in the brain (81). Attenu-
ation of postsynaptic excitatory responses is
achieved when GABA interacts with its recep-
4 ION CHANNEL MODULATION OF tors to stimulate ion conductances that lead to
NEUROTRANSMISSION localized membrane hyperpolarization. In
particular, the conductance of C1- ions is con-
In the remainder of this chapter, we briefly trolled through the ligand-gated GABA, and
review the status of efforts that have in com- GABA, (82-84) receptor subtypes, whereas
mon the potential to enhance the activity of conductance of Ca2+ and K+ ions occurs
multiple neurotransmitter systems through through the GABA, receptor subtype (85).
the modulation of gated ion channels (also see The majority of GABA's inhibitory effect in
reviews in Refs. 10, 78-80). Specifically, we the CNS is mediated by the GAB& receptor
discuss recent advances in the areas of: (1) subtype (86).
y-aminobutyric acid subtype Ahenzodiaz- GABA, receptors belong to the superfam-
epine receptor (GABAA/BzR)inverse agonists; ily of ligand-gated ion channels that include
(2) nicotinic acetylcholine receptor (nAChR) serotonin subtype 3 (5-HT,) receptor, nico-
4 Ion Channel Modulation of Neurotransmission

tinic acetylcholinergic (nACh) receptors, and The GABA, ion channel can be modulated
strychnine-sensitive glycine receptors (81, through ligand interaction with several recep-
87). GABA, receptors are believed to be het- tors (see review in Ref. 108). The GABAA/Bz -
ero-oligomers assembled from eight protein receptor complex has traditionally been differ- -
subunits, drawn from several classes (a1-,, entiated into two general subtypes, based on
Y I - ~8,
, E , T,9, and pl-,) (88-92). The their affinities for the prototypical 1,4-benzo-
subunits of the GABAA/BzRare classified ac- diazepines (Bz) flunitrazepam (23) and diaze- '
cording to the degree of sequence homology. pam (22) (109). Diazepam (22) has high affin-
Each subunit class is defined to exhibit amino ity for the GABAA/Bz receptors composed of
acid homologies of about 60 to 80%, whereas the a,-, and a, subunits and are collectively -
the amino acid homology between the various termed the "diazepam-sensitive" (or "DS")
subunit classes is approximately 30-40% (93, binding sites. The DS binding sites are further
94). categorized as being either Type I or Type I1
Various combinations of these subunits re- BzRs. The Type I receptor has pharmaco-
sult in different GABA, channel isoforms that logical properties similar to those of the
display differential pharmacology, CNS distri- alP,y, isoform, whereas the Type I1 BzR is
bution, and developmental pattern (95). The associated with the a,,,,,&y, subunit-con-
number of different functional isoforms in taining GABA, isoforms. Diazepam (22) does
vivo is unknown, but estimated to be between not have high affinity for the a, and P, sub-
10 (87) and 150 (96, 97). The genetic loss or unit-containing GABAA/BzRisoforms, collec-
mutation of a GABAA channel subunit can tively termed "diazepam-insensitive" (or
have profound neurological consequences. For "DI") sites (110, 111).
example, it has recently been shown that dis- The interaction between the subunits and
rupting the mouse gabrb3 gene, responsible the Bz receptor ligand provides for a wide
for coding the P, subunit, produces EEG ab- range of allosteric regulation of chloride ion
normalities, seizures, poor motor skills, and flux within the associated ion channel (112,
cognitive deficit (98). This research suggests 113). Agonists (e.g., prototypic l,&benzodiaz-
that disruption of the analogous human epines), potentiate GABA-induced C1- flux
GABRB3 gene may contribute to the pathol- and are typically characterized by sedative,
ogy of Angelman syndrome (99), a severe neu- anxiolytic, and anticonvulsant effects (114).
rological disorder characterized by cognitive Partial agonists, antagonists, and inverse ago-
deficits caused by deletionslmutations of ma- nists are also well known (115, 116).
ternal chromosome 15qll-q13 (100, 101). Inverse agonists of the GABA, receptor re-
Positron emission tomography (PET) studies tard GABA-induced C1- flux, thereby indi-
with the high affinity BzR ligand [llC]flu- rectly potentiating the propagation of excit-
mazenil on three Angelman syndrome pa- atory signals. Typically, this type of modulation
tients with maternal deletion of 15qll-q13 produces anxiogenic, somnolytic, and procon-
found a decreased number of GABAA/Bz re- vulsant features (117-121). It deserves men-
ceptors in the frontal, parietal, hippocampal, tion that the anxiogenic pharmacological
and cerebellar regions, which could partially property attributed to inverse agonists has re-
underlie the cognitive deficits of this disorder cently been hypothesized to be a downstream
(102). result of hyperattentional impairments stem-
The GABA, ion channel is formed by a pen- ming from the behavioral assays that involve
tameric assembly of hetero-oligomeric sub- fear- or anxiety-related stimuli (122). Never-
units, with each subunit having four trans- theless, GABAA/Bzreceptor inverse agonists,
membrane-spanning domains (93, 103). The because of their unique ability to reduce the
recombinant GABA, BzR complex assembled inhibitory effects of GABAergic neurotrans-
from two a,, one p,, and two y, subunits most mission, continue to be investigated as thera-
closely resembles the biochemical, electro- pies for several disorders, including dementia
physiological, and pharmacological profile of (123-125) and alcohol addiction (126-129).
native GABAA/Bzreceptors of the mammalian One of the important features of AD'S neu-
brain (104-107). ropathology is the degeneration of cholinergic
Cognition Enhancers

cells within the nucleus basalis of Meynert subunit found amino acid Ile-215 strongly as-
(NBM) with associated loss of afferents to the sociated with the high affinity binding of RY80
neocortex and amygdala (130, 131). The im- (29), an imidazobenzodiazepine selective for
portance of these cholinergic neurons for the GABA, receptors containing the a, sub-
learning and memory in experimental animals unit (155). In another study using chimeric
has been well established (132-139). Because al/a5subunits and site-directed mutagenesis
NMB cholinergic neuronal activity is influ- of the a, subunit, residues a511e215 arid
enced by local GABAergic interneurons (140, a,Thr208 were identified with the high affin-
141), numerous experiments have been un- ity binding of L-655,708 (31),another a, sub-
dertaken to investigate BzR inverse agonist unit-selective ligand (156). -
Within the y, subunit, site-directed mu-
effects on cortical ACh release and perfor-
tagenesis has revealed two residues, Phe77
mance in cognitive tasks. It has been postu-
and Metl30, to be necessary for high affinity
lated that this form of intervention would en- binding of BzR ligands (157, 158). Additional
hance synaptic transmission while preserving investigations using yJa, chimeric subunits
informational fidelity (123). identified two domains of the y, subunit, Lys-
411Try-82 and Arg-1141Asp-161, which to-
4.1.2 PharmacophoreModel for the GABAJ gether are necessary for high affinity binding
Bz Receptor Complex. The Bz receptor, some- (159). Mutagenesis within the y, Lys-411
times referred to as the w binding site, is lo- Trp-82 chimera further identified Met-57,
cated at the interface between the a and y Tyr-58, and Ala-79 as important for this bind-
subunits (95, 121, 142-144). The identifica- ing (160).
tion of conserved residues necessary for drug- Many laboratories have postulated phar-
receptor interaction has been difficult, but macophore models to account for the relation-
progress has been made using site-directed ship between BzR ligand interaction and in-
mutagenesis, photoaffinity labeling, and chi- trinsic activity to modulate the GABAA
meric subunits, as discussed below. receptor function [see Codding (161, 162);
Most notable among the a, subunit resi- Cook (121, 163-172); Crippen (173, 174);
dues to be identified from mutation analyses Filizola (175); Frier (176); Gardner (177);Gilli
as being intricately involved with the and Borea (178); Loew (179, 180); and Wer-
GABAA/Bzreceptor is histidine 101 (rat num- muth (181)l. Among these was a model for un-
bering) or 102 (humadbovine numbering) derstanding binding affinity and pharmaco-
(145,146). Photoaffinity labeling of the bovine logical action of BzR p-carboline ligands,
aHisl02 occurred preferentially with the ago- developed using three-dimensional quantita-
nist [3H]flunitrazepam rather than with the tive structure-activity relationship compara-
inverse agonist [3H]Ro 15-4513, where the tive molecular field analysis (3D QSAR
photoincorporation is associated with an a, CoMFA) (163) and refined employing a proce-
receptor fragment between residues 104 and dure termed GOLPE (generating optimal lin-
the carboxyl terminus (147, 148). This sup- ear PLS estimates) ab initio calculations
ports the view that these structurally distinct (166). This model was later incorporated into
BzR ligands interacted with different amino a unified pharmacophore/receptor model that
acid residues in the binding domains proposed only one binding cleft with multiple
(147-149). It was further postulated from sites for interaction by agonist, antagonist,
these studies that a,H102 contributes to the and inverse agonists (167, 182).
L, lipophilic region, where the pendant phenyl The unified pharmacophore/receptor model
group of diazepam (22) and other 5-phenyl proposed by Cook and coworkers (167, 182)
benzodiazepines are believed to occupy (149). employed CoMFA of the structural parame-
Other amino acids within the a, subunit ters of 136 different BzR ligands, selected
associated with the Bz binding site, affecting from 10 structurally diverse classes of com-
binding affinities by more than 10-fold, are pounds. The model described the BzR site as
Tyr-159, Gly-200, Thr-206, and Try-209 (145, consisting of several key recognition elements,
150-154). Site-directed mutagenesis of the a, including two hydrogen bond donor sites
4 Ion Channel Modulation of Neurotransmission

Figure 14.2. Pharmacophorelreceptor


model of the GABAA/BzRwith ligand di-
azepam (22). Preliminary locations of
the receptor's key amino acids are indi-
cated. (Modified from Ref. 90.)

termed H, and H,; a hydrogen bond acceptor the exact location and function of the amino
site termed 4;four lipophilic regions termed acids in question" (90).
L,, L,, L,, and L,,; and three regions of nega- The unified pharmacophorelreceptor model
tive steric repulsion described as S,, S,, and S, (167, 182, 183) is the most advanced to date
(Fig. 14.2). Another common pharmacophorel and will be used in the following discussion for
receptor model for the a,-, a,-, a,-, a,-, and comparing GABAA/Bz receptor affinities and
a,-containing GABA, isoforms using 19 non- published in uivo pharmacological profiles be-
selective BzR ligands was recently published, tween closely related classes of ligands. De-
which identified similar receptor/ligand inter- tailed data for GABAA/BzR ligand affinity at
actions (175). the various GABA, isoforms have only re-
The Cook group further refined their uni- cently been available, and remain largely in-
fied pharmacophore/receptor model to provide complete for all the many BzR ligands re-
additional insight into the different binding ported to date. Far fewer data have appeared
domains of the GABAA/BzRsubtypes alp3y,, in the literature for a GABAA/BzRligand's abil-
a5P3y2,and a,P,y,. This analysis was based ity to modulate individual GABA, isoforms.
on the affinities of 151 BzR ligands from nine It is difficult to predict the in vivo pharma-
different structural families at five distinct cology of a GABAAiBz receptor ligand based
(a,-3,5,,P3y2) recombinant GABAAIBzR sub- solely on its in vitro binding affinity and mod-
types (183). ulating effect for several different GABA, iso-
Cook and coworkers undertook the difficult forms (114). For example, the in uiuo inverse
task of correlating the data between the amino agonist DMCM (16) is an in uitro negative
acids believed to be involved in ligand binding modulator at the a,-,P,y, and a5@,y2 iso-
and the specific region of their unified phar- forms and a positive modulator at the a5Plyl
macophore1receptor model (90). Some of the isoform (184-187) (Table 14.1). Also, the clas-
amino acid residues likely associated with BzR sic in uivo antagonist flumazenil (Ro 15-1788,
ligand binding are indicated in the unified (26) is an in vitro weak positive modulator at
pharmacophore1receptor model presented in the alP3y2 and a,P,y, isoforms, a positive
Fig. 14.2. There are several key protein-ligand modulator at the a,P, y, and a&, y, isoforms,
interactions that deserve mention, but in the a weak negative modulator at the a5P,y, iso-
author's words, it is clear that "much work form, and a positive modulator at the a,P,y,
remains at the molecular level to determine isoform (187, 188).
786 Cognition Enhancers

Table 14.1 Reported BzR Ligand Modulation of GABA-Induced GABA, Isoform Function
Modulation of GABA-Induced Function
Positive (+); Negative (-1; or Not Determined (ND)
- - - - - -

Ligand f f ~ ffz ff3 ff4 ff s 0L6 Reference"


p-Carboline series
Abercanil(5) + + + + +
ND + ND ND ND
ND + ND ND ND
DMCM(16) - - - - -
- - - ND -
+ + + weak ND +
ND ND ND -
- - - -
- - ND -
+ + ND - weak
Benzodiazepine series
Flunitrazepam (23) + +
+ ND
Diazepam (22) + +
+ +
+ +
Imidazobenzodiazepine
series
Flumazenil(26) + weak + weak + - weak
(Ro15-1788) - ND ND ND
ND + ND ND
ND + ND ND
- weak - weak + weak + - weak
- ND ND ND ND
ND - ND ND ND
ND + ND ND ND
L-655,708(31) - - - weak ND -
RY24 (30) ND ND ND ND -
Pyrazoloquinolinone
series
CGS9895 (34) + weak + + + - weak
CGS8216 (39) - - weak - weak
ND + ND
ND + ND
Other series
L-792782 (47)
-
- weak
- - p p
+ - weak
"Ref. 1: (187);Ref. 2,6:(184, 185);Ref. 3:(188); Ref. 4,5:(156,186);and Ref. 7:(189).

4.1.3 Structure-Activity Relationships with 191) and abilities to modulate BzR-mediated


CABA,/BzR Inverse Agonists GABAergic transmission (192). The p-carbo-
4.1.3.7 P-Carbolines and Pyridodiindoles. lines have intrinsic activities ranging from full
In 1979 0-carboline-3-carboxylicacid ethyl es- agonists [e.g., ZK 93423 (6)and abecarnil(5)l
ter (BCCE) (15) was isolated as an artifact (193-196) to antagonists [e.g., BCCT (8)l
from human urine and found to have high af- (197) to weak/full inverse agonists [e.g., BCCE
finity for the central BzR (190). Since that (15), DMCM (16), ZK 93426 (12),and FG 7142
time, many laboratories have developed p-car- (18)](117-121, 193, 194, 198). The binding
boline analogs with different affinities for affinities and pharmacological profiles for sev-
GABA,/BzR isoforms (see references in Ref. eral representative p-carbolines and their
4 Ion Channel Modulation of Neurotransrnission

close structural analogs, the dihydropyridodi- of the pyridodiindole PRI (19) is similarly de-
indoles, at the GABAA/Bzreceptor are shown creased when its indole N(7)-hydrogenatom is
in Table 14.2. Where available, the affinities replaced with a methyl group (IC,, = 4-1163
for specific GABAABz receptor isoforms are nM) (121).
listed. Additional insight into the BzR pharma-
Most P-carbolines have good affinity for re- cophore was gained through the study of a se-
ceptor isoforms containing the a,, a,, as, and ries of rigid p-carboline analogs, the dihydroy
a, subunits. Some selectivity is generally ob- pyridodiindoles (121,203). These BzR ligands
served for the a,-containing isoform and there helped to define the active conformation and-
is usually little affinity for the isoform having binding alignment of the parent P-carboline
an a, subunit. The exceptions for this are
series. The unsubstituted pyridodiindole PRI
BCCT (8)and BCCE (15), which exhibit mod-
(191, an inverse agonist, was believed to bind
erate affinity for the a, subunit (183).
into the BzR active site in much the same way
As shown on the left in Fig. 14.3, p-carbo-
as BCCE (15) (Fig. 14.3) with the centroid of
lines with agonist activity, such as 6-PBC (5),
were proposed to bind into the BzR so as to the E-ring occupying lipophilic region L, and
orient the centroid of their A-ring into the L, its N5 nitrogen lone pair of electrons interact-
region, whereas the pyridyl N(2) nitrogen and ing with H, (167, 191).
the carbonyl oxygen at C3 formed a three-cen- Substitutions at the 1-, 2-, or 4-positions
tered hydrogen bond with hydrogen bond do- were accompanied by diminished affinity, re-
nor site H, (167). Ligands with a C4 alkoxy sulting from the steric constraints of the bind-
moiety, such as 6-PBC (7), are able to form an ing domain (165). Substitution at the 3-posi-
additional hydrogen bond with donor site H, tion helped to define the boundary of the
and can fully occupy the L, region, believed repulsive region S,. Several &position analogs
essential for potent agonist activity (191,201). [e.g., PRI2Me (21), PRI2MeO (201, and
Inverse agonist of the P-carboline series PRI2Cl ( l l ) ] had very good BzR affinities,
also tend to have a vertical alignment when with pharmacological profiles of the &methyl
modeled into the BzR. However, it was hy- and 3-methoxy adducts maintained as inverse
pothesized that for inverse agonist activity in agonist, but the 3-chloro adduct shifting to an
vivo that these ligands bind into the BzR dif- antagonist (167).
ferently, as shown with BCCE (15) on the High affinity binding P-carbolines require
right side of Fig. 14.3, orienting the centroid of moieties at the 3-position that are capable of
their A-ring into the LDi binding pocket. To accepting hydrogen bonds from the receptor's
accomplish this, hydrogen bonds must form hydrogen bond donors H, and H,. Several
between the indole N(9)-H and the A, hy- p-carbolines with esters, amides, and alkoxy
drogen bond acceptor site, and between the groups at the &position have been developed
pyridyl N(2) nitrogen and the hydrogen bond with excellent BzR affinities (Table 14.2). The
donor site H, (163). Additional hydrogen shape and lipophilicity of the 3-position sub-
bonding to H, was thought to be derived from stituent has a direct effect on GABAAisoform
the ligand's carbonyl oxygen. The ligand's C3 selectivity. For example, the t-butyl ester
side chain was also proposed to interact with BCCT (8)is very selective (20-fold) for the a,-
the hydrogen bond donor site H,. containing GABAA isoform (Ki = 0.72 nM),
Both the p-carboline and the structurally thought to be derived from the y-branching of
related pyridodiiodole BzR ligands require the the ester (197), but still maintains some affin-
indole nitrogen of the B-ring to remain unsub- ity for the a,-containing GABA, isoform (Ki=
stituted for interaction with the receptor's hy- 111 nM). The 3-ethoxy analog 3-EBC (lo),de-
drogen bond acceptor site A, (121). For exam- veloped as a long-lived, water-soluble replace-
ple, replacement of the indole N(9)-H on ment for the metabolically labile 3-position es-
P-CCM (14) with a methyl group is accompa- ters (121), also binds tightly with the a,-
nied by a decrease in binding affinity [IC,, = containing GABAA isoform (Ki = 6.43 nM),
5.0 nM for P-CCM (14) and IC,, > 50,000 for but has little affinity for the a,-containing
9-methyl-P-CCM] (202). The binding affinity GABA, isoform (Xi = 826 nM) (191).
Table 14.2 Binding At3hit.y and In Vivo Pharmacological Profile of Several GABAA/BzR p-Carboline and Pyridodiindole Ligands

1
A

(19) Rz = H; PRI
(21) Rz = CH3; PR12CH3
(20) Rz = 0CH3; PR12CH30
(11) Rz = C1; PRI2C1

P-Carboline Pyridodiindole
Ligand Ki ( n W a

R3 R4 R, R6 R7 a1 a2 a3 a5 % Ref?
Agonist
Abercanil(5) C0,i-Pr H OBn H 12.4
ZK 93423 (6) C0,Et H OBn H 4.10
Partial agonist
6-PBC (7) C0,Et H OPr H 0.49
Antagonist
BCCT (8) C0,t-BU H
BCCP (9) C0,n-Pr H
3-PBC (10) OPr H
PRI2Cl(11)
Antagonist/weak
inverse agonist
ZK 93426 (12) COzEt Oi-Pr IC,, = 0.4 nM
BC6OBz (13) C0,Et OBn 169 284 271
Inverse agonist
p-CCM (14) C0,Me H H H 2.4 7.4 72 44
BCCE (15) C0,Et H H H 1.20 4.9 5.7 26.8
DMCM (16) COzMe H OMe OMe 5.70 8.3 4.0 1.04
3-EBC (17) OEt H H H 6.43 25.1 28.2 826.0
FG 7142 (18) CONHMe H H H IC,, = 444 nM
PRI (19) 1.1 1.2 1.1 40.3
PRI2MeO (20) 3.4 11.7 11.0 225
PRI2Me (21) IC,,-.= 10 nM
"Specific amnity data provided when available for a,,a,, a,, a,, and a, subunits coexpressed with Pay, in human cell lines.
bRef. 1: (183);Ref. 2: (199);Ref. 3: (163);Ref. 4: (187); Ref. 5: (200); and Ref. 6: reported as having an "inactive" profile in (169).
4 ion Channel Modulation of Neurotransmission

Proposed agonist binding Proposed inverse agonist binding

Figure 14.3. Binding conformation of partial agonist 6-PBC (71, left, and inverse agonist BCCE
(15),right, in the GABAA/BzRpharmacophore/receptor model. (Modified from Ref. 167.)

The pharmacological profile of the p-carbo- inverse agonist profile (169). When inverse ag-
lines also varied with structural changes in the onist P-CCM (14) was modified with methoxy
3-position group. Ligands with smaller 3-posi- groups at the 6- and 7-positions and an ethyl
tion groups, such as P-CCM (14), BCCE (15), group at position 4, the ligand DMCM (16)was
and 3-EBC (17),were more selective for the produced, which maintained binding affinity
a,-containing GABA, isoform and maintained and an inverse agonist profile (163). This ob-
inverse agonist profiles. The N-methyl carbox- servation supported the hypothesis that the
amide analog FG 7142 (18)is also an inverse L,, binding region of the a,-containing
agonist, but with diminished BzR affinity GABA, isoform was larger in size than the
(195, 200). The n-propyl ester BCCP (9) and same region of the other isoforms (191).
the t-butyl ester BCCT (8) provided ligands Addition of a methoxyrnethyl group at the
with overall antagonist profiles (121, 204, 4-position of BC6OBz (13)gave ZK-93423 (61,
205). BCCT (8) was later found to be one of the with greatly improved affinity for all GABA,
most selective ligands for the a,-containing isoforms (201). ZK-93423 (61, with a full ago-
GABA, isoform (197,201). In contrast to 3-EBC nist profile, was believed to orient differently
(171,the 3-n-propoxy-P-carbolineanalog, 3-PBC in the BzR in such a way as to permit a hydro-
(10) was made as a set of compounds to fur- gen bond between the methoxymethyl group's
ther investigate the strict steric requirements oxygen atom and the hydrogen bond donor
of the lipophilic binding region L, (121, 163). site H,. This new orientation would permit
The affinity for this ligand was diminished by the benzyloxy moiety to fully occupy region L,
more than an order of magnitude and found to of the receptor, believed necessary for the ag-
have an antagonist profile (166). onist pharmacology (Fig. 14.3). The ligand
Substitution of the 6-position of inverse ag- 6-PBC (7) was made with the smaller propoxy
onist BCCE (15)with a benzyloxy group gave group at the 6-position to test this hypothesis,
BC6OBz (13). This adduct had an equivalent and resulted in a ligand with increased selec-
afiinity for only the a,-containing GABA, iso- tivity for the a, isoform and a partial agonist
form (K, = 7.2 nM) (183) and a diminished pharmacological profile (170, 171).
Cognition Enhancers

4.1.3.2 Imidazobenzodiazepines. Imida- was well conserved (218). The aliphatic ring of
zobenzodiazepines have been a long-studied the 4,5-pyrroloimidazobenzodiazepine,as in
series of GABAA/BzRligands (167, 189, 206- L-655,708 (311, is believed to play an impor- +
213) that bind with good affinity to the a,, a,, tant role in maintaining an active anti confor- .
a3,a,, and a, subunits containing GABA, iso- mation of the &position ester (183). Of partic-
forms, and often with excellent selectivity at ular interest from this series is the inverse
the a,-containingreceptors (189) (Table14.3). agonist L-655,708 (31), a ligand that has at'
The imidazobenzodiazepine Ro 15-4513 least 50-fold selectivity for the a,-containing
(27) is a partial inverse agonist with about 10- isoform and has been investigated preclini-
fold selectivity toward the a,-containing re- cally by Merck for its cognition-enhancing
ceptor (189). In contrast, substituting a fluo- properties (186). Additionally, L-655,708 (31)
rine atom in the &position on Ro 15-4513 (27) has been radiolabeled with tritium and used as
generates the antagonist flumazenil [Ro 15- a research tool for identification of a,-contain-
1788 (26)], and selectivity is lost. This obser- ing GABA, receptors (214).
vation led researchers to hypothesize that the 4.1.3.3 Pyrazoloquinolinones. The pyrazo-
lipophilic region L, may be smaller in the loquinolinone series of BzR ligands have be-
a,P,y,-containing receptor than the related come generally known as the CGS series be-
a,P,y,-containing receptor, and that selectiv- cause of their discovery in the laboratories of
ity might be achieved with the correctly sized Ciba-Geigy in the early 1980s (220). Like the
8-position substituent (215). Consequently, p-carbolines, this series has been well ex-
several a, subsite-selective imidazobenzodiaz- plored and ligands with a continuum of intrin-
epines were synthesized [e.g., RY24 (30) and sic activities have been discovered (166, 209,
RY8O (29)l that supported this hypothesis 220-223) (Table 14.4).
(215). The pyrazoloquinolinones have unique
Molecular modeling with RY24 (30) and pseudoplanar topographies and high receptor
RY80 (29) in the unified pharmacophorelre- affinities. These properties helped to system-
ceptor model suggested that these ligands atically probe the structure-space of the BzR
bind in an orientation that directs their 8-po- and greatly aided the development of a unified
sition substituent into the L, region, giving pharrnacophore/receptor model (167,183). As
them selectivity toward the a,-containing re- illustrated in Fig. 14.5 with agonist CGS-9896
ceptor (Fig. 14.4) (189, 215). Both RY24 (30) (33),the lone pair of electrons of N1 form a
and RY80 (29) were assayed i n vivo and found hydrogen bond with donor site Hz and the lone
to have an inverse agonist profiles (215). pair of electrons of the C3 carbonyl oxygen
Based on the above findings, an investiga- align to form a hydrogen bond with donor site
tion was launched into the modification of the H,. An additional hydrogen bond is believed to
classic BzR agonist diazepam (22) that inves- form between the proton on the N5 nitrogen
tigated A-ring substituents directed toward and the acceptor site A,. The centroid of the
the L, region (216,217). This led to the deriv- D-ring was believed to occupy the lipophilic
ative QH-11-66 (24), the first benzodiazepine region L,.
selective for the a,-containing receptor. In In the course of investigating substitution
contrast to RY24 (30)and RY80 (29),this BzR patterns of the pyrazoloquinolinones, it was
ligand was reported to have an agonist phar- observed that substituents at both the 6- and
macological profile. 7-positions generally had a negative effect on
Further insight into the topography of the receptor affinity, presumably because of steric
Bz receptor came from a series of chiral, interactions in the binding domain of region
framework-constrained 4,5-substituted pyr- L,,. However, substituents only at the 7- or
roloimidazobenzodiazepines and azetidinyl- 8-position were better tolerated and helped to
imidazobenzodiazepines (218, 219). Only the map out the steric constraints of region L,,
(S) enantiomers of these series of ligands (224,226).
bound to the BzR subtypes with high affinity, The pendant D-ring is the most amenable
suggesting that the conformational topogra- toward manipulation in regard to affinity and
phy at the five recombinant receptor subtypes i n uivo pharmacology (167). In contrast to the
Table 14.3 Binding Affinity and in Vivo Pharmacological Profile of Several GABAA/BzRBenzodiazepine
and Imidazobenzodiazepine Ligands

(22) R7 = C1; Diazepam (23) Flunitrazepam Imidazobenzodiazepine


(24) R7 = acetylenyl; QH-11-66

Ligand Ki bM)"
R R, R, R3 R$R, ff1 ff3 ff5

Agonist
Diazepam (22) 14 20 15 11 >3000
Flunitrazepam (23) 2.2 2.5 4.5 2.1 >2000
QH-11-66 (24) 76.3 42.1 47.4 6.8 >3000
Partial agonist
Bretazenil(25) Cod-Bu -CH2CH,CH2- H(Sj HlBr 0.35 0.64 0.2 0.5 12.7
Antagonist
Flumazenil (26) C0,Et Me H H F/H 0.8 0.9 1.1 0.6 148
(Ro 15-1788)
Partial inverse agonist
Ro 15-4513 (27) C0,Et Me H H N& 3.3 2.6 2.5 0.3 3.8
Sarmazenil(28) C02Et Me H H HICl (DS)Ki= 0.2 nM;(DI) Ki= 20 c 2.4 nM
(Ro 15-3505)
Inverse agonist
RY80 (29) C0,Et Me H H CXHIH 28.4 21.4 25.8 0.49 28.8
RY24 (30) C0,t-Bu Me H H (=CH/H 26.9 26.3 18.7 0.40 5.1
L-655,708 (31) C0,Et -CH,CH,CH,- H(S) OMe/H 48.5 27.4 24.5 0.45 83.2
(MSD; FG8094)
"Specific affinity ~rovidedwhen available for a,, a,, a,, a,, and a, subunits coexpressed with P,y, in human cell lines,
bRef.1: (183); Ref. 2: (210);and Ref. 3: (214).
Cognition Enhancers

research for further in vivo investigation of its


potential as a cognition-enhancing agent (227,
228).
A closely related BzR ligand series are the
imidazoquinolines, designed as pyrazolo-
quinoline bioisosteres, in which the C-ring
pyrazolo has been substituted with an imidazo
moiety (223). The imidazo analog of CGS-8216
(39) had a lower binding affinity than that of
the parent series (K, = 22 nM versus 0.22 nM
for [3H]diazepamdisplacement from rat cere-
bral cortex), but affinities increased when the
D-ring was exchanged for an isoxazolyl moi-
ety. The A-ring of this series could also be
changed to a nonaromatic ring and maintain
binding affinity. For example, the A-ring
pyrano derivative generated from this re-
Figure 14.4. Binding conformation of inverse ago- search, S-8510 (44), had a moderate inverse
nist RY80 (29) in the GABA,/BzR pharmacophorel agonist profile and was selected as a therapeu-
receptor model. (Modified from Ref. 189.) tic candidate for the treatment of senile de-
mentia (223).
inverse agonist CGS-8216 (391, partial ago- 4.1.3.4 Miscellaneous Chemotypes. Dain-
nists are the result of substitution at the 4'- ippon Pharmaceutical has recently disclosed a
position with either a chloro, to provide CGS- series of 1,6-naphthridineagents with activity
9896 (331, or a methoxy group, to provide at the benzodiazepine binding site, but no spe-
CGS-9895 (34) (187,220). The binding affmi- cific binding affinity data were provided (229)
ties for a series of these 4'-substituted ligands (Table 14.5). From this series, SX-3933 (49)
suggest that electronegative substituents at was described to have inverse agonist activity
the 4'-position favor selectivity at the a,-con- and is currently under preclinical evaluation
taining isoforms because of a decrease in affin- for cognition enhancement. In mice, SX-3933
ity at the a,-containing isoforms (224). Sub- (0.003-1 mglkg, p.o.1 attenuated scopolamine-
stituents at the 2'- and 3'-positions of the induced memory deficits in a dose-dependent
D-ring can also provide for good receptor affin- manner (229). SX-3933 was also reported to
ity, such as the electron-releasing 3'-methoxy prevent impairment induced by dizocilpine
adduct APQ3'0Me (37) and the 3'-chloro ad- (the noncompetitive NMDA receptor antago-
duct APQ3'Cl (38),although the pharmaco- nist, MK-801) in both a spontaneous alterna-
logical activity shifts to that of an antagonist tion test (ED,, range = 0.1-3 mg/kg, p.0.) and
compared to that of the parent CGS-8216 (39) a novel object recognition test (ED,, range =
(212). 0.1-10 mg/kg, p.0.) (229).
The D-ring can itself be replaced with a 2- Merck researchers have recently disclosed
or 3-thienyl moiety [e.g., 2TPQ (40) and 3TPQ a series of 3-phenyltriazolopyridazines with
(421, respectively] (225) and maintain good af- excellent selectivity for the a,-containing
finity and inverse agonist activity. However, GABA, isoform (186) (Table 14.5). Selectivity
simple methyl substitution on the thiophene for the a, subunit was maintained within the
can shift the pharmacological profile from an series when the A-ring was saturated or had
inverse agonist, observed for the 5-methyl- alternative ring fusion. The inverse agonist
thien-3-yl analog 5-135 (43), to a partial ago- L-792782 (47) was selected from this series
nist, as is the case for 2TPQ5'Me (35) and and evaluated for cognition enhancement, dis-
2TPQ4'5'diMe (36), again showing the sensi- cussed below.
tivity of the receptor's region L, toward small A series of piperazine imidazoquinoxaline
structural changes in the ligand (225). The in- ureas was recently reported by Pharmacia
verse agonist S-135 (43)was selected from this & Upjohn to have high affinity for the
4 Ion Channel Modulation of Neurotransrnission

Table 14.4 Binding Affinity and in Vivo Pharmacological Profile of Several GABAA/BzR
Pyrazoloquinolinone Ligands

Pyrazoloquinolinone

(44) Imidazoquinoline S-8510

Agonist
AF'Q3'C1(32) H/CW H H H IC,, = 3.9 nM
Partial agonist
CGS-9896 (33) W/C1 H H H IC,, = 0.6 nM. 5
CGS-9895 (34) H/H/OMe H H H 0.32 1.1 0.28 0.96 ND 7

Antagonist
APQ3'0Me (37) H/OMe/H H H H IC,, = 0.5 nM
APQ2'C1(38) Cl/H/H H H H IC,, = 70 nM
Inverse agonist

I
"Specific affinity data provided for a,, az,a,, a,, and a, subunits coexpressed with P,y2 in human cell lines.
bRef. 1: (224);Ref. 2: (221);Ref. 3: (225);Ref. 4: (223);Ref. 5: (220);Ref. 6: (222);and Ref. 7: (187).
Cognition Enhancers

iors. Although multiple approaches are now


used to assess efficacy and functional activity
both in uitro and in vivo, it is notable that in-
addition to the proconvulsant and anxiogenic
effects of these compounds, BzR inverse ago-
nists have also been shown to reliably enhance
cognition in preclinical tests. z
One way to potentially capitalize on the
cognitive-enhancing effects of BzR inverse
agonists without producing overt proconvul--
sant or anxiogenic behavior is to target recep-
tors disproportionately localized in brain ar-
eas involved in cognitive processes. In this
regard, expression of GABA, receptors con-
taining the a, subunit is highly specific to the
hippocampus in the rat and human and con-
Figure 14.5. Binding conformation for agonist stitutes approximately 20% of these receptors
CGS-9896 (33)in the GABAA/BzRpharmacophorel (231). As such, compounds that specifically in-
receptor model. (Modified from Ref. 167.) teract with the a,-containing isoform of the
GABAA/BzRhave been an area of high inter-
GABAA/Bz receptor with a full continuum of est. In the following, examples of specific and
intrinsic activities (230). This BzR ligand se- nonspecific BzR inverse agonists are dis-
ries is structurally similar to the 3-phenyltri- cussed.
azolopyridazines mentioned above, and have p-Carbolines: p-CCM (14), ZK 93426 (121,
some similarity to the a,-selective hypnotic and FG 7742 (18). Direct injection of the BzR
drugs zolpidem (45) and zopiclone (46), mar- inverse agonist p-CCM (14) into the rat NBM
keted by Sanofi-Synthelabo and Rhone-Pou- enhanced performance in a two-trial recogni-
lenc Rorer, respectively, for sleeping disor- tion task (232), similar to the positive effects
ders. Urea (48) represents one of the most observed earlier for the peripheral adminis-
potent inverse agonist from this series, with a tration of the same agent (233). Further devel-
Ki value of 6.67 nM. Manipulation of the 5-, 6-, opment of p-CCM (14) and DMCM (16) was
and 7-positions generated analogs of widely never considered because of their rapid ester-
varying intrinsic efficacy. In contrast to urea ase-mediated hydrolysis in vivo, poor solubil-
(48), substitution on the A-ring with a bulky ity even as HC1 salts, and toxicity (166,234).
group at the 7-position resulted in analogs In experiments with other p-carbolines,
that were positive modulators of the GABA, the BzR weak inverse agonist ZK 93426 (12)
channel (230). No preclinical data for cogni- and partial inverse agonist FG 7142 (18) in-
tion enhancement have been reported from jected into the forebrain were observed to pro-
this series. vide transient, task-dependent potentiation of
cortical ACh efflux (125). Behavioral studies
4.1.4 Cognition-Enhancement Experiments. with FG 7142 have found that it improved
As mentioned above, the intrinsic activity of working memory in normal rats (124,235). In
GABAA/BzR ligands was historically deter- addition, FG 7142 was shown to improve pas-
mined by observing behavior after the admin- sive avoidance retention in both rats (236,
istration of BzR ligands. BzR inverse agonists 237) and mice (238). However, other investi-
are well known for their proconvulsant and gators have reported impaired working mem-
anxiogenic effects in animals, actions opposite ory performance in both rats and rhesus mon-
those of classic agonists for this site. As such, keys (239,240). In a clinical study, five healthy
the classification of agonist, inverse agonist, or males were challenged with oral doses of FG
antagonist was often made after observation 7142 increasing to 100-200 mg (and, in one
of response in behavioral assays designed to case, 400 mg). In two of the 12 trials with doses
assess convulsant or anxiety-related behav- of 100 mgor more, subjects experienced severe
4 Ion Channel Modulation of Neurotransmission

Table 14.5 Binding Afiinity and In Vivo Pharmacological Profile of Various


S
a GABAAIBzRLigands

(48) Imidazoquinoxaline
piperazine urea

(45) Zolpidem (46) Zopiclone

Agonist
Zolpidem (45) 26.7 156 383 >10,000 >10,000 1
Zopiclone (46) 28 64 29 46 ND 4
Inverse agonist
L-792782 (47) 1.4 2.7 1.4 0.8 ND 2
Urea (48) Ki = 6.67 nM 3
SX-3933 (49) Not reported 5
"Specific affinity data provided when available for a,, nz, a,, a,, and a6 subunits coexpressed with P3y2in human cell lines.
bRef.1: (191); Ref. 2: (186);Ref. 3: (230); Ref. 4:(187); and Ref. 5: (229).

anxiety and the study was terminated (119). to partially antagonize scopolamine's effects
Nevertheless, FG 7142 remains a valuable on memory and attention (241). NO further
preclinical research tool. development is expected.
In a single clinical study, ZK 93426 (12) /midazobenzodiazempines Ro 15-3505 (28);
was evaluated for its effect on scopolamine- Sarmazenil; Roche Holding AG), RY24 (30), and
induced cognitive impairments and was found L-655708 (31); FG8094; Merck); and the Triazo-
Cognition Enhancers

lopyridazine L-792782 (47; Merck). Ro 15-3505 strated positive results in animal models of
(28) demonstrated convincing efficacy in pre- cognition (249, 250). S-8510 was shown to
clinical measures of arousal and cognitive be- ameliorate the memory impairments of sco- -
havior such as T-maze and delayed match-to- polamine-treated or basal forebrain lesioned
position assays (242-245). However, this rats in a water maze and mice in passive-
compound also demonstrated anxiogenic ac- avoidance behavioral paradigms (251, 252).
r
tivity that precluded its clinical development EEG measurements confirmed the activating
for cognitive impairment (246, 247). effects of S-8510 on rat brain function (253)
An entry into the area of a,-selective li- and to enhance LTP in vitro (254). It was also
gands is represented by the imidazobenzodi- disclosed that S-8510 did not induce anxiety or
azepine RY24 (30). RY24 has been reported to convulsions, even at 10-100 times the thera-
show cognitive-enhancing effects after direct peutically effective dose (255). An additional,
hippocampal injections (Helmstetter et al., interesting feature of this compound is that it
unpublished, as discussed in Ref. 183). How- also displays antidepressant properties in
ever, at similar concentrations this compound mice (254). This finding is made particularly
also produced an increase in freezing behavior interesting, in that there remains a high de-
indicative of anxiogenic activity. Note that no gree of comorbidity between depression and
proconvulsant effects were seen up to the dementia in geriatric populations (see, e.g.,
highest concentration tested (10 pg/pL). In- Ref. 256). 5-8510 has been reported to be in
terestingly, the procognitive and anxiogenic phase 2 clinical trials in Japan as a potential
effects were seen only at lower concentrations treatment for senile dementia (257) and, ac-
and were absent at higher concentrations. cording to a recent press release (PR News-
This combined with the fact that no procogni- wire, July 25,2001) has recently been included
tive effects were noted after peripheral admin- in a joint development venture between
istration indicates that, at higher concentra- Shionogi & Co. Ltd. and GlaxoSmithKline.
tions, this compound may possess agonist The pyrazoloquinoline CGS-8216 (39) was
activity at additional subtypes in multiple reported to be an inverse agonist (258, 259)
brain regions that may have led to its anxio- and to have cognition-enhancing properties
genic profile. for mice in a T-maze behavioral paradigm
Merck has recently disclosed a series of BzR (260).
inverse agonists with greater selectivity for
GABA, receptors containing the a, subunit 4.1.5 Future Direction. The only nonago-
(248). A lead compound, L-655708 (31), dem- nist GABAABzreceptor ligand in clinical use
onstrated good brain-penetrating properties is the antagonist flumazenil (26, Ro 15-1788,
and receptor occupancy (156). However, there Hoffman-LaRoche). Flumazenil has been clin-
is a paucity of data with regard to its activity in ically described as an agent with few intrinsic
behavioral assays of cognitive activity. Subse- properties and is used to reverse the effects of
quent chemistry efforts led to the 3-phenyl- benzodiazepines in conscious sedation, gen-
triazolopyridazine, L-792782 (47), which pro- eral anesthesia, and the management of sus-
duced a marked improvement in a water-maze pected benzodiazepine overdose. Reports from
match-to-position test (186). In this test, rats new clinical studies, however, show that
were placed in a standard water-maze appara- flumazenil (26) does possess intrinsic activity
tus with a hidden platform. After animals had and has significant negative effects on cogni-
"found" the platform on a first trial, a second tion, cardiovascular physiology, and mood
trial followed at either a 0- or 4-h intertrial (261).
interval. L-792782 markedly decreased the Continued research into the identification
time to find the platform on the second trial of subtype-selective GABAA/Bz receptor li-
regardless of intertrial interval. gands can be expected to provide agents with
lrnidazoquinoline S-8510 (44) and Pyrazo- more specific physiological activity. This may
quinolinones CGS-82 7 6 (39). The fused imid- result in new treatments for a variety of disor-
azopyridine S-8510 (44) is a GABAA/Bzrecep- ders, including cognitive deficits, with de-
tor weak inverse agonist that has demon- creased potential for adverse side effects.
4 Ion Channel Modulation of Neurotransmission

4.2 Nicotinic Acetylcholine Receptor have shown that nAChR agonists can act pre-
synaptically to facilitate neurotransmitter re-
4.2.1 Physiology and Pharmacology of the lease. For example, nAChR agonists applied to
nACh Receptor. Acetylcholine (ACh) controls cells expressing either the a,& nAChRs [nic- -
neurotransmission through interaction with otine, carbachollatropine, anatoxin-a, and epi-
both nicotinic and muscarinic types of recep- batidine in mouse thalamus slices (277)l or a,,
tors. The nicotinic acetylcholine receptors nAChRs [nicotine in cultured rat hippocampal
(nAChRs) are ligand-gated ion channels neurons (278, 279)], in the absence of high
(LGIC) that regulate the flux of ions (Na+,Kt, external Ca2+,evoked the release of GABA, .
Ca2+)through the neuronal membrane (262- ACh, and glutamate.
264), whereas the muscarinic receptors are The neurotransmitter release mediated by
members of the G-protein-coupled receptor the a, nAChR subtype was shown to be pre-
superfamily (GPCR). nAChRs are found on dominantly the result of Ca2+ influx through
skeletal muscle at the neuromuscular junc- the activated a, nAChR channel (278-281).
tion, in autonomic ganglia of the peripheral Potentiation of neurotransmission mediated
nervous system, on sensory nerves and some through the a4P2 nAChR subtype was more
peripheral nerve terminals, and at numerous complicated, in that it was facilitated through
sites in the spinal cord and brain. The nAChRs an intracellular increase in Ca2+as a result of
are further subdivided into neuronal nAChRs Ca2+ influx from either the a,& nAChR or
and the nicotinic receptors of the neuromus- from voltage-dependent Ca2+ channels acti-
cular "iunction. The neuronal nAChRs in- vated by a,& nAChR-elicited depolarization
volved in CNS neurotransmission are distinct (277).
from those of the skeletal muscle (265) and The binding affinity to the a,& site is fre-
sympathetic ganglia (266). All nAChRs are quently evaluated in homogenized rodent
thought to be homo- or hetero-oligomeric as- brain tissue using radioligands such as
semblies of five subunits, drawn from several [3H]cytisine, [3Hlnicotine, [3Hlacetylcholine,
classes (267,268). In mammalian or avian spe- [3~methyl~bamylcholine (MCC), and [3Hlepi-
cies, muscle nAChRs consist of a,, P,, y, and 6 batidine. The regulation and functional activ-
subunits, whereas neuronal receptors are ities have been investigated through several in
composed of a, to a, and p, to p, subunits vitro expression systems. Transient expres-
(262, 269-271). In the rodent CNS, the pre- sion of chick, rat, and human a4P, nAChRs in
dominant nAChR suptypes are a,& and the Xenopus oocytes, and stable expression sys-
homoligomer a, (272), and these subtypes tems using chick a,& in a mouse cell line
have been implicated in the functions of learn- (MI0 cells) and human a4P2 in a human cell
ing and memory (273). Numerous nAChRs line (K177 cells) have been used. Studies on
with distinct biophysical and pharmacological endogenous a,& nAChRs have been carried
properties can be generated by the expression out in rodent thalamic tissues, and the re-
of a single a-type subunit (homomeric) or by sponses in these systems have been measured,
coexpression of a- and P-subunits (hetero- either as flux of radioactive ions (e.g., 86Rh+or
meric). The composition and distribution of ',Nat) or as calcium influx detected with cal-
discrete subtypes of nAChRs in the brain still cium-sensitive dyes (273).
remain largely unknown, although it has been Early drug discovery efforts in the nAChR
established that certain subunits will prefer- area were achieved largely through observa-
entially combine to form functional channels tion of the behavioral effect of @)-(-)-nicotine
(263,269, 274). [hereafter designated simply as nicotine (50)
Considerable attention has been given to in Fig. 14.61 and its resulting behavioral ef-
two nAChR subtypes: the heteromer contain- fects in humans. Acute treatment with nico-
ing a4P2 subunits and the a, subunit ho- tine improves cognitive performance in ro-
momer. Both of these receptors have been dents (282, 283) and primates (284) for a
shown to participate in fast excitatory trans- variety of behavioral paradigms. Nicotine is
mission by way of postsynaptic mechanisms also known to generate anxiolytic effects in
(275, 276). In addition, recent experiments humans (285). Recent clinical studies have
Cognition Enhancers

the high nanomolar to micromolar range


(291). Because ganglionic-type nAChRs are
believed to mediate, at least partially, the gas- .
trointestinal and cardiovascular liabilities of
nicotine, significant pharmaceutical research
efforts have focused on the development of,
novel neuronal nAChR modulators with
high selectivity for central versus ganglionic
Figure 14.6. "Binding data: rat brain/[3Hlcytisine nAChRs. Subtype-selective nAChR modula-
(299). tors with activity for either the a, or a,& sub-
types have demonstrated the potential to be-
suggested that nicotine may be useful for the come valuable therapeutic agents for a variety
palliative treatment of attention deficit associ- of disorders (291, 292). Described below are
ated with Alzheimer's disease (286, 287). several important classes of neuronal nAChR
Moreover, epidemiological studies on ciga- agonists and their structure-activity relation-
rette smoking suggest that nicotine has pro- ships (see reviews in Refs. 10, 273, 291, 293-
tective effects in AD patients. However, nico- 298).
tine also produces undesirable effects on the
cardiovascular, gastrointestinal, endocrine, 4.2.2 Structure-Activity Relationships for
and reward systems (288), as well as having nAChR Agonists
poor oral bioavailability and a short duration 4.2.2.1 Nicotine Derivatives. A large num-
of action (289, 290). Therefore, nicotine itself ber of nicotine analogs have been reported,
represents a poor choice for the safe and effec- and the SAR of nicotine derivatives has been
tive treatment of Alzheimer's dementia in an presented in a recent review by Tonder et al.
elderly population. (295). Described herein are two classes of nic-
Nicotine is highly selective for a,& versus otine derivatives: 5-substituted nicotine ana-
a, with respect to binding affinity (binding Ki logs (e.g., SIB-1508Y,51) and pyrrolidine ring-
= 1.05 nM versus 4 @) and moderately selec- opened nicotinoids (e.g., RJR-2403,57).
tive with respect to functional activity (func- 4.2.2.1.1 5-Substituted Nicotine Derivatives.
tional EC,,: 4 @versus 54 a.
Nicotine also Substitution at the &position of nicotine's
binds with micromolar affinity to muscle-type pyridyl ring is generally tolerated, but bulky
receptors, and affects activation in the mid to groups such as phenyl reduce activity (Table
high micromolar range. Moreover, nicotine 14.6) (300, 301). The analog with an ethynyl
binds with micromolar affinity to ganglionic group at the 5-position, SIB-1508Y (51), dis-
receptors and elicits functional responses in played the same binding activity as that of
Table 14.6 Binding Data o f 5-Substituted Nicotines

Compound Stereochemistry R Ki (nM)


(51)(SIB-1508Y) (8 Ethynyl 3"
(52) (R) Ethynyl 75"
(53) (R,s) Me 1.5~
(54) (RS) Et 11"
(55) (RS) Br 19"
(56) (RS) Ph 37"
"Rat ~ortex/[~Hlnicotine[K~ (nicotine): 4 nMl (300).
*Rat brain/[3Hlnicotine (304).
'Rat c~rtex/[~H]nicotine (302).
4 Ion Channel Modulation of Neurotransrnission 799

Table 14.7 Binding Data of trans-Metanicotines

Compound

"Rat brain/[3Hlnicotine (322).

nicotine. Compound (52), the enantiomer of ing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-


SIB-1508Y, exhibited less affinity for the dine (MPTP)-treated monkeys (a model for
r3H]nicotine binding site and was less effica- Parkinson's disease) trained to perform a de-
cious in a measure of DA release from rat stri- layed matching-to-sample task have shown
atal slices (55% relative to nicotine, cf. 163% cognitive improvement after SIB-1508Ytreat-
for SIB-1508Y) (300). Saturation of acetylene ment (306,307).Of note is that this compound
(54) as well as replacement of the ethynyl moi- has also been shown to elicit antidepressant-
ety in SIB-1508Y with bromine (55) resulted like effects in the learned helplessness rat
in modest reduction of the binding affinity but model of depression (308). SIB-1508Y had
significantly decreased efficacy in the DA re- reached phase I1 clinical trials as a potential
lease assay [28% and 69% relative to nicotine treatment for Parkinson's disease, but no fur-
for (54) and (551, respectively]. Worthy of note ther development has been reported.
is that replacement of the ethynyl moiety in 4.2.2.7.2 Pyrrilidine Ringopened Nicotin-
SIB-1508Y with a phenyl group (e.g., 56) oids. The nicotinoids, characterized as having
shifted the subtype selectivity in the calcium an opened pyrrolidine ring, have been dis-
flux assay using human recombinant nAChRs cussed in several reviews (273,293,295). De-
from a tendency to activate p2-containing re- scribed herein is a series of trans-metanicotine
combinant nAChRs to p,-containing recep- analogs as nAChR agonists.
tors, although both compounds exhibited good R. J. Reynolds Tobacco Co. researchers dis-
potency at displacing [3H]nicotine from rat closed a series of trans-metanicotine analogs
cortical membranes (302). This observation as nAChR agonists (309-313). Of the analogs
led to the discovery of SIB-1553A (111)(see with good binding affinity to the a4p2-typere-
Fig. 14.11) as a selective nAChR agonist, dis- ceptor, most showed low activity at the mus-
cussed later. An enantioselective synthesis of cle- and ganglionic-type receptors. Alkyne
SIB-1508Y (51) has recently been reported (64) is the only compound with significant ac-
(303). tivation of the ganglionic-type nAChR. Stud-
4.2.2.1.1.1 SIB-1508Y (51; Altinicline). ies on the structure-activity relationship have
SIB-1508Y (51in Table 14.6), is a partial ago- been reported and are summarized in Table
nist of the human a,p2 nAChR expressed in 14.7. First, secondary amines bind much more
HEK293 cells (EC,, = 1.8 + 0.7 p M ) (305). tightly than either primary or tertiary amines.
However, SIB-1508Y is also more efficacious For example, binding affinity follows the trend
than nicotine in increasing DA release from 2" (RJR-2403) > lo(58) > 3" (59). Second,
rat striatal slices (305). Preclinical studies us- bulky substituents on the aliphatic nitrogen
Cognition Enhancers

(66) R = Me, K : 75 nM a (68) K : 704 nM a


(67) R = n-C5H1 4: 6600 nM a -7'

Figure 14.7. "Binding data: rat


(322).
brair~/[~H]nicotine

significantly reduce binding affinity (60 ver- stimulates the release of ACh, DA, NA, and
sus FUR-2403). Third, substitution on the ole- 5-HT as effectively as nicotine in rat neocortex
finic amine side chain also reduces binding af- (317).
finity. Comparison of the binding affinities of RJR-2403 has been described as equal to or
RJR-2403 with (66) and (67) (Fig. 14.7) re- better than nicotine as a cognitive enhancer in
veals a 3 and 254 times reduction in binding behavioral assays (274). This compound ame-
affinity when a methyl and n-pentyl groups liorated scopolamine-induced impairments in
are introduced, respectively, on the carbon ad- passive avoidance as well as working and ref-
jacent to the aliphatic nitrogen. Fourth, a erence memory impairments in a radial arm
chain length of four carbon atoms between maze task caused by NBM lesions in rats
heterocycles and side-chain nitrogen is opti- (318). Later studies using the radial maze
mal for high affinity binding (58versus 61 and showed that the positive cognitive effects of
62). Fifth, the trans double-bond geometry FUR-2403 were long lasting (360 min postoral
provides the best binding activity. Binding af- administration) (319). RJR-2403 also showed
finity follows the trend trans olefin (RJR- significant antinociceptive effects in mice and
2403) > alkyne (64) > cis olefin (63) > satu- rats in a variety of pain models (320). Prelim-
rated analog (65). Finally, the nature of the inary pharmacokinetics studies showed that
heteroaryl moiety is critical to the binding ac- RJR-2403 is metabolically unstable and the
tivity. In general, the binding affinity is in the major metabolic pathway in rats is the oxida-
order of pyridinyl (RJR-2403) > pyrimidinyl tion of the carbon a to the basic nitrogen (321).
(68) > quinolinyl (69) > isoquinolinyl (70) Positive results were reported for clinical tri-
(Fig. 14.7). als of RJR-2403. However, further clinical de-
4.2.2.1.2.1RJR-2403 (57; Metanicotine). velopment was suspended, presumably be-
RJR-2403 (57) was selected for further devel- cause of issues surrounding patent protection.
opment because of its high binding affinity for 4.2.2.1.3 lsoxazole and lsothiazole Deriva-
the a,& nAChR in rat cortex [Ki = 26 nM tives. Bioisosteric replacement of the pyridine
(314)l and equivalent efficacy to that of ACh ring in nicotine generated a series of novel
for human a,& nAChRs expressed inxenopus isoxazole compounds that are selective and po-
oocytes, with fourfold greater potency (EC,,: tent neuronal nAChR agonists, as exemplified
FUR-2403 = 16 2 4.6 a; ACh = 57 -t 13 p M ) by ABT-418 (71) (Table 14.8) (299). Among
(315, 316). The compound was about 9 times the variety of substituents examined at C3 of
less potent and slightly less efficacious than the isoxazole, methyl turns out to be optimal,
nicotine in stimulating DA release from rat even though other substituents, such as C,-C,
striatum (314). However, in vivo microdialysis linear alkyl, CF,, Br, and benzyl (not phenyl),
experiments have demonstrated that RJR2403 still provide potent analogs. The 3-des-methyl
I Figure 14.14. Example of pharmacophoric element selection for molecular modeling of nicotine.
Pharmacophoric elements A and B are nitrogens and element C is on the nAChR receptor with
which element B would optimally connect. Carbon, green; nitrogen, light blue; hydrogen attached
to the basic nitrogen, white; putative nAChR binding site, dark blue.
4 Ion Channel Modulation of Neurotransmission

Table 14.8 Binding Data of Isoxazoles

Compound Stereochemistry R1 R2 Ki (nMIa


(71) (ABT-418) (s) Me Me 4.2'
(72) (R) Me Me 52.gb
(73) (S) H Me 333b
(74) (R) H Me 7.4b
(75) 6') Me H 210'
"Rat brain/[3Hlcytisine.
bRef.299.
'Ref. 294.

analog of ABT-418, (75), was shown to possess The binding activity of the reverse isox-
50 times lower binding affinity than that of azole (76) is significantly reduced relative to
ABT-418 for the [3H]cytisine binding site that of ABT-418 (Fig. 14.8). Replacement of
(294). Substitution of the pyrrolidine moiety oxygen in ABT-418 with sulfur generates
in ABT-418 generally reduces activity (323). isothiazole (79) with reduced binding affinity
The enantiomer of ABT-418, (72), has 13 (Table 14.9). It is interesting to note that the
times less binding affinity than that of ABT- N-unsubstituted isothiazole (77) is sixfold
418, compared with the 14-fold difference in more active than the isoxazole counterpart
binding affinity for the corresponding nicotine (73), but still 12 times less active than ABT-
analogs. ABT-418 has approximately 80-fold 418, in terms of binding activity, and also less
more potent binding affinity than that of the efficacious with respect to stimulation of dopa-
desmethyl analog (731, whereas nicotine has a mine release from striatal synaptosomes.
binding affinity 15-fold greater than that of 4.2.2.1.3.1 ABT-418 (71). From a series of
the desmethyl analog. Also of note is that the isoxazole analogs, ABT-418 (711,was selected
opposite trend is observed with the two (R)- for further evaluation (324-326). It is a full
enantiomeric isoxazole counterparts. The (R)- agonist at the brain a&, nAChR, with re-
NH-isoxazole (74) has a binding affinity sev- duced affinity for ganglionic-like nAChRs
enfold greater than that of the N-methyl (327, 328). In vitro, ABT-418 stimulated the
analog (721, but binds with an affinity 2 times
less than that of ABT-418. Isoxazole (74) also Table 14.9 Binding Data of Isothiazoles
demonstrated comparable efficacy to that of
ABT-418 and nicotine in stimulation of DA
release from striatal synaptosomes.

Compound Stereochemistry R Ki (nM)"

Figure 14.8. "Binding data: rat brair~/[~HIcytisine


(299). "Rat brainK3H1cytisine(299).
802 Cognition Enhancers

Table 14.10 Binding Data of 3-%idyl Ethers

I
R1
Compound n Stereochemistry R1 RZ K, (nM)"

"Rat brainl[3Hlcytisine (336).

release of [3H]ACh from rat hippocampal syn- using transdermal administration of ABT-418
aptosomes (EC,, = 2.6 p M ; nicotine EC,, = 1 have been reported to be in progress (78).
piV0 (328) and [3Hldopaminefrom rat striatal 4.2.2.I .4 Pyridyl Ether Derivatives. A series
slices (EC,, = 380 nM;nicotine EC,, = 40 of 3-pyridyloxymethyl heterocyclic ether com-
nM) (327). Like nicotine, ABT-418 has poor pounds have been identified with subnanomo-
oral bioavailability in dogs and monkeys lar affinity for brain nAChRs (336) (Table
(<5%) and moderate oral bioavailability in 14.10). Of particular note are A-85380 (81)and
rats (27%) (329). ABT-418 was shown to be A-84543 (87).A-85380 exhibits high binding af-
effective in animal behavioral models de- finity (Ki = 52 pM), for a4P2nAChRs, compa-
signed to access cognition enhancement (re- rable to that of epibatidine, the most potent
viewed in Ref. (328)).Positive effects were ob- nAChR ligand reported to date. This com-
served for both mice and rats in passive pound stimulated ion flux at the human a,P2
avoidance and Morris water-maze tasks. Stud- nAChR subtypes at 163% relative to nicotine.
ies with nonhuman primates have demon- A-85380 (81)is also a full nicotine agonist
strated positive effects on cognition using the at recombinant human a, nAChRs and yet
delayed matching-to-sample task (330) and a possesses potent activity at ganglionic-like
task designed to measure distractibility (331). nAChRs, as evidenced by 113% of the nicotine
An initial clinical trial of ABT-418 in AD pa- response in an assay examining cation flux
tients yielded positive results in both selective through IMR-32 cells. The IMR-32 assay
reminding tasks (332) and nonverbal learning serves as a model for activity at human periph-
tasks (333).A controlled clinical trial also sug- eral ganglionic receptors, which are believed
gested that ABT-418 may be potentially useful to partially mediate undesired cardiovascular
in the treatment of attention deficit hyperac- and gastrointestinal effects of nicotine. Not
tivity disorder (ADHD) (334). Phase I1clinical surprisingly, a radioiodinatedanalog of A-85380
trials with oral ABT-418 were reported to has demonstrated utility as a research tool for
have had positive effects in enhancing acute in vivo studies of central nAChRs (337339).
attention in AD patients, but the compound's A-84543 (€471,another full agonist at hu-
development was terminated for undisclosed man (Ki= 150 pM), has been shown to
reasons (335). More recently, clinical studies have 32-fold selectivity to stimulate ion flux at
4 Ion Channel Modulation of Neurotransmission

Figure 14.9. "Binding data: rat braid


[3H]cytisine (294).

human a,P, nAChRs compared to human than the unsubstituted analog (97) (Fig. 14.9).
ganglionic nAChRs, and less efficacy (77% of Both (97) and (98) are less efficacious than
nicotine response) at human sympathetic gan- A-84543 (<40% of nicotine response) at human
glionic nAChRs (340).Various substituents at recombinant a,& and ganglionic-type receptom.
the C5 position of the pyridyl moiety of SAR studies on the heteroaryl moiety in
A-84543 have been evaluated. According to A-84543 (87) revealed that the pyridyl nitro-
the binding data, large substituents are well gen in the 3-position is important, and that
tolerated at the C5 position. However, func- additional nitrogens in the ring are generally
tional activity can change from agonist to an- detrimental to activity. It is interesting to note
tagonist by means of varying the substituents that the 3-methyl-5-isoxazole moiety, which
on the pyridine ring (341). served as a bioisostere for pyridine in ABT-
It should be noted that the N-methylation 418, is a poor substitute for pyridine in
for the pyridyl ether series has a different im- A-84543 (see 99, Fig. 14.9). With respect to the
pact from that in the nicotine series (Table N-methyl analogs, the pyrrolidinyl analog (87)
14.10). For example, the N-H pyrrolidine ana- is threefold more active than azetidine (83)
log (85) possesses comparable affinity to that and 480-fold more active than piperidine (93).
of the corresponding N-methyl analog A-84543 Extensive SAR studies were conducted
(87). In the case of corresponding azetidines, with the aim of reducing propensity for pe-
the unsubstituted analog A-85380 is ninefold ripheral ganglionic-like nAChRs, and it was
more potent than the N-methyl counterpart discovered that the 2-methyl substitution of
(83).With regard to stereochemistry, the N- pyridine moiety results in the reduced activity
methyl compounds with ( S )configuration ex- at both ganglionic-like and human a4P2recep-
hibit more potent binding affinity than that of tors. For example, both (85) and (88) pos-
their (R)counterparts, whereas the unsubsti- sessed efficacy comparable to that of nicotine
tuted N-H enantiomers have similar affinity in the IMR-32 assay, whereas their respective
regardless of the stereochemistry. Structure- 2-methyl analogs, (89) and (921, generated
activity studies on the methyleneoxy moiety in only 8% and 11% response, respectively, com-
A-84543 revealed that replacement of the ox- pared with that of nicotine. The 2-methyl pyri-
ygen atom with 4- (94), 4 H 2 - (95), and dine analogs also have 100 to 300 times lower
-CH,O- (96) (Fig. 14.9) reduces affinity at the affhity than those lacking the 2-methyl sub-
rat a,& nAChR by about 2000-, 150-, and 120- stituent for native a,& nAChRs and much re-
fold, respectively. Replacement of the pyridine duced efficacy at human recombinant a4P2re-
moiety in A-84543 (87) with a phenyl ring (97) ceptors. The pattern of binding affinities
decreases binding affinity by 280 times, but regarding stereochemistry and N-methylation
the corresponding m-fluorophenyl derivative parallels that observed for the corresponding
(98, Ki = 5 n M ) is about eightfold more potent 2-desmethyl series.
804 Cognition Enhancers

Table 14.11 Binding and in Vivo Data of 3-Pyridyl Ethers

Compound n Stereochemistry R1 R2 Ki ( n W a MED (p.rn~Ukg)~

"Rat brai~~/[~H]cytisine.
bMinimumeffective dose (MED) in mouse hot-plate assay, i.p. (294, 342).

Of potential relevance to the SAR of these that a different nAChR subtype is responsible
compounds for cognition enhancement is their for the analgesic activity, although other fac-
SAR in antinociceptive assays. In that regard, tors such as species differences and pharmaco-
it is important to note that A-85380 (81) (Ta- kinetic properties cannot be ruled out.
ble 14.10), which possess affinity for a,& re- With respect to the activation of cation flux
ceptors comparable to that of (?)-epibatidine, in IMR-32 cells, compounds (100) and ABT-
failed to demonstrate a significant antinoci- 594 were shown to be more potent and (in the
ceptive effect in the mouse hot-plate model at case of ABT-594) more efficacious than the
doses up to 6.2 pmol/kg (Table l4.ll), whereas corresponding deschloro analog. The 6-bromo
epibatidine shows a robust activity at 0.1 analog (102) maintains both binding activity
pmolkg. Compound (82), an enantiomer of and analgesic activity, whereas the 5-chloro
A-85380, also did not show a significant anal- analog (103) failed to demonstrate analgesic
gesic activity at doses up to 6.2 pmol/kg, de- activity despite a binding affinity similar to
spite its high affinity for central a4P2nAChRs that of compound (102). The N-methyl analog
(Table 14.11) (342). In contrast, the 6-chloro of ABT-594, (104), dramatically reduces both
analogs (100) and ABT-594 (101) not only binding and analgesic activity.
maintained high affinity in a L3H1cytisine dis- The SAR studies on both the azacycle ring
placement assay but also demonstrated anal- size and azetidine N-methylation have been
gesic effects at 0.62 pmol/kg comparable to carried out (Fig. 14.11) (342). Pyrrolidine an-
that of epibatidine. Like epibatidine, both en- alogs (105) and (106) failed to demonstrate
antiomers have similar analgesic activity. As significant activity in the hot-plate assay, even
shown in Table 14.11, the binding affinity to at doses 10-fold higher than that at which
the i3H1cystine site (i.e., the putative a,& (100) and ABT-594 (101) showed robust ef-
nAChR) does not necessarily correlate well fects. The in vitro tests showed only a modest
with analgesic activity. For example, both decrease in potency with the increased ring
ABT-418 and ABT-594 are a,& agonists, but size. N-Methylation of ABT-594 gave (104),
profound analgesic-like effects were not ob- with substantially reduced the [3H]cytisine
served for ABT-418, whereas ABT-594 dem- binding affinity and ganglionic-like activity,
onstrated significant analgesic activity (343). and loss of analgesic activity. Also of note is
The difference in activity between these two that one or two methyl substituents at the
agonists may reflect interactions with differ- 3-position of the azetidine ring in ABT-594
ent nAChR states, but this has yet to be (107 and 108) (Fig. 14.10) as well as one-car-
verified (344,345). It has also been postulated bon homologation of the linkage (109) signifi-
4 Ion Channel Modulation of Neurotransmission

(107) R' = Me, R2= H ; 4:7.6 nM a; hot plate MED: >62 mrnol/kgb
Figure 14.10. "Binding data: rat braid
(108) R' = R2 = Me; 4:37 nMa; hot plate MED: >62 rnrnol/kgb
[3H]cytisine; bminimum effective dose
(109) 4:11 nMa; hot plate MED: >62 rnmol/kgb (MED) in mouse hot-plate assay (346).

cantly reduces binding affinity and analgesic (101)because the latter shows less cardiovas-
activity in the mouse hot-plate assay. It will be cular toxicity in dogs (294).The separation be-
of interest to determine whether a similar tween antinociceptive doses and lethal doses
SAR will be found when examining the poten- in mice is fivefold greater than that for epiba-
tial efficacy of these compounds in behavioral tidine (351). However, a recent study on the
models of cognitive function. analgesic and toxic effects of ABT-594, nico-
4.2.2.1.4.1 ABT-089 (89). ABT-089 (89) tine, and epibatidine indicates that the acute
was identified as the backup compound to safety profile of ABT-594 is not significantly
ABT-418. The agonist ABT-089 is nearly as improved over that of other nicotinic analge-
potent as nicotine for stimulating ACh release sics (351). ABT-594 has the affinity for a,&
from rat hippocampal tissue. However, ABT- neuronal nAChRs comparable to that of (?)-
089 was 25% less potent and only 70% as effi- epibatidine, but its affinity for neuromuscular
cacious as nicotine in stimulating dopamine nAChRs is 4000 times less than that of (?)-
release from rat striatal tissue (314). ABT-089 epibatidine. Moreover, this compound is about
has also been characterized as a weak agonist 30 times less potent and less efficacious at gan-
at the human a, nAChR subtype (1.5% re- glionic-like nAChRs in IMR-32 cells. The high
sponse at 1 a) and to inhibit the response to selectivity for neuronal a&, nAChRs is re-
a)
ACh (IC,, = 48 (347).In vivo studies with sponsible for an improved therapeutic index
ABT-089 demonstrated cognition enhance- over that of (2)-epibatidine. ABT-594 is also
ment in a variety of rat and monkey behav- less potent than epibatidine in assays of acute
ioral models (348, 349) and has recently been and persistent pain and in the rotarod assay.
shown to reduce distractibility in adult mon- However, it displays a clear separation be-
keys (331). As previously described, ABT-089 tween its motor and analgesic effects (352).
is a relatively poor activator of ganglionic ABT-594 shows good oral bioavailability
nAChRs, suggesting a reduced propensity for across species (30-SO%), with oral half-lives
negative side effects at high doses (350). ABT- ranging from 1.4 to 4.2 h. ABT-594 rapidly
089 showed good oral bioavailability (30-70% enters the brain, exhibiting a brain-to-plasma
across rat, dog, and monkey), superior to both ratio of about 2 within 1.5 h (294,342). Recent
ABT-418 and nicotine (294). It is noteworthy studies on ABT-594 showed an increase in
that the secondary amine functionality serves FGF-2 expression in various rat brain regions,
to enhance the oral bioavailability compared suggesting a therapeutic significance in neu-
to the corresponding N-methyl analog (91) rodegenerative disorders (353),but no preclin-
(62% versus 6%in dog), presumably enhanc- ical data for cognitive enhancement have been
ing its stability to first-pass metabolism (336). reported. ABT-594 is currently in phase 111
ABT-089 is currently in phase I clinical trials trials as an antinociceptive agent (292, 314,
as a potential treatment for Alzheimer's dis- 354).
ease, schizophrenia, and attention deficit hy- 4.2.2.1.5 Phenylthioether Derivatives
peractivity disorder. 4.2.2.1.5.1 SIB-1553A (111). Based on the
4.2.2.1.4.2 ABT-594 (101). A-98593 (100) shift of nAChR subtype selectivity from SIB-
was originally selected for further develop- 1508Y (51)to ligand (56) (Table 14.61, Merck
ment and was later replaced with ABT-594 (then SIBIA Neuroscience) scientists designed
Cognition Enhancers

of aged mice. In this paradigm, SIB-1553A was


more efficacious and better tolerated than nic-
otine. SIB-1553A has been reported to reverse
working and reference memory deficits associ-
ated with age, drug-induced cholinergic dys-
function, and specific lesion of choliner*
neurons in rodents and monkeys (356). Addi-
tionally, SIB-1553A caused dose-dependent
improvements in performance on the delayed
Figure 14.11. matching-to-sample task in MPTP-impaired
monkeys (306). It is interesting that neither
(S)- nor (R)- alone was as active as the race-
compound (110), incorporating the phenyl
and pyrrolidine rings of (56) but lacking the mate in any of these behavioral experiments.
pyridine ring of nicotine and SIB-1508Y (Fig. On January 7, 1999, Sibia issued a press re-
14.11) (302). Compound (110)did show selec- lease announcing that SIB-1553A had entered
tivity over P4-containingnAChR cell lines, but phase I1 Clinical trials as a potential treat-
it lacked potency and efficacy in stimulating ment for AD.
the release of neurotransmitters from brain 4.2.2.2 Epibatidine Derivatives. Epibatidine
slices of different regions in rat brain. Exten- (112 in Table 14.12), a trace alkaloid discov-
sive SAR studies culminated in the discovery ered from skin extracts of an Ecuadorian frog,
of SIB-1553A (Fig. 14.11) as a potent and effi- was reported to be a nonopioid analgesic agent
cacious nAChR agonist. A functional assay with a potency 200-fold greater than that of
employing cell lines stably expressing human morphine in mice (357, 358). The absolute
recombinant nAChR subtypes confirmed the configuration of the natural epibatidine was
selectivity for P4-containingnAChR subtypes. assigned as (lR, 2R, 4s). Epibatidine remains
Electrophysiological recording of current re- the most potent naturally occurring nAChR
sponses in Xenopus oocytes expressing recom- ligand reported to date, with potency in many
binant human nAChRs showed that SIB- pharmacological and behavioral assays a few
1553A was most efficacious on a4P4 and had 100-fold greater than that of nicotine. The ac-
weak activity on a3P4and a7receptors. With tivity of epibatidine as a potent nonopioid an-
respect to its ability to displace [3H]nicotine algesic agent has attracted significant atten-
from rat cortical membranes, this compound tion (359). However, it remains unknown
is significantly less potent than nicotine, indi- which subtype(s) is responsible for the antino-
cating that SIB-1553A binds preferentially to ciceptive effects of epibatidine, although cen-
a less abundant endogenous nAChR subtype tral action appear to be involved (360). In
than to the most abundant subtype, presum- contrast to nicotine, both enantiomers of epi-
ably composed of a, and P, subunits. SIB- batidine are highly potent at several nAChR
1553Awas more efficacious than SIB-1508Y in subtypes. Also unlike nicotine, epibatidine is
stimulating rat hippocampal ACh release (51) ineffective in models of cognitive perfor-
or nicotine (355). For example, subcutaneous mance. Further, epibatidine administration
administration of racemic SIB-1553A as well has been associated with adverse effects such
as both enantiomers at 40 mgkg resulted in a as hypertension, convulsions, and respiratory
10- to 12-fold increase of acetylcholine from depression (361, 362). It should be noted that
hippocampi of freely moving rats, and this ef- nicotine has not been developed as an analge-
fect could be attenuated by nAChR antago- sic agent because of its poor spectrum of an-
nists such as mecamylamine. tinociceptive activity, low intrinsic activity
SIB-1553A has been evaluated for potential compared with that of the opioids, and the
cognitive-enhancement effects in an animal poor side-effect profile (360, 363, 364). It has
model. When tested in a sequential spontane- been suggested that the a1P16y(~)and a3P4
ous alternation task, this compound was variant nAChR subtypes found at the neuro-
found to reverse the working memory deficits muscular junction (265) and sympathetic gan-
4 Ion Channel Modulation of Neurotransmission

Table 14.12 Binding and in Vivo Data of Epibatidine Analogs

Compound R1 R2 Ki (nM) ED,, (nmol/mouse)" _


(112) ( l R , 2R, 4S), natural H 2'-C1 0.045~ 0.5
(113) ( I S , 2S, 4R) H 2'-C1 0.058~ 0.6
(114) (racemic) H 2'-C1 0.027"
(115) (racemic) H 2'-F 0.027~ 0.31
(116) (racemic) H 2'-Br 0.023~ 0.33
( 117) (racemic) H 2'-I 0.070~ Not done
(118) (1R,2R, 4 s ) H 2'-Me 0.13b
(119) (racemic) H 2'-OH 107~ 52.4
(120) (racemic) H 2'-NH2 1.3~ 27% @ 112
(121) (racemic) H 2'-NMe, 26.4d 10% @ 32.5
(122) (racemic) H 2'-CF3S03 8.5d 19.2
(123) (racemic) H 2'-H 0.020~ 0.2
(124) ( l R , 2R, 4 s ) Me 2'-C1 0.26b
(125) ( I S , 2S, 4R) Me 2'-C1 O.llb
(126) (racemic) Et 2'-C1 13.6"
(127) (racemic) H 6'-C1 33"
"Tail-flick test (366).
bBindingdata: rat brair~/[~HInicotine
(358).
'Binding data: rat brain/[3Hlepibatidine(368).
dBinding data: rat brai~d[~Hlepibatidine
(366).
'Binding data: rat brain/[3Hlmethylcarbamylcholine(MCC)(367).

glia (266) mediate many of the undesired func- with (?)-epibatidine (365). The deschloro de-
tional effects of (2)-epibatidine. Nevertheless, rivative of epibatidine (123) is comparable to
the antioceptive properties of epibatidine have epibatidine in terms of binding affinity for
led to a search for novel agents with enhanced a,P, nAChRs and functional activity in mod-
selectivity for the a,& receptor subtype over els of ganglionic (PC12) and muscle (TE671)
that of other nicotinic receptor subtypes, and nAChR function, but its analgesic potency is
these efforts culminated in the discovery of significantly reduced in the formalin test but
ABT-594 as a novel antinociceptive agent comparable to epibatidine in the tail-flick
(294). It remains to be determined whether model (366, 367). N-Ethylation (126) reduces
these compounds will display efficacy as cogni- the binding activity by 486 times (368). A
tive-enhancing agents. number of substituents at the 2'-position have
N-Methylation of natural epibatidine (112) been evaluated. In general, electron-with-
and its enantiomer (113)reduced affinities for drawing groups and small alkyl groups (115,
rat a4P2nAChRs by 6 and 2 times, respec- 116, 117, 118) maintain activity, whereas
tively. With respect to functional assays, the electron-donating groups (OH, NMe,) (119,
impact of N-methylation on the activities of 121) reduce activity with the exception of NH,
the two enantiomers is relatively small but dif- (120). The 6'-chloro analog (127) is 55 times
ferential, and the N-methyl products (124 and less active in terms of binding affinity (367).
125) showed modest enantioselectivities (358) The racemic 8-azabicyclo[3.2.lloctane ho-
I (Table 14.12). N-Methyl (?I-epibatidine (114) moepibatidine derivatives were found to have
demonstrated the analgesic activity in the analgesic activity in the hot-plate model (369,
I mouse tail-flick model similar to that observed 370) (Fig. 14.12). Compound (128) was shown
:
Cognition Enhancers

Figure 14.12.

to have the same activity as that of epibatidine a4p2and a,/3,6y(~)was relatively unchanged.
at fourfold higher dosage. The N-methyl ana- The in vivo studies of these pyridazine analogs
log (129) possesses activity comparable to that have not yet been reported (373). Recently,
of epibatidine, but the N-isopropyl derivative identified epibatidine analogs include (138)
(130) is 15 times less potent. The tropinone [Ki = 0.03 nM (rat brai~d[~HIcytisine) (37411
analog (131)was shown to be inactive even at and (139) [Ki = 0.26 nM (rat brair~/[~HIepiba-
high doses. The synthesis of the bis-homoepi- tidine) (37511 (Fig. 14.12).
batidine derivative (132) was reported, al- 4.2.2.3 Anabaseine Derivatives. The natu-
though its biological activity has not yet been ral product anabaseine (140) (Fig. 14.13) was
disclosed (371). isolated from the marine worm Hoplonem-
Replacement of the chloropyridyl ring of etines hydrobiologia (376). In vitro analysis
(?I-epibatidine with methylisoxazole pro- found anabaseine to have approximately 20
vided (?)-epiboxidine (133) as a potent times lower affinity than that of nicotine for
nAChR agonist (372) (Fig. 14.12). This analog rat brain nAChRs, with a fivefold selectivity
is 10 times less active than natural epibatidine for the a,& subtype over the a, subtype (377,
and about 17-fold more potent than ABT-418 378). In Xenopus oocytes, however, ana-
in inhibiting [3H]nicotine binding to a4& baseine had a twofold higher intrinsic potency
nAChRs in rat cerebral cortical membranes. than that of nicotine at the expressed a,
Although (?)-epiboxidine exhibits potent ac- nAChR subtype.
tivity at ganglionic-type nAChRs in PC12 DMAB-anabaseine and GTS-21 (141 and
cells, it is less toxic than epibatidine in mice. 142, respectively) are derivatives of ana-
Bioisosteric replacement of the chloropyr- baseine (1401, obtained through condensation
idinyl moiety in epibatidine with pyridazine with the appropriate benzaldehyde (379,380)
generated (136) (Fig. 14.12). Both (136) and (Fig. 14.13). DMAB-anabaseine was more po-
its N-methyl derivative (137) maintained tent than nicotine, but had similar efficacy, at
much of the potency of natural epibatidine, the a, nAChR subtype. Studies in rat brain
but the selectivity between a,& and a3P4sub- indicate GTS-21 binds 20-fold more potently
types was enhanced by eight- and 25-fold, re- than nicotine to the a,& nAChR subtype (Ki
spectively. However, the selectivity between = 19 ? 4 nM)and 6 times less potently than
4 Ion Channel Modulation of Neurotransmission

passive-avoidance behavior and performance


in the Morris water maze (384). GTS-21 has
also been shown to enhance classical condi- -
tioning of aged rabbits in an eye-blink task .
(385387) and to improve learning perfor-
mance for normal monkeys in the delayed
matching-to-sample task (381). Positive neu- 'Z
(140) anabaseine roprotective effects of GTS-21 have also been
described (388-391). Psychological tests of .
GTS-21 on healthy young male subjects indi-
cate a positive effect on some measures of cog-
nition (392). GTS-21 is currently in phase I
clinical trials as a potential therapy for Alzhei-
mer's disease (393,394).
The in vitro activity attributed to GTS-21
(142) may not completely reveal its in vivo
pharmacology. GTS-21 is primarily metabo-
lized in humans to 3-(4-hydroxy, 2-methoxy-
benzy1idene)-anabaseine, or 40H-GTS-21
(143 in Fig. 14.13) (395,396). This metabolite
was later shown to be a selective partial ago-
nist for both human and rat a, nAChR sub-
(141) DMABA R1 = N(CH3)2, R' = H types, demonstrating good potency (EC,,: hu-
(142) GTS-21 R1 = 0CH3, R2 = 0CH3 man = 26 2 7 a; rat = 10 ? 2 p M ) and
(143) 40H-GTS-21 R1 = OH, R2 = 0CH3 efficacy compared to that of ACh (human =
50%; rat = 40%) (397).Some of the physiolog-
Figure 14.13. ical and behavioral effects of GST-21 may be
attributable to the actions of this primary me-
nicotine to the a, nAChR subtype (Ki = 650 ? tabolite. Both GTS-21 and 40H-GTS-21, how-
34 nM) (381). In clonal human K177 cells, ever, appear to be very weak agonists of the
GTS-21 had a 100-fold binding selectivity for human a4P2nAChR subtype, further support-
the a4P2nAChR subtype over the a, nAChR ing a role of a, nAChRs in cognitive processes.
subtype (Ki = 20 nM and 2 a, respectively)
(381). Interestingly, GTS-21 has been charac- 4.2.3 nACh Receptor Pharmacophore Model.
terized as an a,-selective agent, having partial Several pharmacophore models proposed over
agonist activity at the a, nAChR subtype the years are presented in a recent review (295).
(-28% of ACh response from rat a, nAChR The classic Beers and Reich model (Fig. 14.14)
expressed in Xenopus oocytes), while showing proposes that the essential elements of the nic-
negligible activity at the a,& nAChR subtype otinic pharmacophore are a protonated or quat-
(378). GTS-21 also failed to activate the hu- ernized nitrogen atom (A) (e.g., protonated pyr-
man a4P2 nAChR subtype expressed in K177 rolidine nitrogen of nicotine) and an eledron-
cells (381). negative atom capable of formation of a
In animal models, both DMAB-anabaseine hydrogen bond (B)(e.g.,the pyridine nitrogen of
(140) and GTS-21 (142) improved reference nicotine) (398).The distance between the center
memory in aged rats using a 17-arm radial of charge (A) and the center of the van der Wads
maze (382) and normalized impaired auditory surface of the pyridine nitrogen was 5.9 A (the
gating in mice, suggesting the a, nAChR has a Beers-Reich distance). Subsequently, Sheridan
role in sensory gating (383). GTS-21, but not performed ensemble distance geometry with
DMAB-anabaseine, was effective for enhanc- several known nicotinic agonists and proposed a
ing acquisition in both one-way active avoid- pharmacophore with an additional element to
ance and Lashley 111maze training (382). In the Beers and Reich model: a dummy point (C)
NBM-lesioned rats, GTS-21 improved both or an atom to define a line along which the hy-
810 Cognition Enhar

drogen bond may form (399). This element can A-85380 based nAChR ligands possess st;able
be exemplified by the pyridine ring centroid or conformers featuring similar spatial arrmnge-
the carbonyl carbon. ment of the Sheridan pharmacophoric eleme!nts.
The Sheridan model suggested the optimal The most recent model developed by -

distances between the three elements: A-B Olesen et al. suggests the essential groups are
(internitrogen distance), 4.7 0.3 A; A-C, 4.0 as follows: (1)site point a, correspondin)g to
2 0.3 A; B-C, 1.2 A. The Sheridan models also the protonated nitrogen atom; (2)site poinlt b,
suggested the Beers-Reich distance of 5.9 A. corresponding to the electron negative a.tom
The discovery of epibatidine as an exception- capable of forming a hydrogen bond; (3) site
ally high affinity ligand for nAChRs led to the point c, which is the center of a heteroiaro-
proposal that the optimal internitrogen dis- matic ring or a C----0 bond (Fig. 14.15). 'The
tance for high affinity binding may be close to site points a and b are placed 2.9 A from the
5.5 A as the lowest energy conformer of epiba- corresponding atoms in the direction of the
tidine had an internitrogen distance of 5.51 A lone pairs. Optimal pharmacophoric parame-
(400).A-85380, which possesses affinity simi- ters were estimated as follows: a-b, 7.3-8.( 9 A;
lar to that of epibatidine, showed an interni- a-c, 6.5-7.4 A; Aabc, 30.4-35.8". This th:ree-
trogen distance of 6.1 A in the minimum en- element model was able to explain 65%of the
ergy conformer (340). However, based on the variation seen in the p(IC,,) values (295:). It
argument that the receptor-bound conforma- should be emphasized that it is oversimplified
tion of ligands may not be the same as the to assume that the binding affinity of nAC:hR
lowest energy conformations either in a vac-
uum or in solution, Koren et al. conducted
computational studies on higher than mini-
mum energy conformers of compounds such a-b: 7.3-8.0 A
as epibatidine and A-85380. These studies j b a-C:6.5-7.4 A
show that the internitrogen distances for Aabc: 30.4-35.t
these stable conformers with relative energies
not exceeding 0.42 kcdmol are about 4.4 A,
which is close to the proposed ranges in the
Sheridan model (401).Therefore, it can be con- Figure 14.15. Olesen nicotinic pharmacopl.lore
cluded that epibatidine and the high affinity model. (Modified from Ref. 295.)
4 Ion Channel Modulation of Neurotransmission

ligands be determined by the limited set of selective nAChR agonists is expected to


distance or angle parameters as discussed generate agents with improved physiological
above. Nevertheless, the proposed pharma- activities and safety profiles.
cophore models have proved to be useful in
rationalizing the activity data as well as in the 4.3 5-HT, Receptor
design of new nAChR ligands.
With respect to the binding mode of nAChR 4.3.1 Physiology and Pharmacology of the'
agonists, Dougherty et al. reported a strong 5-HT, Receptor. The neurotransmitter sero-
correlation between the cation-.rrbinding abil- tonin [5-hydroxytryptamine (5-HT)]activates
ities and the EC,, values for acetylcholine at at least seven distinct (5-HT, to 5-HT,) recep- -
the receptor for a series of tryptophan deriva- tors in the central and peripheral nervous sys-
tives incorporated at the a-Trp-149 site in the tems to produce important modulatory effects
nAChR. This study suggests that the a149 (404). With the exception of the 5-HT, recep-
side chain accounts for the possible v-cation tor, all 5-HT receptors are members of the G-
interaction between the quaternary ammo- protein-coupled receptor family that function
nium group of acetylcholine and the nAChRs through adenylyl cyclase or phospholipase C
(402). Studies on the interaction of aromatic second messengers. The 5-HT, receptor, how-
amino acid side chains with the cation-con- ever, is a member of the superfamily of ligand-
taining heterocyclic ring fragments of nico- gated ion channels and serves to moderate
tinic ligands also showed that the tryptophan neuronal depolarization by increasing the flux
side chain was most pronounced in terms of of Na+, K+, and Ca2+ (404-408). The struc-
interaction with the cation fragments, fol- ture of the 5-HT, receptor closely resembles
lowed by tyrosine and phenylanine (403). that of other members of the ligand-gated ion
Because a crystal structure of nAChR is not channel family, especially the nAChRs (409,
available, the nAChR agonist binding site re- 410), and is thought to be a pentameric struc-
mains unknown. Nevertheless, the pharma- ture assembled from structurally distinct sub-
co~horemodels and wcation studies should units. Currently, two subunits [5-HT,,(,, and
provide valuable guidance in the design of 5-HT,, (411)l and an alternatively spliced
more selective and potent nAChR agonists for variant [5-HT,,@, (408,41211 have been iden-
the treatment of CNS-related diseases. tified, although it is speculated that additional
5-HT, subunits may exist and could explain
4.2.4 Future Direction. Significant phar- differences between Ca2+ permeability ob-
maceutical research efforts have gone into the served in native and recombinant 5-HT, re-
search for novel neuronal nAChR modulators ceptor channels (406,413,414).
with selectivity for central versus ganglionic 5-HT, receptors are generally localized in
nAChRs, and these efforts have culminated in presynaptic nerve terminals or fibers (415). Ex-
the identification of: (1) ABT-418, GTS-21, periments with rat striatal synaptosomes have
RJR-2403, and ABT-089 as cognition-enhanc- demonstrated that presynaptic 5-HT, receptors
ing agents; (2) SIB-1508Yfor the treatment of have a high permeability for Ca2+ (416). In-
Parkinson's disease; and (3) ABT-594 as an creased intracellular Ca2+has been observed in
analgesic agent. Through the discovery of isolated nerve terminals (synaptosomes)treated
these novel agents, significant knowledge on with a 5-HT, receptor agonist, a phenomenon
nAChR has been gained. However, this is still that could facilitate action potential-dependent
insufficient to provide predictive in vitro re- neurotransmitter release (417). In the mamrna-
ceptor screens. Therefore, future studies lian brain, 5-HT, receptor agonists have been
should be directed at further understanding observed to stimulate the release of (1) ACh
which of the nAChR isoforms mediate specific from rat dorsal hippocampus (418); (2) dopa-
pharmacological functions of interest. As the mine in the corpus striatum (419) and in the
crystal structure of the nAChR becomes avail- olfactory tubercle (420); (3) GABA and gluta-
able, structure-based design of nAChR ago- mate in the solitary tract nucleus (421);and (4)
nists can be realized. Continued pharmaceuti- cholecystokinin in the cerebral cortex and nu-
cal research into the development of subtype- cleus accumbens (422). In contrast, 5-HT, re-
81 2 Cognition Enhancers

Table 14.13 Shared Pharmacological Properties Between 5-HT, and nACh Receptors
nACh Receptors
5-HT3
Receptors Agonist Antagonist
Agonist N-Methylbufotenine Iodide (432,433) Ethanol (440), Halothane (434) and
(at ganglionic nAChR) Isoflurane (434,435) (at the a,
.T
nAChR)
Serotonin (5-HT) (443,444)

Antagonist Acetylcholine (ACh) (442) Chlorpromazine (436)


(+) and (-1 nicotine (442) QX-222 (436)
Choline (Ch) (442) d-Tubocurarine (439) (at the a, nAChR)
Epibatidine (442) Tropisetron (437) (at the a, nAChR)
DMPP (442)
GTS-21 (442)
Quipazine (442)
Tropisetron (445)
(all at the a, nAChR)

ceptors have been observed to mediate inhibi- was found to coassemble with the 5-HT,, sub-
tion of ACh release in human cerebral cortex unit inxenopus oocytes to form a Ca2+perme-
synaptosomes (4231, in rat cortical synaptosomes able channel (430). However, analysis of na-
(424,4251, and in the rat frontal cortex (418). tive 5-HT, receptors purified from porcine
The in vitro affinity of compounds for central cerebral cortex failed to reveal the presence of
5-HT, receptor sites is often determined by ra- nACh receptor subunits (a, to a, or P2) (431).
dioligand binding assay, or more specifically, by Nevertheless, the prevalence and regional dis-
the ability to displace radioligands from 5-HT, tribution of this subunit coassembly remain to
sites of rat entorhind cortex. Several radioli- be determined.
gands have been used, including [3HlLY278584 The structural similarity between 5-HT,
(426), [,HIGR 65630, and [,HIBRL 43694 (427). and nACh receptors provides for an interest-
The in vitro antagonistic activity at the 5-HT, ing but complex pharmacological overlap (Ta-
receptors is carried out on the rat isolated vagus ble 14.13). An overlap of agonist activity is
nerve (RVN) or guinea pig isolated ileum (GpI). known with N-methyl bufotenine iodide [the
5-HT, receptor agonists cause a rapid depolar- quaternary salt of serotonin; 5-HT,, Ki = 75
ization of the vagus nerve. Antagonists cause nM (432, 43311. General anesthetics such as
parallel, rightward displacements of the agonist isoflurane increase the apparent agonist affin-
concentration response curve. The functional ity for both 5-HT, and nACh receptors, but
activity is expressed by the pA, value, which is also cause channel blockade of the nACh re-
the negative logarithm of the molar concentra- ceptor (434, 435). Mutual receptor antago-
tion of an antagonist that necessitates the dou- nism has been observed with chlorpromazine
bling of the agonist dose to counteract the effect and quaternary linocaine derivative QX222
of that antagonist and restore the original re- (436), tropisetron (437,438), and also with d-
sponse (428, 429). The most frequently used tubocurarine (439).Ethanol has been found to
method for assessing the in vivo activity of potentiate agonist activity at the 5-HT, recep-
5-HT, receptor is accomplished through moni- tor (440) while inhibiting the nACh receptor
toring a transient, dose-dependent reflexive fall (441). The nACh receptor agonists ACh, (S)-
in heart rate and blood pressure (von Bezold- and (R)-nicotine, epibatidine, 1,l-dimethyl-4-
Jarisch reflex) evoked by 5-HT, or a 5-HT, re- phenylpiperazine (DMPP), and GTS-21 (142
ceptor agonist, in urethane-anesthestized rats. in Fig. 14.13) have been shown to function as
This effect can be blocked by prior administra- 5-HT, antagonists (442). 5-Hydroxytrypt-
tion of a 5-HT3 antagonist such as ondansetron. amine (5-HT), the endogenous agonist of the
Recently, the nicotinic a, receptor subunit 5-HT, receptor, is an antagonist of nACh re-
4 Ion Channel Modulation of Neurotransmission

ceptors (443,444). The 5-HT, antagonist qui- rat vagus nerve (PA, = 6.5) through selective
pazine and tropisetron have been reported to screening. The N-imidazolyl (147) was found
be an agonist of the a, nACh receptor subtype to be at least 10-fold more potent (PA, = 7.61) -
(445).It seems likely that further examples of than the parent dimethylamino derivative .
pharmacological overlap will continue to be (146) and became a template for further elab-
uncovered. oration. The 1-methylindole analog (148),
Currently, 5-HT, antagonists have found which was marginally more potent than (147)"
their greatest therapeutic value in the treat- in vitro, demonstrated oral activity in the BJ
ment of cancer chemotherapy-induced emesis test in the rat (ED,, = 0.11 mg/kg). However,
(406). Release of 5-HT from the enterochro- it potentiated the pentobarbitone sleeping -
mafin cells in the gastrointestinal track often time in the mouse, presumably because of the
results from cancer chemotherapy with cyto- imidazole moiety, which can bind to and in-
toxic agents, such as cisplatin (446, 447). hibit the hepatic cytochrome P450 oxidase
Blockade of 5-HT, receptors in the CNS or on system. This side effect was overcome by the
peripheral vagal afferent fibers prevents the introduction of a methyl group at the 2-posi-
initiation of the vomit reflex. tion of the imidazole moiety. The resulting
There is a considerable literature indicat- 2-methyl derivative (149) maintained the in
ing that 5-HT, agonists impair, whereas vitro activity (PA, 7.61), but its oral activity
5-HT, antagonists facilitate, learning and (ED,, = 2.5 mgkg in the BJ test in the rat)
memory (448-451). The mechanisms by was substantially reduced, presumably attrib-
which 5-HT, antagonists achieve their posi- utable to first-pass metabolism. Incorporating
tive effects on cognition are not clear. It would the side chain into the tetrahydrocarbazolone
be reasonable to hypothesize that this is at- system generated the conformationally re-
tributable to positive modulation of acetylcho- strained compound, ondansetron (144, GR
line release in the neocortex (but not hip- 65630) (PA, = 8.6), which was more potent
pocampus), where such agents would be than the acyclic ketone (148) on rat vagus
expected to have no effect or inhibit ACh re- nerve and had much improved oral activity in
lease at behaviorally effective doses (418). An- the rat (ED,, = 7 g/kg, p.0.). Like its acyclic
other alternative is that 5-HT, antagonists counterpart (148), it had no effect on the cy-
achieve their effects on cognition indirectly, tochrome P450 oxidase system. Ondansetron
through inhibition of GABAergic interneu- displayed more than 1000-fold selectivity for
rons that regulate the release of many neuro- the 5-HT, receptor over any other receptors
transmitters, including glutamate (451-453). examined, including 5-HT2- and 5-HT,-like
However, as mentioned earlier, there is grow- receptors. Ondansetron is a racemic com-
ing evidence that multiple 5-HT, receptor pound and both of its enantiomers have simi-
subtypes exist that may have distinct distribu- lar in vitro activity. The quaternary derivative
tion or functional properties, which may ac- (145) maintained activity, suggesting that the
count for their effects. Several 5-HT, receptor imidazole moiety is protonated in the binding
antagonists are described that have been re- interaction with the receptor.
ported to improve cognition in various behav- Considerable efforts have gone into the
ioral models. SAR studies on tetrahydrocarbazolones. First,
substituting the indole nucleus at C6 (e.g.,
4.3.2 Structure-Activity Relationships for 151,152), a potential site of metabolism, gen-
5HT,r Antagonists erally reduces potency, with the exception of
4.3.2.1 lmidazolyl lndolyl Derivatives. The the 6-F derivative (150). Second, substitution
SAR studies of imidazolyl tetrahydrocarbazo- at the 9-position is well tolerated (e.g., 153,
lones, exemplified by ondansetron (144) as 154), but some long-chain lipophilic substitu-
5-HT, antagonists, were presented in a review ents reduce activity (e.g., 155). Third, the
by Oxford et al. (428) (Fig. 14.16). The discov- carbonyl function in this series is critical to
ery of ondansetron began with the indolylpro- potent 5-HT, antagonist activity. The corre-
panone (146), which was identified as a weak sponding alcohols (156, 157) and the tetrahy-
antagonist of 5-HT,-induced depolarization of drocarbozole (158) are less potent than the
Cognition Enhancers

I
Me
(144) ondansetron
pA2 8.6 K, 1.6

(147) R1=H, R2=H, pA27.61


(148) R1= H, R2= Me, pA2 7.67
(149) R1 = R2= Me, pA28.0

I
R
(150) R = F, pA2 8.6 (153) R = Et, pA2 8.7
(151) R = Br, pA2 7.5 (154) R = CH2Ph, pA28.2
(152) R = OMe, pA2 6.1 (155) R = (CH&Ph, pA26.8

Me
(156) X: B0H;pA2 6.9
(157) X: a OH; pA2 7.1
(158) X: H; pA2 6.4

Figure 14.16. pA, values (428): Ki, rat brain wrte~/[~H]Gr-65630


(429).

tetrahydrocarbazolone (144) by about 30 and tron as potent and selective 5-HT, antagonists
100 times, respectively. Finally, the indole nu- (Table 14.14) (429). Similar to ondansetron,
cleus is superior to the benzofuran (159) and the l,7-annelated indoles show little stereose-
benzothiophen (160) moieties. lectivity. The (-)-isomers are only slightly
Researchers from Solvay reported a series more potent than the (+)-isomers. In this se-
of l,7-annelated indole derivatives of ondanse- ries the five- and six-membered ring analogs,
4 Ion Channel Modulation of Neurotransmission

Table 14.14 Binding Data of 1,7-Annelated


Indole Derivatives

Compound X KT
(+)-I61
(+)-I62
(+)-I62
(- )-I62 (cilansetron)
(+)-I63
(+)-I63
(-1-163
(?)-I64
(?)-I65 (168) X = CH pA2 10.2
(?)-I66 (169) X = N, Ki0.16 n M (alosetron)
"Rat brain corte~/[~H]GR-65630
(Ki for (2)-ondanse-
tron: 1.6 nM) (429).
Figure 14.17.

to the side chain imidazole moiety with a ni-


(161) and (1621, are about sevenfold more po- trogen provided alosetron (169), which is
tent and the azepine (163) twofold more po- achiral and yet 10-fold more potent than on-
tent than ondansetron (144), whereas azocine dansetron in terms of the binding affmity.
(164), morpholino (165), and thiomorpholino 4.3.2.1.1 Ondansetron (144; Zofran; GR
(166) exhibit a binding affmity comparable to 65630). Ondansetron is the best-character-
that of (144). ized 5-HT, antagonist [IC,, = 103 pM in re-
From a series of l,7-annelated indole deriv- combinant h5-HT,, receptor (45611 in behav-
atives, cilansetron [(-)-I621 was selected for ioral studies (144 in Fig. 14.16). Although
further pharmacological profiling both in vitro ondansetron has been occasionally shown to
and in vivo (Table 14.14) (454). In the RVN enhance memory in normal adult animals in
and GpI, cilansetron [PA, 9.94 (RVN); 7.80 avoidance (457,458),spatial (451),or discrim-
(GpI)] is about 10-fold more potent than on- ination (459) tasks, the majority of studies in
dansetron [PA, 8.99 (RVN);6.80 (GpI)]. In the unimpaired animals have found no effect
von Bezold-Jarisch reflex test (BJR) in unre- (460-462). However, ondansetron has been
strained conscious rats, cilansetron (ED,, = routinely shown to antagonize the impairing
26 &kg, p.0.) is orally active at a dose 6 times effect of scopolamine, a muscarinic cholinergic
lower than that of ondansetron (ED,, = 165 antagonist (461-465). In addition, ondanse-
pgkg, p.0.). Solvay announced Phase I11stud- tron relieved deficits in spatial learning in
ies for cilansetron for the treatment of diar- young rats caused by destruction of basal fore-
rhea-predominant irritable bowel syndrome, brain cholinergic neurons (466) or in aged rats
in July 2001 (455). (4641, and in a visual discrimination task in
The C-linked imidazole derivatives were aged rhesus monkeys (467).
also prepared (Fig. 14.17). The 2-imidazolyl- A clinical trial on young healthy individuals
methyl analog (167) is less potent than ondan- was conducted with ondansetron (144) to
setron, but compound (167) is a highly potent measure its effects on scopolamine-induced
5-HT, antagonist and has been used as the cognitive, behavioral, and physiological re-
radioligand [,H]GR 67330 in binding experi- sponses (468). This study found that a single
ments. Replacement of the a! carbon attached dose of ondansetron only minimally attenu-
1 Cognition Enhancers

ated the scopolamine-induced changes. In an- gation task (477). However, no improvement
other pilot study from the same investigators, in spatial workinghhort-term memory was ob-
elderly humans demonstrated no cognitive en- served in untreated adult rats (478).
hancement from ondansetron alone, nor had Itasetron (171; DAU 6215; Boehringer In-
cognitive deficits induced by scopolamine gelheim Corp.) is a selective and high &nity
treatment attenuated (469). A recent study antagonist of the 5-HT, receptor (Ki = 3.75
conducted in 189 patients with dementia of nM) currently in clinical trials for the tr&t-
the Alzheimer's type, ondansetron (10 or 50 ment of emesis (452). In scopolamine-im-
pg bid for 24 weeks) failed to show any cogni- paired rats, acute administration of itasetron
tive improvement over placebo (470). Ondan- attenuates memory deficits in the Morris wa-
setron is currently not approved by the FDA ter maze and the passive-avoidance task (438,
for use in dementia, but is marketed as an 479, 480). Positive effects for aged rats were
antiemetic. also observed in an avoidance task (479,481)
4.3.2.1.2 Alosetron (169; GR-68755). Alo- and in the Morris water maze (479,482).
setron (169 in Fig. 14.17) is apotent (Ki = 0.16 Tropisetron [ICS-205,930, Novoban, (172)
nM) and selective 5-HT, antagonist (471),and in Fig. 14.18; Novartis] is a potent 5-HT, re-
- duration of action and a wider
it has a longer ceptor antagonist (Ki = 0.38-3.1 nM) (483-
effective dose range than that of ondansetron 485) that has recently been found to possess a,
(472). Studies in the marmoset have shown nAChR subtype antagonist activity (437) (see
alosetron to improve cognitive performance in Table 14.13) and a , nAChR partial agonist ac-
an object discrimination reversal task (10 ng/ tivity (445). In rat behavioral studies, tropise-
kg, s.c. bid) (473) and to attenuate scopol- tron attenuated scopolamine-induced mem-
amine-induced impairment in the acquisition ory deficits in the passive-avoidance test (438),
of an object discrimination task (1mg/kg, i.p.1 and spatial navigation deficits in the Morris
(474). In healthy humans, alosetron (10 and water-maze task (463), and improved the re-
250 pg) showed significant improvement in re- tention of a conditioned response in rats with
ducing spatial and verbal memory deficits in- p-chloroamphetamine-induced deficits (486).
duced by scopolamine (475). In another clini- Tropisetron is currently marketed for the
cal study, alosetron (20 mg orally) enhanced treatment of nausea and vomiting associated
accuracy on a computerized attention task but with chemotherapy treatments (485).
failed to reverse d-amphetamine-induced def- GYKI-46903 (173; Egis Gyogyszergyar) is a
icits in healthy male subjects (476). potent 5-HT, antagonist (Ki = 20 ? 2 nM)
Alosetron was approved for U.S. use in Feb- reported to be under development as a poten-
ruary 2000 for the treatment of irritable bowel tial treatment for dementia (487,488).In rats,
syndrome (IBS)in women whose predominant GYKI-46903 was shown to attenuate scopol-
bowel symptom is diarrhea, although the amine-induced memory impairments in the
-product was withdrawn in November 2001 be- stepdown passive-avoidance task and the
cause of serious side effects, particularly isch- eight-arm radial maze (489).
emic colitis. Earlier studies in men for anxiety Mirisetron (174; SEC-579; WAY-100579;
disorder and schizophrenia, and Phase I1stud- American Home Products Corp.) is a 5-HT,
ies for nonulcer dyspepsia, have also been dis- antagonist (IC,, = 1.2 nM) (490) that im-
continued. proved spatial learning of lesioned rats in the
4.3.2.2 Other Chemotypes. Several other water maze (466) and enhanced acquisition of
5-HT, antagonists have demonstrated cogni- a visual object discrimination for aged mon-
tion-enhancing effects in animal models. How- keys (467). This compound had reached phase
ever, data from human studies have yet to be I Clinical trials for use as a potential treat-
reported. (R)-Zacopride (170 in Fig. 14.18; ment for anxiety, but no further development
Synthelabo) is undergoing clinical develop- has been reported.
ment as a -potential treatment for cancer
chemotherapy-induced emesis. In atropine- 4.3.3 Future Direction. 5-HT, receptor an-
treated rats, (R)-zacopridesignificantly atten- tagonists were initially hailed as potential
uated memory impairments in a spatial navi- treatments for anxiety, Alzheimer's disease,
4 Ion Channel Modulation of Neurotransmission 817

(171) itasetron (172) tropisetron

(173) GYKI-46903 (174) mirisetron

Figure 14.18.

schizophrenia, pain, and drug dependency. AP) and 3,4-diaminopyridine (3,4-DAP), were
Despite some early encouraging results, no initially evaluated for cognition enhancement
5-HT, antagonists have been approved for the in AD, but gave poor results (493). New com-
treatment of cognitive dysfunction. It would pounds that are selective inhibitors of the K t
be important to know whether 5-HT, antago- M-current, or the channels that underlie this
nists produced any significant improvement current, appear to offer better promise as cog-
over placebo in the clinical trials. At present, nitive enhancers.
their therapeutic application for cognition en- The M-current [I,(,,] is an outward K t
hancement remains unknown. conductance through M-type voltage-gated
Kt channels. This current, which is induced
4.4 Potassium M-Channel
by membrane depolarization and is relatively
slowly activating and deactivating, modulates
4.4.1 Physiology and Pharmacology. Potas-
the subthreshold electrical excitability of neu-
sium (Kt ) channels serve a modulatory func-
tion in excitable and nonexcitable cells by reg- rons in response to synaptic inputs (494). M-
ulating K t conductance (491,492). Within the current is so named because it was inhibited
CNS, many typesof K+ channels are known by activation of muscarinic acetylcholine re-
with differential patterns of distribution. ceptors (495). Inhibition of M-current results
Opening of neuronal Kt channels generally in enhancement of the release of excitatory
acts to dampen neuronal excitability by pre- or neurotransmitters and their postsynaptic ef-
postsynaptic mechanisms. Nonspecific Kt fects (496,497). This net amplification of sig-
channel blockers, such as Caminopyridine (4- nals that originate through normal synaptic
Cognition Enhancers

activitv
" makes the M-channel an attractive vous system. If true, agents that selectively
target for the development of cognitive en- inhibit M-current by directly interacting with
hancers (123,498). the M-channel may enhance cognition with-.
The molecular identity underlying the M- out the adverse side-effect profile typically
current had been established as the coassem- observed with direct muscarinic agonists or
bly of channel subunits (499, 500), KCNQ2 acetylcholinesterase inhibitors. Several candi-
(501) and KCNQ3 (502), and it now appears date M-channel modulators are discussed be?
that KCNQ5 may play an additional role in the low.
generation of an M-type current (503). Muta-
tions in the genes encoding either of these 4.4.2 Structure-Activity Relationships for
channel subunits can result in inactive chan- M-Channel Blockers
nels, causing a form of idiopathic generalized Linopirdine (DuP 996; 175), XE997 (180),
epilepsy (500-502, 504). and DMP 543 (181). The M-current blocker
Several endogenous molecules are known linopirdine (3,3-bis(4-pyridinylmethy1)-1-phe-
to inhibit the M-current, including acetylcho- nylindolin-2-one; DuP 996; 175) is one of a
line, uridine and adenosine triphosphate series of cognition-enhancing agents devel-
(505), bradykinin (506-5091, angiotensin I1 oped by DuPont-Merck (527, 528) that has
(510),endothelin 1 (5111, substance P, and lu- been the focus of intense investigation (Fig.
teinizing hormone-releasing hormone (512). 14.19) (reviewed in Refs. 496, 529). In slices
On the other hand, M-current is increased (po- from rat brain cerebral cortex, hippocampus,
tentiated) by somatostatin and P-adrenore- and caudate nucleus, linopirdine was found to
ceptors through a CAMP-dependent process increase ACh (EC,, value of 4.5 and other
(513). Recently, the novel anticonvulsant reti- neurotransmitters in response to a depolariz-
gabine has been shown to activate human ing stimulus, but had no effect on basal release
KCNQ2 and KCNQ213 channels expressed in (530,5311,suggesting use dependency. In vivo
CHO cells, perhaps contributing to the phar- microdialysis studies have shown an increase
macology of this compound (514). in the release of ACh from rat hippocampus at
Of the five known classes of muscarinic a dose of 10 mg/kg, S.C. (532).
ACh receptors, M-current is preferentially in- Mechanistic studies have indicated that li-
hibited by m l or m3 subtypes (515, 516). Ex- nopirdine (175) inhibits M-current (IKcM,) by
periments with mice lacking the m l receptor channel blockade from the extracellular side
exhibit a loss of muscarinic regulation of M- (529,533,534). Interestingly, linopirdine's ef-
current and are resistant to pilocarpine-in- fect on neurotransmitter release was demon-
duced seizures (517). Recently, specific anti- strated to be brain region specific, indicative of
sense plasmids have been used to strongly a complex in vivo mode of action (535). The
suggest the G-protein GCY,as the primary mechanism underlying the effects of linopir-
transducer of muscarinic inhibition of IK(M, dine on neurotransmitter release, in particu-
(518). lar the potentiation of ACh release from basal
M1 mAChR agonists (that likely inhibit M- forebrain cholinergic neurons, is not known,
current. in addition to their other actions) but could be explained by an action on presyn-
have received considerable attention as possi- aptic KCNQ2 and/or KCNQ3 channels (536).
ble cognitive enhancers (519-521). Although Several substitutions were made for li-
many m l agonists have produced positive re- nopirdine's phenylindolinone "core" to iden-
sults in animal models (522-5251, most of tify more active analogs (530). This was done
these compounds generate unacceptable side in relation to three regioisomer variations of
effects in humans (e.g., 526). It is possible that the pyridinylmethyl "pendent" moiety, while
the cognition-enhancing properties of m l ago- attempting to maintain asymmetry in the con-
nists (and, perhaps, cholinesterase inhibitors) structs. Two compounds worth noting are
are the consequence of a downstream M-cur- xanthene (176) and acenapthenone (177) de-
rent inhibition, whereas the side effects result rivatives that were found to be approximately
primarily from muscarinic receptor mediated equipotent with linopirdine for their ability to
over stimulation of the parasympathetic ner- enhance depolarization-induced ACh release
4 Ion Channel Modulation of Neurotransrnission

(175)
0
linopirdine

Figure 14.19. Potassium M-


current blockers.

from rat brain hippocampal slices. Further core structure of linopirdine was substituted
SAR studies focused on substitution of only with an anthrone moiety to provide XE991
one of the pair of pyridinylmethyl groups (180),a more lipophilic analog. XE991 showed
while maintaining the phenylindolinone core approximately 10-fold greater potency than
(537). Of the racemic compounds generated, that of linopirdine in inhibiting M-current in
the (?)-ethylbutpate (178) and (2)-valeroni- cultured superior cervical ganglion neurons
trile (179) derivatives deserve mention. Each and in KCNQ2/3 channels expressed in Xeno-
analog replaced one of the two pendant groups pus oocytes (297). Further structural modifi-
with an isostere capable of acting as a hydro- cation was done to reduce in vivo N-oxidation
gen-bond acceptor and was found to be as good by replacing the pendant groups with 2-fluoro-
as, or superior to, linopirdine as enhancers of 4-pyridinylmethyl groups, generating DMP
ACh release. Furthermore, when the racemic 543 (181). Both compounds were superior to
ethylbutyrate derivative (178) was resolved, linopirdine for enhancement of ACh release
the biological activity of the (+)-isomer was from rat brain slices (EC,,: linopirdine = 4.2
found, surprisingly, to be only slightly higher f l ;XE991 = 490 nM, DMP 543 = 700 nM)
than that of the racemic mixture. The (-1- and had greater in vivo potency and duration
isomer was inactive and reported not to be an of action (538). An improved synthesis of
antagonist to ACh release. DMP-543 was later reported (539).
Further research to develop a second-gen-
eration clinical candidate with improved phar- 4.4.3 Cognition-Enhancement Experiments.
macokinetic and pharmacodynamic proper- Linopirdine (175) has been assayed in a wide
ties has focused on core and pendant group range of animal models for cognitive enhance-
modifications of linopirdine (175) (530). The ment. In mice, linopirdine enhanced perfor-
Cognition Enhancers

mance in an active avoidance task (540) and cellular Ca2+ dynamics. As such, this class of
improved working memory deficits caused by compounds may normalize the normally
ethylcholine aziridium (AF64A)in the T-maze pathological levels of Ca2+ seen after cerebral -
(541). In rats with and without hypoxia-in- insult, which may otherwise lead to cell death .
duced memory deficits, linopirdine improved and cognitive dysfunction. One compound
performance in the passive-avoidance task, from this class, MEM 1003, is currently in late
suggesting augmentation of task acquisition preclinical trials and may enter European
and consolidation of information skills (540, clinical trials in 2002 (SCRIP, September 20,
542). Linopirdine was also reported to im- 2001).
prove the spatial learning of septal lesioned
rats in the Morris water maze (543), but has
produced conflicting results for untreated rats 5 CONCLUSION
in similar tasks (543-545). In contrast, li-
nopirdine did not improve performance in As the world's population ages, effective treat-
matching-to-sample paradigms using pigeons ment for the cognitive impairments of demen-
or squirrel monkeys (546). Initial clinical tri- tia becomes an increasingly important goal.
als conducted with linopirdine in AD patients The limited success of currently marketed ace-
have been reported to show trends toward cog- tylcholinesterase inhibitors may be partially
nitive improvement (78). However, in phase attributed to factors such as potency, selectiv-
I11 clinical trials linopirdine failed to show ity, or brain penetration. However, it is also
consistent efficacy (547) and continued devel- likely that the potential of these drugs is lim-
opment was terminated (548). ited because of their focused targeting of only
Phase I clinical studies with DMP 543 one of the several neurotransmitter systems
(181),up to a single dose of 55 mg, demon- known to be disturbed in dementing illnesses.
strated that it was well tolerated and had an An additional potential limitation of these me-
improved mean elimination half-life of 30-57 dicaments is that they do not necessarily in-
h (linopirdine was 0.4-3.2 h) (549). To date, crease the fidelity of the signaling event, but
preclinical studies describing cognitive en- instead simply increase the overall back-
hancement with these compounds have not ground level of central ACh. This approach
been published. The development of DMP 543, remains viable only until a critical number of
after reaching phase I1 clinical trials as a po- ACh producing neurons degenerates, at which
tential therapy for the treatment of Alzhei- time a rapid decrease in central ACh can be
mer's disease, has now been discontinued (Du- expected.
Pont Pharm, 2000 Annual Report). The purpose of the present review has been
to consider alternative, ion channel-based ap-
4.4.4 Future Direction. Potassium chan- proaches to the development of cognitive en-
nels, especially the KCNQ family, are widely hancers. Existing preclinical data indicate
involved with the physiology and pathophysi- that these approaches are at least as effective
ology of the human body. Research into their as cholinesterase inhibitors in enhancing
biology will continue to blossom as more cognition. The agents described herein all fa-
cloned KCNQ subunits are available, along cilitate synaptic transmission in several neu-
with selective agents to modify their action. rotransmitter systems, primarily through en-
An additional area of potentially fruitful re- hancement of release. Thus, they work as
search is in the area of central Ca2+ channel positive modulators of normal brain circuit
modulation. Nimodipine, a centrally acting functioning, rather than affecting neurotrans-
Ca2+ channel antagonist marketed in the mitter levels without regard for temporal pa-
United States by Bayer AG for the treatment rameters that are likely critical to meaningful
of subarachnoid hemorrhage, is known to pro- signaling. Another potential advantage of the
tect against the cognitive impairment that mechanisms discussed above is that they
normally follows cerebral insult (550). This ef- present a multifaceted secondary pharmaco-
fect is thought to be attributed to the ability of therapy that would seem to be more appropri-
nimodipine to normalize the function of intra- ate for treating the complex neuropathology of
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CHAPTER FIFTEEN

Drugs to Treat Eating and Body -F

Weight Disorders -

PHILIP A. CARPINO
JOHN R. HADCOCK
Pfizer Global Research & Development-Groton Labs
Department of Cardiovascular and Metabolic Diseases
Groton, Connecticut

Contents
1 Introduction, 838
1.1Eating and Body Weight Disorders:
Definitions, Causes, Comorbidities, 839
1.1.1Obesity, 839
1.1.2 WastingICachexia Secondary to Other
Diseases, 840
1.1.3 Eating Disorders, 840
1.2 Guidelines for Treatment of Eating
and Body Weight Disorders, 842
1.2.1 Obesity, 842
1.2.2 Eating Disorders~WaatingDisorders,
842
2 Clinical Applications, 843
2.1 Overview: Current Drugs, 843
2.1.1 Drugs to Treat Obesity, 843
2.1.1.1 Fat-Absorption Inhibitors, 843
2.1.1.2 Appetite Suppressants, 843
2.1.1.3 Lipolytic and Thermogenic
Agents, 857
2.1.2 Drugs to Treat Eating Disorders, 857
2.1.3 Drugs to Treat Wasting Diseases, 858
2.2 Adverse Effects and Precautions, 858
3 Drug Metabolism, 860
3.1 Absorption/Metabolism of Antiobesity Drugs,
860
3.1.1 Orlistat, 860
3.1.2 Sibutramine, 860
3.1.3 Phentermine, 861
3.1.4 Benzphetamine, 861
3.1.5 Phendimetrazine, 863
3.1.6 Diethylpropion, 863
3.1.7 Mazindol, 866
Burger's Medicinal Chemistry and Drug Discovery 3.2 Metabolism of Appetite-Stimulant Drugs,
Sixth Edition, Volume 6: Nervous System Agents 866
Edited by Donald J. Abraham 4 Physiology and Pharmacology, 867
ISBN 0-471-27401-1 O 2003 John Wiley & Sons, Inc. 4.1 Body Weight, 867
837
Drugs to Treat Eating and Body Weight Disorders

4.1.1 Neuroendocrine Regulation of Energy 6.4 Orlistat Derivatives, 881


Homeostasis by the Hypothalamus, 869 7 Future Directions, 881
4.1.2 PeripherdCentral Adiposity Signals, 7.1 Antiobesity Compounds and New Drugs to .
872 Treat Binge Eating in Clinical Development,
4.1.3 Nucleus Tractus Solitaris (NTS) and 883
Peripheral Satiety Signals, 873 7.1.1 Axokine, 883
4.1.4 Adrenergic and Serotonergic 7.1.2 Rimonabant, 885 t
Regulation of Food Intake, 873 7.1.3 Topiramate, 885
4.1.5 Genetics, 874 7.1.4 Combined NorepinephrineDopamine
4.2 Eating DisorderslCachexia, 874 Reuptake Inhibitors, 885
5 History, 874 7.1.5 Leptin, 885
5.1 Discovery of Sibutramine, 874 7.1.6 0,-Adrenergic Receptor Agonists, 886
6 Structure-Activity Relationships, 875 7.1.7 CCK, Receptor Agonists, 886
6.1 SAR of 2-Phenethylamines, 875 7.2 New Targets, 886
6.2 SAR of Dronabinol Analogs, 877 8 Conclusions, 888
6.3 Mazindol Analogs, 880 9 Abbreviations, 888

1 INTRODUCTION The biochemical and pharmacological mech-


anisms that underlie eating and body weight dis-
Eating and body weight disorders are a diverse orders are complex. These diseases are rarely
group of endocrine, metabolic, and psychiatric caused by any single genetic factor, although de-
diseases that are associated with atypical eat- fects in certain well-defined molecular targets or
ing behaviors and/or significant changes in pathways can enhance the onset of these condi-
body weight. Eating behavior is an essential tions, especially under certain environmental
physiological activity that is required to fur- stimuli and in the presence of certain behaviors.
nish nourishment and energy and is one of These diseases are characterized by perturba-
many factors that determine body weight and tions in numerous physiological systems, but of-
appearance. Eating behavior is quite variable, ten as a consequence, not a cause, of the initial
but becomes pathological when it leads to se- pathology. The central nervous system (CNS)
rious health consequences such as malnutri- plays a critical role in the origin and progression
tion or excess adiposity. Major eating disor- of the diseases, with the hypothalamus regulat-
ders, which occur predominantly in young ing the interactions between various neuro-
women, include anorexia nervosa, bulimia transmitters and neuropeptides that are in-
nervosa, and binge eating disorder. Body volved in maintaining energy homeostasis and
weight also varies considerably between indi- with other brain regions controlling serotoner-
viduals. A healthy body weight depends on a gic function, which plays an important role in
range of genetic factors that govern metabolic the development of psychiatric comorbiditiesas-
processes that seek to maintain a state of en- sociated with many eating disorders.
ergy homeostasis. Extreme variations from a Significant advances have recently been
"normal" body weight are associated with in- made in the treatment of these disorders.
creased risks of developing numerous comor- Combinations of pharmacological and non-
bidities. A decrease in body weight, especially pharmacological approaches, including coun-
in lean or fat-free body mass, occurs second- seling, cognitive behavioral therapy, lifestyle
arily in many diseases and is often a noticeable changes, and drug therapy, are generally re-
symptom of some cancers and other adverse quired to successfully manage these diseases.
conditions. An increase in body weight, partic- Pharmacotherapy, however, is limited by the
ularly fat mass, reflects a positive change in availability of safe and efficacious drugs and is
energy balance, in which energy intake ex- rarely a stand-alone treatment for any of these
ceeds energy expenditure and excess energy is diseases. Several classes of drugs, some of
deposited in adipose tissue. Prototypical body which have been available for decades, have
weight disorders include obesity and cachexia. been approved for the treatment of obesity,
1 Introduction

Table 15.1 Classification of Body Composition by Body Mass Index


(BMI) and Risk of Associated Comorbidities
BMI (kg/m2) Classification Risk of comorbidities
<18.5 Underweight Increased
18.5 to 24.9 Normal Average
25 to 29.9 Overweight Somewhat increased
230 Obese
30 to 34.9 Obese, Class I Moderately increased
35 to 39.9 Obese, Class I1 More severe
240 Obese, Class I11 Most severe

bulimia nervosa, and cachexia, although there The incidence of obesity has dramatically
is still a great medical need for new agents increased over the past decade, reaching epi-
with improved properties. demic proportions in industrialized countries
This chapter describes (1) the physiology throughout the world (2). In the United
and pharmacology of the most common forms States, the disease varies significantly by age,
of eating and body weight disorders; (2) clini- race, and gender and is more prevalent in cer-
cal guidelines for treatment; (3)current drugs tain socioeconomic groups that are predomi-
and their mechanisms of action, adverse effect nantly poor, less educated, and less affluent
profiles, structure-activity relationships, and (3). The proportion of obese American men
metabolic degradation pathways; and (4) new and women has increased by approximately
agents in development.
50% over the past decade, from 12% of the
1.1 Eating and Body Weight Disorders:
population in 1991 to 17.9% in 1998 (3). A ma-
Definitions, Causes, Comorbidities jority of adult Americans and a significant
number of children are now considered either
1.I .I Obesity. Obesity is a condition of ab- overweight or obese (4). Interestingly, more
normal body weight resulting from an accu- people in the world are classified as over-
mulation of extra adipose tissue, generally in weight and obese rather than as malnour-
response to a state of positive energy balance ished, according to the World Health Or-
that occurs when energy intake exceeds en- ganization.
ergy expenditure. Obesity is characterized by Excess adiposity and above-average body
an elevated body mass index (BMI), a com- weight, two distinguishing hallmarks of obe-
monly used descriptor of body composition sity, are associated with numerous health
that is defined as the weight of an individual in risks, resulting in the designation of obesity as
kilograms divided by the square of the height a serious disease (5, 6). According to recent
in meters, or kg/m2 (1).Three discrete classes epidemiological data, obesity increases sus-
of obesity have been established based on ceptibility to a wide range of both cardiovas-
BMI, depending on the risks of associated co- cular and metabolic diseases (7, 8), including
morbidities (see Table 15.1). A preobese state hypertension (91, non-insulin-dependent dia-
is called overweight, with above-average risks betes mellitus or NIDDM (10, ll),and hyper-
of comorbidities. Morphological features of lipidemia (121, and is an independent risk fac-
obesity are usually distinct and often gender tor for certain cancers, including breast,
specific, although there is considerable indi- colorectal, and endometrial cancers (13, 14).
vidual variability. Adiposity in men forms High BMIs also cause debilitating musculo-
mostly in the abdomen, resulting in a unique skeletal (15) and respiratoryhleep disorders
"apple" shape; in women, excess fatty tissue (16) that result in diminished quality of life
generally accumulates in the upper body (17). Because of these comorbidities, the risk
and/or in the hips and the buttocks, giving a of mortality for individuals with BMIs greater
unique "pear" shape. than 30 kg/m2 is nearly twice that for individ-
840 Drugs to Treat Eating and Body Weight Disorders

Table 15.2 Common Comorbidities Associated with Obesity


- -

Metabolic/Endocrine
Cardiovascular Diseases Diseases Joint Diseases CNS
Congestive heart failure Diabetes Osteoarthritis Depression
Hypertension Insulin resistance Rheumatoid arthritis Pain
Deep vein thrombosis Glucocorticoid imbalance Bone fractures T
Coronary artery disease Gall bladder disease Lower back pain
Stroke Hypercholesterolemia Carpal tunnel syndrome
Hypertriglyceridemia
Gout
Pancreatitis
Liver disease
Cancers Respiratory diseases Immune impairments Other
Breast cancer Asthma Impaired wound healing Infertility
Colorectal cancer Chronic obstructive Impaired immune response Incontinence
pulmonary disease (COPD)
Renal cell cancer Chronic bronchitis Renal failure Renal failure
Endometrial cancer Sleep apnea

uals with normal BMIs (18). Obesity is now 1 .1 .2 Wasting/Cachexia Secondary to Other
the second leading cause of preventable death Diseases. Wasting diseases such as cachexia
in the United States after smoking, with ap- are body weight disorders that are character-
proximately 300,000 deaths a year directly at- ized by excessive loss of lean body mass, espe-
tributable to the disease or its comorbidities cially muscle tissue, resulting in profound
(19). A comprehensive listing of the comor- weight loss. The decrease in body weight that
bidities associated with obesity is provided in occurs with these diseases fails to stimulate an
Table 15.2. adaptive response that would normally en-
The causes of obesity are complex, but a hance appetite. Profound loss of lean body
combination of behavioral, genetic, hormonal, mass ultimately leads to organ failure and
economic, and environmental factors all play death. Wasting diseases can be caused by a
critical roles in the origin and progression of variety of factors such as change in taste per-
the disease. Expression changes in genes and ception, decreased food intake, increased sati-
single-nucleotide polymorphisms can predis- ety, or malnutrition, and often occur second-
pose individuals to become overweight or arily in diseases such as AIDS and cancer or
obese. However, lifestyle choices (i.e., low with certain injuries such as severe burns.
physical activity), food preferences (i.e., high Some eating disorders such as anorexia ner-
fat diets, energy-dense foods), and certain be- vosa and several forms of cancer (i.e., lung
haviors (i.e., overeating) hasten the actual cancer) tend to cause severe wasting, which
pathogenesis, generally when caloric intake requires separate therapeutic management
exceeds energy output. The body has devel- apart from the primary disease.
oped numerous methods for managing physi-
ological states of negative energy balance and 1.1 .3 Eating Disorders. Eating disorders
enhancing survival, but few mechanisms for such as anorexia nervosa, binge eating disor-
coping with sustained states of positive energy der, bulimia nervosa, and night-eating syn-
balance and preserving long-term health. It drome are primarily behavioral diseases that
should be noted that only a small percentage are associated with irregular eating patterns
of individuals develop obesity as a result of and/or weight control. The two major eating
specific genetic defects in essential metabolic disorders, anorexia nervosa and bulimia ner-
processes (20). vosa, are often caused by unrealistic percep-
1 Introduction 841

Table 15.3 Symptoms Used to Define Anorexia Nervosa and Bulimia Nervosa as Determined
by the American Psychiatric Associationa
-- -

Anorexia nervosa
1. Refusal to maintain weight greater than the lowest weight considered normal for age and height.
2. Intense fear of gaining weight or becoming fat, even though underweight.
3. Distorted body image in women.
4. Three consecutive missed menstrual periods without pregnancy. T
Bulimia nervosa
1. Recurrent episodes of binge eating (minimum average of two binge-eating episodes a week for at least
3 months). -
2. A feeling of lack of control over eating during the binges.
3. Regular use of self-induced vomiting, laxatives, diuretics, or vigorous exercise to prevent weight gain.
4. Persistent preoccupation with body shape and weight.
"Ref. 5.

tions of ideal body shape and body weight. An- caused by excessive fears of body weight or fat
orexia nervosa results from extreme food gain, leading to dieting and self-imposed star-
restriction (starvation) and less frequently vation. AN is difficult to diagnose in clinical
from other behaviors such as extensive exer- practice because of the extreme measures pa-
cise, and is characterized by a body weight tients undertake to hide the disease. Loss of
that is less than 85% of expected relative body weight, especially body fat, leads to
weight (21). Binge eating disorder consists of amenorrhea, which results in decreased estro-
episodic compulsive eating behavior that re- gen production and diminished bone mineral
sults in body weight gain (22). Bulimia ner- density. Several other side effects of AN in-
vosa is a binge eating disorder that is accom- clude hypotension, hypothermia, pancreatitis,
panied by inappropriate compensatory actions and metabolic abnormalities associated with
such as vomiting, laxative use, or less fre- protein and electrolyte insufficiencies. The
quently, excessive exercise (21). Night-eating death rate from AN is 12 times higher than
syndrome occurs with many sleeping disor- that for other age-matched, young women in
ders (apnea) and results in excessive caloric the population. Leading causes of mortality
intake during nighttime periods of wakeful- include ventricular tachyarrhythmias that re-
ness (23). Anorexia nervosa, bulimia nervosa, sult from electrolyte imbalance (hypokalemia)
and binge eating disorder occur frequently or protein malnutrition (cachexia).
with other diseases of the CNS such as depres- Bulimia nervosa (BN) is an eating disorder
sion, anxiety, and various personality disor- that is becoming increasingly prevalent in
ders and are listed as psychiatric/behavioral Western societies, often occurring in approxi-
disorders in the Diagnostic and Statistical mately 1 3 %of women over the course of their
Manual of Mental Diseases, 4th edition (24). lifetime. Unlike anorexia nervosa, BN is not
Several reviews describe these illnesses in associated with an abnormal state of body
great detail (21,25). weight, in that most women with the disease
Anorexia nervosa (AN) is a chronic disease are within 15% of their ideal body weight.
that is associated with many life-threatening Common symptoms of BN are listed in Table
comorbidities (26). This disorder, which af- 15.3. Risk factors for BN include a previous
fects predominantly young women, often experience with anorexia nervosa, low self-es-
starts in middle adolescence, with a mean on- teem, and certain personality traits. In the
set of action of 17 years of age, and is likely to earliest stages of the disease, patients begin to
occur in approximately 0.5% of women over diet, but the diet-induced hunger cannot be
the course of their lifetime. The clinical crite- controlled. This failure then leads to binge
ria used to define AN are listed in Table 15.3. eating behavior, followed by purging actions
Body weight is controlled by restriction of food (vomiting, laxative, or diuretic use) or non-
intake, although extensive exercise is some- purging behavior (excessive exercising, fast-
times used as a substitute. The disease is often ing) to remove excess calories. As the disease
Drugs to Treat Eating and Body Weight Disorders

progresses, binge eating and the compensa- treatment program. The successful mainte-
tory behavior(s) become mechanisms for cop- nance of lower body weight generally requires
ing with and seeking temporary relief of co- rigid adherence to strict behavioral modifica-
morbidities such as depression or anxiety (26). tions (31).
A typical binge eating episode consists mostly Several drugs for weight loss and weight
of high carbohydrate meals. The average du- maintenance are currently available. These
ration of a meal can be greater than 1 h, with drugs are recommended for patients wit?^
more than 4000 kcal ingested in a single meal. BMIs greater than 30 kg/m2 without addi-
In extreme instances, the amount of food in- tional risk factors or with BMIs greater than
gested at a single setting can be more than 27 kg/m2 with two or more risk factors (29):
20,000 kcal and can last for hours (27). The Obesity is now considered a chronic disease
physical complications of bulimia nervosa that must be managed accordingly.
tend to be limited to hypokalemia, metabolic
alkalosis, arrhythmias, and gastric and esoph- 1.2.2 Eating DisordersNVasting Disorders.
ageal rupture and rarely result in death (25). Few clinical guidelines have been established
Binge eating disorder is the only major eat- for the treatment of eating and wasting disor-
ing disorder that is found appreciably in both ders. Disease-associated cachexia is usually
sexes (35%men; 65% women) (28).A majority managed with nutritional therapy and phar-
of binge eaters are overweight and experience macotherapy involving either anabolic agents
one or more symptoms of classical depression. or appetite stimulants. Eating disorders are
Binge eating behavior occurs alone and ap- treated with a combination of nutritional
pears to be uncontrollable, although it may be therapy, pharmacotherapy, and/or cognitive
soon followed by feelings of embarrassment or behavioral therapy (CBT). For anorexia ner-
guilt. vosa, oral or p a r e n t e d nutritional therapy is
first used to restore a healthy normal weight.
1.2 Guidelines for Treatment of Eating This is followed by behavioral therapy to re-
and Body Weight Disorders move unhealthy preoccupations with weight
loss and to change perceptions about body fat
1.2.1 Obesity. An expert panel of physi- and appearance. Severe cases of anorexia, es-
cians has published several recommendations pecially after onset of cachexia, are best man-
for the treatment of obesity (29, 30). The aged within an in-patient hospital setting.
guidelines call for a 5-10% decrease in body Pharrnacotherapy is generally used to ease
weight by first decreasing total caloric intake fear of food intake, enhance nutritional ab-
and increasing physical activity. This overall sorption, and protect against comorbidities,
decrease in body weight, although small in although it is not very successful in treating
magnitude, is normally adequate to restore the disease itself. For bulimia nervosa, the ini-
"metabolic fitness" by decreasing blood pres- tial goal of treatment is to remove the under-
sure, blood glucose, and serum triglyceridel lying cause of any overeating behavior such as
cholesterol levels. It is recognized that exer- diet-induced hunger or depression and elimi-
cise and diet often prove difficult to implement nate the psychological need for and depen-
on a routine basis and often prove ineffective dency on compensatory behaviors. Pharmaco-
over the long term in causing weight loss, pri- therapy has proven remarkably effective in
marily because weight loss by diet alone re- the treatment of this disease. The manage-
sults in compensatory increases in energy ef- ment of binge eating disorder requires behav-
ficiency and decreases in basal metabolic rate. ioral therapy to restore restraint in eating be-
In such cases where lifestyle changes fail to havior ("self-denial")and pharmacotherapy to
produce the desired reductions in body weight, address the underlying psychiatric compo-
antiobesity pharmacotherapy is subsequently nents of the diseases (32). Because a majority
recommended. Surgery is an option for pa- of patients with binge eating disorder are also
tients with clinically severe obesity (i.e., BMIs overweight, lifestyle changes are necessary to
> 40 kg/m2 or BMIs > 35 kg/m2 with coexist- stimulate weight loss. For all eating disorders,
ing conditions) who do not respond to any prevention of relapse is still a major challenge.
2 Clinical Applications 843

The role of drug therapy in the treatment of weight loss therapy, including nonsystemic fat
eating disorders has been reviewed elsewhere absorption inhibitors, appetite suppressants, .
(21, 33). and thermogenidlipolytic agents (see Table
15.4). These drugs can either decrease energy -
2 CLINICAL APPLICATIONS expenditure or enhance fat metabolism. They
generally decrease body weight by producing,
2.1 Overview: Current Drugs
negative states of energy balance. Fat absorp-
A limited number of safe and efficacious drugs tion inhibitors and lipolytic agents act primar-
are available for the pharmacological treat- ily at molecular targets in the periphery, -
ment of eating and body weight disorders. whereas appetite suppressants generally me-
Compounds (1-9) are used with varying fre- diate their effects in the central nervous sys-
quencies as antiobesity drugs, generally as tem (CNS).Most centrally acting appetite sup-
part of a comprehensive treatment program pressants have low molecular weights and are
involving lifestyle and behavioral changes (see highly lipophilic, properties that promote
Table 15.4). These drugs generally do not transcellular diffusion across the blood-brain
modulate the pathophysiology of obesity be- barrier into the brain.
cause cessation of therapy usually results in Several recent reviews describe in greater
the return of any lost weight. Several antiobe- detail the different pharmacological treat-
sity agents have been removed from the mar- ments for obesity and the clinical efficacies of
ket or are now no longer prescribed as weight both old and new agents (34-36). Worldwide
loss drugs, primarily because of safety con- and U.S. sales of selected drugs used for the
cerns. These include thyroid hormone (10) treatment of eating and body weight disorders
and appetite suppressants such as dexamphet- are presented in Table 15.8 (37).
m i n e (ll),aminorex (12),fenfluramine (131, 2.1.1.1 Fat-Absorption Inhibitors. Orlistat
dexfenfluramine (14), and phenylpropanol- (1, Ro 18-0647, tetrahydrolipstatin) is a non-
m i n e (15) (see Table 15.5). systemic fat absorption inhibitor approved for
Few drugs are available to specifically treat chronic use as a weight loss treatment. It pre-
eating disorders, in part because these dis- vents the breakdown of triglycerides in the
eases are so complex, with features of eating, gastrointestinal tract and blocks the intestinal
psychiatric, and body weight disorders. In gen- absorption of fatty acids (38). It acts as an ir-
eral, antidepressant medications such as (16- reversible inhibitor of gastric and intestinal
24) are used to treat the underlying psychiat- lipases by reacting with specific serine resi-
ric symptoms associated with bulimia nervosa, dues found in the catalytic sites (39). Orlistat
binge eating disorder, and, less frequently, an- is modestly effective at reducing both body
orexia nervosa, and to prevent relapse of many weight and decreasing frequency of comor-
of these disorders (Table 15.6). For anorexia bidities such as diabetes, hypertension, and
nervosa, a variety of different drugs are used hyperlipidemia. In one Pyear clinical trial,
to overcome the side effects generally associ- obese patients with BMIs greater than 30
ated with malnutrition and the fears associ- kg/m2 lost 5-10% of their body weight in their
ated with food intake and body weight gain first year on orlistat therapy and showed sig-
(see 25-29, Table 15.6). nificantly less weight regain in their second
Several drugs (30-33) have recently been year of the study (40).
approved as appetite stimulants or anabolic1 2.1.1.2 Appetite Suppressants. Appetite sup-
growth-promoting agents in wasting diseases, pressants induce satiety mechanisms and, less
generally as short-term treatments until a frequently, increase energy expenditure by in-
normal body weight is achieved (see Table teracting with sympathetic pathways in the
15.7). These agents are often prescribed in CNS. These drugs decrease food intake by ac-
conjunction with other drugs used to treat the tivating doparninergic, sympathomimetic (ad-
primary illness such as cancer or AIDS. renergic), and/or serotonergic systems in the
brain. Modulations of these pathways occur
2.1.1 Drugs to Treat Obesity. Three classes through direct and indirect mechanisms. Indi-

I
E
of antiobesity drugs are currently used in rect-acting drugs increase concentrations of
Table 16.4 (Continued)
Trade DEA Dose
Generic Name Structure Name(s) Originator(s) Class Class (rnglday)
Bontril; Amarin Appetite 111 70-210
Plegine Pharmaceuticals; suppressant
Wyeth

Caffeine (8) Lipolytic agent No label

Thermogenicl No label 75
lipolytic
agent
Table 15.5 Miscellaneous Antiobesity Drugs
Generic Name Structure Class Status
Thyroid hormone (10) I Thermogenic agent Rarely prescribed as weight loss
I agent
" because of
hyperthyroidism

R = I, T4, L-thyroxine (prohormone)


R = H, T3, L-triiodothyronine (hormone)

Dexamphetamine, Dexedrine (11) Appetite suppressant Rarely prescribed as weight loss


agent, DEA Class I1 agent

Appetite suppressant Withdrawn from market because


of risk of primary pulmonary
hypertension

Fenfluramine (13) Appetite suppressant Withdrawn from market because


of risk of cardiac valvular
lesions (valvulopathy)
Table 15.5 (Continued)
Generic Name Structure Class Status
Dexfenfluramine (14) Appetite suppressant Withdrawn from market because
of risk of valvulopathy

Phentermine (3)/fenfluramine(13) Appetite suppressant Withdrawn from market because


0
A
of risk of valvulopathy
w Phentermine (3)ldexfenfluramine(14) Appetite suppressant Withdrawn from market because
risk of valvulopathy
Phenylpropanolamine (15,PPA) Appetite suppressant Removed from market because
of risk of hemorrhagic stroke
Table 15.6 Agents for Treatment of Anorexia Nervosa (AN), Bulimia Nervosa (BN),
and Binge Eating (BE)
- -

Trade Dose
a
Generic Name Structure Name Originator Indication Class (mdday)
-

Fluoxetine (16) Prozac Lilly ANb Antidepressant 60(BN)


BN (SSRI) NA)
BEc

p H 3
H

Sertraline (17) Zoloft Pfizer BNc Antidepressant


BE^ (SSRI)

Paroxetine (18) GSK BN" Antidepressant


(SSRI)
Table 15.6 (Continued)
Trade Dose
a
Generic Name Structure Name Originator Indication Class (rndday)
Fluvoxamine (19) Luvox Solvay BNc Antidepressant
(SSRI)

0,
CH3

Tofranil Novartis BN".~ Antidepressant 150-300


BE"^ (TCA)

Desipramine (21Ib Norpramin Aventis BN".~ Antidepressant 150-300


(TCA)
Table 15.6 (Continued)
Trade Dose
a
Generic Name Structure Name Originator Indication Class (mglday)
Metoclopramide (25) Reglan Robins BNc Prokinetic 40-60
0 agent

Xanax Pharmacia AN" Anxiolytic 0.5-1.5


agent
Conjugated Premarin Wyeth AN" Estrogenic
estrogents: agent
Estrone (-60%):

HO
(27)

Equilin (-30%):

0)
tn
W

Ethinyl estradiol AN" Estrogenic 0.01-0.05


agent

"SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic amine antidepressant; MAOI, monoamine oxidase inhibitor.
*Withsymptoms of depression.
"Off-label.
dSecond-linetherapy.
2 Clinical Applications 855

Table 15.8 Worldwide and U.S.Sales in Year 2000 of Selected Drugs used for the Treatment
of Eating and Body Weight Disordersa
Worldwide Sales U.S. Sales
Indication ($, millions) ($, millions) -
Sibutramine Obesity (OBI
Phentermine OB
Phendimetrazine OB
Orlistat OB
Mazindol OB
Ephedrine OB
Diethylpropion OB
Oxandrolone Cachexia (C)
Megestrolb C
"Adapted from IMS Health Global Services, 2001.
bMost of the sales for Megestrol were for other indications.

dopamine (DA, 341, norepinephrine (NE, 351, petite. Sympathomimetic drugs have been his-
and serotonin [5-hydroxytryptamine (5-HT), torically classified as either direct- or indirect-
361 at postsynaptic neuronal receptors by (1) acting agents.
The majority of appetite-suppressant drugs
are congeners of 2-phenethylamine (P-phen-
ethylamine, 37), a compound with close struc-

(34) Dopamine (DA)

(37) 2-Phenylethylamine, R = H
(38) Amphetamine, R = CH3

tural similarity to many biogenic amines such


as NE and DA. The prototypical 2-phenethyl-
(35) Norepinephrine (NE) m i n e derivatives are amphetamine (38) and
its dextrorotatory isomer dexamphetamine
( l l ) , both of which stimulate NE and DA re-
lease and inhibit NE and DA reuptake. These
drugs exhibit potent anorectic activity, but
they also have extensive central excitatory
properties (euphoria, restlessness) that re-
strict their general utility. Compound (11)is
no longer prescribed as a weight loss agent
because of its small therapeutic index, al-
though it is still routinely prescribed for other
(36) Serotonin (5-hydroxytryptamine - 5-HT) conditions such as attention deficit hyperac-
tivity - disorder (ADHD).
stimulating the release of these neurotrans- Two amphetaminelphenethylamine ana-
mitters stored in intracellular granules or (2) logs, sibutramine (2)and phentermine (31,ex-
inhibiting the uptake of synaptic levels of hibit minimal central excitatory activities.
these neurotransmitters by membrane trans- Sibutramine, a combined NE and 5-HT re-
porters. Direct-acting drugs, in contrast, act uptake inhibitor, is the only amphetamine-
on pre- or postsynaptic receptors to affect ap- like derivative that is currently approved for
Drugs to Treat Eating and Body Weight Disorders

long-term use in weight loss therapy (41). In that reduces the central excitatory activity as-
clinical trials, sibutramine has been shown to sociated with the Bphenethylamine class of
reduce total daily energy intake, decrease fat appetite suppressants, without affecting ano-7
intake, and lower feelings of hunger (42). It rectic activity. Diethylpropion is recom-.
also has been reported to increase energy ex- mended for obese patients with elevated blood
penditure, although the data are somewhat pressure or cardiovascular diseases. These
conflicting (43). Sibutramine has been found drugs all decrease appetite by increasing N E ~
to prevent body weight regain after weight release from nerve terminals.
loss (44). The long-term effectiveness of si- Mazindol (6) is the only non-2-phenethyl-
butramine in reducing obesity-related comor- m i n e indirect-acting syrnpathomimetic drug
bidities has yet to be conclusively established, approved as a short-term appetite suppres-
but sibutramine has been shown to decrease sant. The drug was the principal anorectic
cholesterol and triglyceride levels after 2 years agent used in many countries outside the
of therapy (44). An extensive review of the hu- United States until the introduction of Orli-
man clinical trials with sibutramine was re- stat and Sibutramine. Mazindol is a weak in-
cently published (45). hibitor of NE reuptake and a potent inhibitor
Phentermine (3),a close-in analog of am- of both 5-HT and DA reuptake, although other
phetamine with an extra methyl group adja- activities may be partially responsible for the
cent to the primary amino group, is approved anorectic effect. This drug is postulated to
for short-term weight-loss therapy, generally bind at the "cocaine site" on the DA trans-
lasting up to 3 months. Phentermine stimu- porter, yet it exhibits few of the undesirable
lates synaptic NE release, without affecting pharmacological activities associated with co-
dopamine release or reuptake. Phentermine caine administration (46). Mazindol exists in
was often combined off-label with either fen- two tautomeric forms, with the open-ring ben-
fluramine (13)or dexfenfluramine (14), stim- zophenone tautomer (39) preferred under
ulators of 5-HT release and inhibitors of 5-HT acidic conditions and the cyclic form preferred
reuptake, to give extremely effective weight- under neutral conditions.
loss combinations called "fenlphen" or "d-fen/
phen." These combinations, which never re-
ceived U.S. Food and Drug Administration
(FDA) approval, exhibited greater efficacy
than any of the agents alone, probably because
they targeted two important pathways in-
volved in the regulation of food intake. Both
"fenlphen" and "d-fen-phen" were associated
with cardiac side effects (valvulopathy), par-
tially attributed to the fenfluramine or dexfen-
fluramine part of the combination. Fenflura-
mine and dexfenfluramine have been removed
from the market, but phentermine is still used
as monotherapy for weight loss, although gen-
erally as an adjunct to diet and exercise. The
anorectic effects of phentermine generally de-
crease with time.
Benzphetamine (6), diethylpropion (4), The biological activities of the different ap-
and phendimetrazine (7) are amphetamine- petite suppressants are summarized in Table
like drugs that have been available for several 15.9. Because these drugs can increase synap-
decades, but that are now considered second- tic levels of multiple neurotransmitters, they
tier agents for weight loss. These drugs pro- often exhibit complex polypharmacology by
duce modest reductions in body weight and interacting with entire families of biogenic
are indicated for short-term use only. Benz- m i n e receptors that often have multiple func-
phetamine contains a bulky N-benzyl group tions.
2 Clinical Applications 857

Table 15.9 Comparative Summary of Pharmacological Mechanisms of Weight-Loss Drugs


and Selected Drugs to Treat Eating Disorders"
5-HT NE DA
Reuptake 5-HT Reuptake NE Reuptake DA
Compound Inhibition Release Inhibition Release Inhibition Release
Sibutramine (2) + ++ + z
Phentermine (3) +
Dexfenfluramineb(14) + +++
Diethylpropion (4) + -
Mazindol(5) + + ++
Benzphetamine (6) +
Phendimetrazine (7) +
Dexamphetamine (11) + ++ + ++
Fluoxetine (16) +++
Sertraline (17) +++
Paroxetine (18) +++
Fluvoxamine (19) +++
Imipramine (20) ++ +
Desipramine (21) ++
weak activity; (++), moderate activity; (+ + +), potent activity.
"(+),
bNolonger available.

2.1.1.3 Lipolytic and Thermogenic Agents. 2.1.2 Drugs to Treat Eating Disorders. Clas-
Caffeine (8),a methylxanthine derivative oc- sical antidepressants drugs, such as selective
curring naturally in coffee and tea, is a central 5-HT reuptake inhibitors, tricyclic mines,
stimulant occasionally prescribed for short- and monoamine oxidase inhibitors, are used to
term weight reduction. Caffeine has been treat selected eating disorders, manage the
shown to increase energy expenditure and underlying psychiatric symptoms associated
stimulate lipolysis. The lipolytic activity of caf- with most atypical feeding behaviors (depres-
feine is mediated through antagonism of aden- sion, anxiety), and to prevent relapse of all
osine receptors (mainly A,-R) in adipose tis- eating diseases after treatment (see Table
sue. Some of the pharmacological activities of 15.6). These agents are generally used in con-
caffeine may also be attributed to inhibition of junction with cognitive behavioral therapy
phosphodiesterases, which increase intracel- and nutritional counseling. Selective seroto-
lular concentrations of a cell-signaling mole- nin reuptake inhibitors (SSRIs) prevent re-
cule called cyclic adenosine 3',5'-monophos- uptake of synaptic 5-HT by transporters lo-
phate (CAMP). Caffeine is often combined cated on neuronal membranes. The SSRI
with D-(-)-ephedrine (91, a naturally occur- fluoxetine (16) is approved for the treatment
ring direct-acting sympathomimetic agent of bulimia nervosa (50) and is used off-label in
found in the plant Ephedra equisedina, which the treatment of binge eating disorders (51).
is available as an over-the-counter drug. Other marketed SSRIs such as sertraline (171,
Ephredrine is a weak p,-adrenergic receptor paroxetine (181,and fluvoxamine (19) are con-
agonist that increases intracellular CAMP lev- sidered therapeutically equivalent to fluox-
els. The caffeinelephredine combination has etine and sometimes used interchangeably
been shown to significantly increase energy with fluoxetine to treat bulimia nervosa, with
expenditure (thermogenesis) and fat metabo- the choice depending on the adverse effect pro-
lism in both obese women and adolescents file of the particular SSRI. Sertraline has been
(47-49). This combination is more efficacious shown to decrease frequency of binge eating
than either agent alone, possibly because it disorder behavior (52); fluvoxamine has been
has synergistic effects on the stimulation of found to prevent relapse of bulimia nervosa
CAMP. after psychotherapy (53). SSRIs are generally
Drugs to Treat Eating and Body Weight Disorders

not effective in treating anorexia nervosa, pri- crease risk of fractures, and prevent adult
marily because malnutrition and low body onset of osteoporosis, a potential concern for
weight cause drastic reductions in synaptic young, anorectic women with prolonged epi-
levels of 5-HT (21,541. SSRIs are efficacious in sodes of amenorrhea and decreased endoge-
preventing relapse of anorexia nervosa after nous estrogen production.
weight regain and normalization of 5-HT lev- The pharmacological mechanisms of the
els (55). prototypical drugs used to treat eating disoT-
Tricyclic m i n e antidepressants (TCAs) ders are summarized in Table 15.9.
are nonselective 5-HT and NE reuptake inhib-
itors. Two TCAs, imipramine (20) and desi- 2.1.3 Drugs to Treat Wasting Diseases.
pramine (211,are used to treat bulimia ner- Several centrally and peripherally acting ap-
vosa, primarily as second-line therapies. petite stimulants and anabolic agents are used
Imipramine, a tertiary amine, is a 5-HT re- in the treatment of wasting diseases (see Ta-
uptake inhibitor with weak NE reuptake ac- ble 15.7). A progesterone derivative, meges-
tivity. Desipramine, a secondary m i n e and trol (301, has been shown to enhance caloric
the des-ethyl analog of imipramine, is a NE intake and weight gain in anorectic and ca-
reuptake inhibitor. Other TCAs used less fre- chectic AIDS patients. The exact mechanism
quently to treat BN include amitriptyline (22) by which this agent stimulates appetite is not
and its N-desmethyl analog nortripyline (23). yet known. An anabolic steroid and testoster-
Monoamine oxidase inhibitors are a class of one analog called oxandrolone (31,a class I11
antidepressant drugs that inactivate enzymes controlled substance) has been found to stim-
responsible for degrading biogenic amines, ulate weight gain, improve physical strength,
thus elevating extracellular or synaptic con- and increase lean body mass in anorectic AIDS
centrations of neurotransmitters such as NE patients (59). Dronabinol [32, A9-tetrahydro-
and 5-HT. Two forms of the enzyme are cannabinol (A9-THC)], a synthetic derivative
known: monoamine oxidase (MAO) A, which of one of the active components in Cannabis
is found within nerve terminals and is highly satiua L (marijuana), stimulates appetite
selective for NE and 5-HT; and monoamine through activation of central cannabinoid re-
oxidase B, which is found extracellularly, pri- ceptors, most likely the cannabinoid receptor
marily in platelets, and is highly specific for 1 (CB,-R) subtype, which is found almost ex-
nonphenolic 2-phenethylarnine derivatives clusively in the brain. Dronabinol has been ap-
-

(56). Phenelzine (24) is a non-selective MA0 proved for use in body wasting disorders in
inhibitor that forms an irreversible adduct AIDS patients. Recombinant human growth
with the enzyme through a phenethyl radical hormone (33, rhGH, somatotropin) is also
intermediate. It is used occasionally to treat used to stimulate protein anabolism and in-
bulimics, generally when all other therapies crease body weight gain (lean body mass), with
fail. one marketed rhGH preparation called seros-
Several drugs are used to restore a normal tim, approved for the treatment of AIDS wast-
body weight in anorectic patients and to pre- ing (60). Somatotropin mediates many of its
vent onset of comorbidities (26, 57). Metoclo- pharmacological effects through a hormone
pramide (251, a prokinetic dopamine receptor synthesized by the liver, insulin-like growth
antagonist and a muscarinic agonist, de- factor 1 (IGF-1).
creases bloating during nutritional therapy by
2.2 Adverse Effects and Precautions
increasing gastric emptying, thereby enhanc-
ing nutrient absorption (33, 58). Anxiolytic Side-effect profiles of many antiobesity drugs
agents such as alprazolam (26) are helpful in have led to high attrition rates, lessening the
easing fear of food intake and body weight overall appeal of pharmacotherapy as a treat-
gain and in reestablishing normal eating pat- ment option. In general, anti-obesity drugs
terns. Estrogen replacement therapy through should have fairly mild and non-life-threaten-
use of conjugated estrogens (estrone, 27; equi- ing side effects, because of the potential off-
lin, 28) or ethinyl estradiol (29) is often pre- label use of such compounds for cosmetic pur-
scribed to increase bone mineral density, de- poses in relatively healthy individuals.
2 Clinical Applications

Orlistat can cause a number of unpleasant Other sympathomimetic appetite suppres-


gastrointestinal events such as oily spotting, sants (benzphetamine, diethylpropion, mazin-
flatus discharge, fecal urgency, fattyloily stool, dol, and phendimetrazine) are associated with
.
and fecal incontinence that are related to its insomnia, restlessness (i.e., frequent awaken-
mechanism of action (inhibition of triglyceride ing), and occasional mild euphoria, primarily
breakdown) and its nonsystemic site of action because of their central stimulant properties.
(GI tract) (61). These side effects are generally Toleration usually develops to many of these
more pronounced in obese patients on a high side effects. Drug therapy with these agents is
fat diet. Despite the GI effects, orlistat is gen- restricted to 12 weeks. -

erally considered one of the safest antiobesity Caffeine causes several centrally mediated
drugs, primarily because it shows low sys- side effects including nervousness, irritability,
temic exposure, which generally minimizes and sleeplessness. Caffeine also acts on kid-
the likelihood of general compound-related or- neys to increase diuresis. Convulsions and in-
gan toxicity. creased heart rate can occur with particularly
The adverse effects of amphetamine and high doses of the drug.
related sympathomimetic appetite suppres- The SSRIs used in the treatment of eating
sants are well documented. All of these agents disorders such as bulimia nervosa are gener-
are classified by the U.S. Drug Enforcement ally well tolerated. In clinical trials with fluox-
Administration (DEA) as controlled sub- etine, patients reported increased incidences
stances (classes 11-IV) according to their po- of dry mouth, anxiety, nervousness, insomnia,
tential for causing addiction (see Table 15.4). and sexual dysfunction. Interestingly, two
Class I1 agents such as amphetamine are commonly reported side effects of fluoxetine
highly abused, with prescription restricted to treatment are anorexia and weight loss (63).
special circumstances; class IV anorectic However, fluoxetine is not approved as a ther-
drugs such as sibutramine, phentermine, di- apy for the treatment of obesity, primarily be-
ethylpropion, and mazindol have minimal cause such SSRI-induced weight loss cannot
abuse potential. be maintained. In one controlled trial with flu-
Sibutramine is contraindicated in obese pa- oxetine, severely obese patients (BMIs > 35.6
tients with preexisting cardiovascular dis- kg/m2) reportedly lost significant body weight
eases because it causes a small but significant during the first 20 weeks of the study, but re-
increase in both systolic blood pressure and gained most of the lost weight in the second 20
supine heart rate (62). Sibutramine elevates weeks, despite continuation of drug treatment
synaptic levels of NE, resulting in activation of (64).
sympathomimetic pathways involved in blood The tricyclic amine antidepressants such
pressure regulation. Sibutramine does not ap- as desipramine and imipramine have been rel-
pear to cause valvular heart disease, unlike egated to second-line therapy, mainly because
other agents that potently stimulate 5-HT re- they cause hypotension, tachycardia, blurred
lease like dexfenfluramine. vision, dry mouth, constipation, fatigue, and
The principal side effects of phentermine sedation. attributed in part to their adrener-
A

are insomnia, restlessness, and euphoria. gic, anticholinergic, and antihistaminergic


Some patients rapidly develop tolerance to properties. The monoamine oxidase inhibitor
-

this agent, resulting in discontinuation of phenelzine causes numerous side effects re-
therapy. The combination of phentermine sulting from its irreversible inhibition of both
with fenfluramine or dexfenfluramine was as- brain and liver monoamine oxidases and its
sociated with increased incidences of both pri- nonselective inhibition of other enzymes. The
mary pulmonary hypertension (PPH) and car- liver activity of phenelzine prevents degrada-
diac valvulopathy, but it is unlikely that tion of sympathomimetic amines in food prod-
phentermine alone causes these same prob- ucts, leading to elevated levels of potentially
lems. Phentermine, nonetheless, contains a toxic norepinephrine-like pressor substances.
warning label listing PPH and cardiac valve Adverse effects of phenelzine include severe
lesions as possible adverse events. hypertensive crises, nausea, and vomiting.
Drugs to Treat Eating and Body Weight Disorders

Figure 16.1. Plasma metabolites of orlistat.

These side effects can last for weeks, depend- are also illustrated. The pharmacokinetic
ing on the rate of resynthesis of new enzyme. properties and metabolic degradation path-
Drugs used in the treatment of wasting dis- ways for antidepressant drugs that are used in
eases exhibit several side effects, some of the treatment of eating disorders (i.e., SSRIs,
which are mechanism related. Oxandrolone is TCAs, MAOIs) have been summarized in pre-
an anabolic steroid with potent androgenic ac- vious volumes (67).
tivity that disrupts the hypothalamo-pitu-
3.1 Absorption/Metabolism of Antiobesity
itary-gonadal axis. It can adversely affect
Drugs
growth and sexual development in children
and suppress gonadotrophic function in
3.1.1 Orlistat. Orlistat acts in the GI tract,
adults. It also causes masculinization (i.e.,
where it inhibits pancreatic lipases located in
hoarseness, hair growth) in women; acne and
the lumen. Systemic exposure of the drug is
decreased spermatogenesis in men; and
not required for pharmacological activity.
edema, jaundice, and cholestatic hepatitis in
With negligible oral bioavailability (F < 5%),
both sexes (65). Dronabinol(32) causes a wide
orlistat is primarily excreted unchanged in the
variety of psychotropic effects including dys-
feces. However, several metabolites including
phoria, anxiety, and hallucination that are at-
(40) and (41) have been identified in the
tributed to activation of cannabinoid recep-
plasma of both normal and obese volunteers.
tors within the CNS. This drug can also cause
These compounds are formed by hydrolysis of
tachycardia and orthostatic hypotension (66).
both the N-formyl leucine ester moiety and
Megestrol is associated with respiratory ail-
the lactone ring and do not exhibit any inhib-
ments, elevated liver enzymes, and hypergly-
itory activities toward pancreatic lipases (68)
cemia (66).
(see Fig. 15.1).

3 DRUG METABOLISM 3.1.2 Sibutramine. Sibutramine is readily


absorbed into the systemic circulation, reach-
The absorption and metabolic profiles of anti- ing maximum levels within 2.5 to 3.5 h (69).It
obesity drugs and appetite stimulants in hu- undergoes rapid biotransformation by the cy-
mans are described below. Several novel bio- tochrome P450 family of isoenzymes in the
transformation pathways in rodent species liver (primarily P450 3A& to give the des-
3 Drug Metabolism 861

Figure 15.2. Biotransformation of sibutramine in humans.

methyl compound BTS 54 354 (42) and the In humans, after an oral dose, phentermine is
di-desmethyl analog BTS 54 505 (43; see Fig. converted into the N-hydroxy and N-nitroso
15.2) (70). The R- and the S-enantiomers of derivatives (52) and (53), whereas in rats,
both sibutramine and BTS 54 354 are demeth- phentermine is oxidized to 4-hydroxyphenter-
ylated at different rates, to give a complex mine (54), which is then conjugated and ex-
plasma mixture of both primary and second- creted (73, 74).
ary Bphenethylamine metabolites (44-47).
The half-lives of the R-enantiomers of the two 3.1.4 Benzphetamine. The short-acting ano-
desmethyl and di-desmethyl metabolites (44) rectic benzphetamine is first metabolized in
and (46) are considerably longer than the half- humans to norbenzphetamine (55) through
life of the parent drug. The two enantiomers of N-demethylation and then to 1-(4-hydroxy-
BTS 54 505 (46), (47) are further deactivated pheny1)-2-(N-benzy1amino)propane (56)
through oxidation and conjugation, to give through phenyl ring oxidation (75). Metham-
compounds that are cleared through the phetamine (57) and amphetamine (38) are
kidney.
The pharmacological activities of sibutra-
mine metabolites have been evaluated. The
R-enantiomers of BTS 54 354 and BTS 54
505 (44 and 46) show potent NE, 5-HT, and
DA reuptake inhibitory activities, with IC,,
values less than 13 and 140 nit4 for NE re-
uptake inhibition and 5-HT reuptake inhibi-
(55) Norbenzphetamine
tion, respectively (see Table 15.10) (71). The
S-enantiomer of BTS 54 354 (45) exhibits
weak inhibitory activity for inhibition of up-
take of NE, 5-HT, and DA, whereas the S-
isomer of BTS 54 505 (47) displays good ac-
tivity for inhibition of NE and DA reuptake.
Sibutramine metabolites may be primarily
responsible for the potent anorectic activity
of the parent drug.

3.1.3 Phentermine. Phentermine is an am-


phetamine analog with a quaternary carbon
atom adjacent to the primary amino group.
Unlike amphetamine, which is primarily me-
tabolized first to phenylacetone (49) through
a-hydroxlyation and then to benzoic acid (501,
as shown in Fig. 15.3 (72), phentermine un-
dergoes N-oxidation and aryl ring hydroxyla-
tion in different animal species (see Fig. 15.4). (57) Methamphetamine
862 Drugs to Treat Eating and Body Weight Disorders

Table 15.10 Pharmacological Activities of Sibutramine Metabolites in Rat Synaptosomes


from Male Wistar Hypothalamusa
NE Reuptake 5-HT Reuptake DA Reuptake
Inhibition, Inhibition, Inhibition, -
Compound Structure Ki (nM) Ki (nM) Ki (nM)
Sibutramine I

"Ref. 71.

also formed, but only as minor metabolites. The secondary amino group in (55) is then
Interestingly, only the D-enantiomers of (57) oxidized further to give the N-hydroxyl deriv-
and (38) are detected in urine (76). In hepatic ative (68),which is converted by a flavoprotein
microsomes obtained from rats pretreated mixed-fundion amine oxidase into the nitrone
with phenobarbital, benzphetamine initially derivative (59). Degradation of the nitrone
undergoes demethylation to give norbenz- metabolite, followed by oxidation yields 2-ni-
phetamine (55), as shown in Fig. 15.5 (77). troso-1-phenylpropane (60).
3 Drug Metabolism

/
- WH
Major
Pathway /
___)

/
0
NH2 NH2
Amphetamine (38) (48) (49)

1 Minor pathway

Conjugates +
NH2

Figure 15.3. Metabolism of amphetamine.

3.1.5 Phendimetrazine. Phendimetrazine


is readily absorbed from the GI tract after an
oral dose in humans. It exhibits a short plasma Q+3
half-life (t,,, = 1.9 h), primarily attributable to
high clearance, and requires qid dosing to
maintain adequate plasma levels (78). A spe- 0 d N H
cial slow-release drug capsule has been devel-
oped that extends the half-life to 9.8 h. Two (61) Phenmetrazine

w3
primary metabolites, phenmetrazine (61) and
phendimetrazine N-oxide (621, are formed by
N-dealkylation and N-oxidation and are
cleared through the kidney (79). / I

3.1.6 Diethylpropion. Diethylpropion un-


dergoes P450-mediated mono-N-de-ethyla-
LJ N: O-
'CH~

tion, to give an active metabolite called ethyl-


(62) Phendimetrazine N-Oxide
propion (63; see Fig. 15.6). Compound (63)is a

Phenterrnine (52) (53)

Figure 15.4. Biotransformation of phentermine in rats and humans.


864 Drugs to Treat Eating and Body Weight Disorders

Figure 15.5. Metabolism of benzphetamine in activated rat liver microsomes.

moderately potent substrate for the NE trans- conjugate called hippuric acid (65) (81). A pro-
porter (IC,, = 99 nM) and an inhibitor of NE posed pathway for the conversion of (64) to
uptake (IC,, = 360 nM), in contrast to dieth- (65) is shown in Fig. 15.6. In one study,
ylpropion, which shows only weak activity in norephedrine analogs (66) and (67) were
these assays (see Table 15.11) (80). Ethylpro- found in only neglible quantities in urine, sug-
pion is further metabolized by P450 enzymes gesting reduction of the keto group is not a
to the di-des-ethyl derivative (64) and benzoic major route of elimination for compound (64)
acid (50),which exists in plasma as a glycine (see Table 15.11) (82).These norephedrine an-

O \ 0
Ethylpropion
Diethylpropion

1
glycine glycine N-acyltransferase

Figure 15.6. Metabolism of diethylpropion to hippuric acid.


Table 15.11 Pharmacological Activities of Diethylpropion and Ethylpropion"
DA 5-HT NE
Uptake Release Uptake Release Uptake Release
Ic50 Ic50 Ic50 Ic50 Ic50 Ic50
Compound Structure (nM) (nM) (nM) (nM) (nM) (nM)
Diethylpropion >10,000 >10,000 >10,000 >10,000 >10,000 >10,000
(4)

N-

Ethylpropion
(63)
Drugs to Treat Eating and Body Weight Disorders

tricyclic heterocyclic template and hydrolysis


of the imidazoline ring (85).

3.2 Metabolism of Appetite-Stimulant Drugs

Dronabinol (32) is an orally active cannabi-


noid derivative with low bioavailability (10- r

dogs do not inhibit DA, 5-HT, or NE uptake or


(32) Dronabinol - Pyran Numbering System
stimulate DA, 5-HT, or NE release (80).

3.1.7 Mazindol. Mazindol exhibits a rapid 20%), attributed in part to high first-pass
onset of action and a long duration of action in metabolism (86). In humans, dronabinol un-
humans, primarily because of its slow absorp- dergoes allylic oxidation of the terpene ring,
tion and elimination (83, 84). The majority of to give 11-hydroxy-As-tetrahydrocannabinol
drug is excreted unchanged in urine, although (70). This metabolite is oxidized by alcohol
two metabolites, (68) and (69), have been dehydrogenase enzymes in the liver to yield
identified that are formed by oxidation of the ll-nor-A9-tetrahydrocannabinol-9-carbox-
ylic acid (711,which occurs as a conjugate in
plasma (see Fig. 15.7) (87). The C-3 pentyl
chain in (71) undergoes additional oxida-
tion, to give 4'-hydroxy-ll-nor-A9-tetrahy-
drocannabinol-9-carboxylic acid (72), which
is degraded further to the dicarboxylic acid
derivative (73). Several other metabolites
(74, 75) are formed in small amounts
through allylic oxidation of the C8 position
on the dronabinol A ring, followed by oxida-
tive carboxylation of the C-3 side chain (88).
An interesting metabolite of As-THC is
formed in mice through aromatization of the
terpene ring, to give cannabinol (76) (see
Fig. 15.8) (89). The biological activities of
many of these metabolites have not been
fully described in the literature.
Megestrol (30) is metabolized into three
products in humans, as shown in Fig. 15.9,
although the majority of drug is excreted un-
changed. Megestrol undergoes allylic oxida-
tion, hydroxylation adjacent to the carbonyl
group on the A-ring, and conjugation, to give
metabolites (771, (78), and (79) (90).
1.
i
ii 4 Physiology and Pharmacology

Figure 15.7. Metabolic degradation of dronabinol.

Oxandrolone (31)is rapidly absorbed into 4 PHYSIOLOGY A N D PHARMACOLOGY


the systemic circulation after an oral dose. It
4.1 Body Weight
undergoes oxidation on the cyclopentyl ring,
to give a diol (80) called 16ghydroxy-oxan- Body weight disorders, especially obesity, are
drolone (see Fig. 15.10). The major plasma me- complex physiological processes that result
tabolites are glucuronide conjugates of both from disruptions to endogenous systems in-
(31)and (80) (91). volved in the regulation and maintenance of
Drugs to Treat Eating and Body Weight Disorders

Figure 15.8. Conversion of dronabinol in mice to cannabinol.

(79) (78)

Figure 15.9. Proposed oxidative biotransformation of megestrol.

Figure 15.10. Metabolic hydroxylation of oxandrolone.


4 Physiology and Pharmacology 869

(-) $ food intake; ? EE


(+) ?food intake; & EE

Figure 15.11. Pathways in the regulation of energy homeostasis.

energy homeostasis. Elucidation of the under- the excess calories are stored as adipose tissue,
lying mechanisms involved in obesity and leading to obesity. Several recent reviews de-
related disorders has come primarily from re- scribe the regulation of body weight in exten-
ceptor and hormone knockout mice and trans- sive detail (94-96).
genic animal models (92, 93). Body weight is
controlled through an integrated process that 4.1 .I Neuroendocrine Regulation of Energy
balances energy intake with energy expendi- Homeostasis by the Hypothalamus. The hypo-
ture. This system encompasses many overlap- thalamus, a collection of neuronal bodies lo-
ping interactions between adipose tissue, cated near the thalamus at the base of the
muscle, the adrenal glands, the GI tract, and brain, coordinates signals from the autonomic
the CNS (hypothalamus, nucleus tractus soli- nervous system and regulates many bodily
taris) (see Fig. 15.11). It also includes numer- functions, including metabolism and temper-
ous satiety, anorectic, and orexigenic factors, ature. The role of the hypothalamus in the
several neurotransmitters (5-HT, NE, DA), control of energy balance was discovered
and various circulating nutrients (glucose, lip- through neuronal lesion studies: ablation of
ids) (see Table 15.12). As a central integrator neurons located in the lateral hypothalamic
of these signals, the hypothalamus responds to area (LHA) was shown to cause leanness,
the body's varied energy needs by shifting be- whereas destruction of neurons in the ventro-
tween anabolic and catabolic pathways, that medial nucleus (VMN) was found to result in
is, stimulating food intake and increasing en- obesity (97). Several hypothalamic regions
ergy reserves or inhibiting food intake and de- have now been shown to be involved in the
creasing body weight. The intricate mecha- regulation of energy homeostasis, including
nisms that control these processes can the LHA, VMN, and arcuate nucleus (ARC),
sometimes be disrupted. When energy input located adjacent to the third ventricle. The
exceeds energy output for long periods of time, ARC contains a discrete set of neurons that
870 Drugs to Treat Eating and Body Weight Disorders

Table 15.12 Hormones and Neurotransmitters that Alter Food Intake or Energy Expenditure
Substances that Affect Energy
Anorectic Substances Orexigenic Substances Expenditure
Cocaine- and Agouti gene-related Glucocorticoids
amphetamine-related peptide
transcript product
-?
Cholecystokinin Anandamide Histamine
Corticotropin-releasing y-Butyric acid Leptin
hormone
Enterostatin Galanin a-Melanocytc+stimulating hormone
Gastrin release peptide Ghrelin Neuromedin U
Glucagon-like peptide 1 Growth hormone- Norepinephrine
releasing hormone
Glucagon-like peptide 2 Glucocorticoids Serotonin
Insulin Melanin-concentrating Thyroid hormones
hormone
Leptin Neuropeptide Y
a-Melanocyte stimulating Norepinephrine
hormone
Neuromedin B Opioids
Neuromedin U Orexin
Neurotensin Pancreatic polypeptide
Serotonin

coexpress two orexigenic hormones, called ag- immune, and stress responses. Both the PVN
outi gene-related peptide (AGRP) and neu- and the VMH contain mRNA for a CRH recep-
ropeptide Y (NPY), and another grouping of tor subtype, termed CRH,-R, that is involved
neurons that coexpress anorectic hormones in decreasing food intake and increasing en-
such as a-melanocyte-stimulating hormone ergy expenditure in rats (101). Neurons in the
(a-MSH) and peptidic hormone derived from LHA secrete an orexigenic hormone called
cocaine and amphetamine-related transcript melanin-concentrating hormone (MCH) that
(CART) (see Fig. 15.12). a-MSH is a proopio- acts at specific receptors in the PVN. A newly
melanocortin (P0MC)-derived peptide in the discovered 33 amino acid neuropeptide, called
melanocortin (MC) family. Neurons in the orexin A, is synthesized in the PFA and LHA
ARC project to other sites within the hypo- and may mediate its orexigenic activities
thalamus, including the dorsomedial nuclei through receptor subtypes found in the PVN
(DMN), paraventricular nucleus (PVN), peri- and the VMN. More complete descriptions of
fornical area (PFA), and LHA, and to other the anatomical distribution of hypothalamic
regions of the brain. The hypothalamic path- neurons that secrete neuropeptides and their
ways involved in food intake and energy ho- receptors have been described elsewhere (97,
meostasis have been reviewed (98-100) 100).
Several hypothalamic regions outside the A functional melanocortinergic system in
ARC also synthesize neuropeptides involved the hypothalamus is essential for maintaining
in the regulation of energy homeostasis or normal body weight. This system consists of
contain receptors that respond to ARC hor- two opposing hormones, AGRP and a-MSH,
mones (see Figs. 15.13 and 15.14). The PVN and two MC receptor subtypes, MC,-R and
contains multiple subtypes of receptors for MC4-R (see Fig. 15.12). The neuropeptide
NPY and POMC-derived peptides such as a-MSH, an endogenous agonist for both
a-MSH. Neurons in the PVN synthesize and MC3-R and MC,-R, decreases food intake and
release corticotrophin-releasing hormone increases energy expenditure in rodents.
(CRH), an important central hormone that is AGRP, an inverse agonist of MC3-R and
involved in the regulation of many endocrine, MC4-R, stimulates food intake by antagoniz-
4 Physiology and Pharmacology 871

LHA - Lateral hypothalamic area


NTS - Nucleus tractus solitaris
PN - Posterior nucleus
PVN - Paraventricular nucleus
VMN - Ventromedial nucleus
1 - Ob-Wleptin receptor

t t

Figure 15.12. Projections of ARC neurons to other hypothalamic regions.

ing t h e actions o f a-MSH (102). AGRP trans- knockout mice can be reversed by peripheral
genic animals, POMC gene KO, MC3-R KO, administration o f a l o w dose o f a-MSH. T h e
a n d MC4-R KO mice are all obese. Interest- obese phenotypes in MC3-R and MC4-R KO
ingly, t h e obesity observed in t h e POMC mice are caused by distinct mechanisms. T h e

ARC PVN

Key:

-
I POMC Proopioimelanocortin
AGRP - Agouti-related protein
NPY - Neuropeptide Y
\
CART - Cocaine- and amphetamine-related transcript
MC - Melanocortin
MSH - Melanocyte stimulating hormone

Figure 15.13. ARC and PVN neuron innervations.


Drugs to Treat Eating and Body Weight Disorders

OX1 - Orexin 1
MCH - Melanin concentrating hormone
Figure 15.14. LHA neuronal projec- o b --~Leptin receptor
tions.

morbid obesity in MC,-R knockout mice is at- 4.1.2 PeripheralICentral Adiposity Sig-
tributed to hyperphagia, whereas the obesity nals. Several peripheral signals including the
associated with MC3-R knockout mice is at- pancreatic hormone insulin and the adipocyte-
tributed to metabolic deficiencies. MC3-R derived hormone leptin are transported across
knockout mice have decreased lean body mass the blood-brain barrier into the arcuate nu-
in conjunction with increased adipose mass; cleus and play important roles in the regula-
however, they are not hyperphagic (103). tion of energy balance. Leptin provides a crit-
AGRP transgenic mice are similar to MC,-R ical connection between energy reserves
KO mice. (adipose tissue) and the brain (108). Leptin
The functional importance of other hypo- mediates its effects through specific receptors
thalamic neuropeptide systems in the physio- (Ob-R) on ARC neurons (109) that either in-
logical regulation of body weight in humans is hibit synthesis/secretion of orexigenic neuro-
less clear. Many neuropeptides including hormones in the ARC, including NPY and
MCH. NPY. and orexin A stimulate food in- AGRP. or stimulate secretion of anorectic hor-
take upon exogenous administration. MCH mones such as a-MSH, neurotensin, and the
knockout mice are lean and mice overexpress- peptide product from CART (see Figs. 15.12
ing MCH in the hypothalamus are obese (104, and 15.13). It also stimulates MCH and orexin
105). NPY gene knockout mice show normal neurons in the LHA (see Fig. 15.14). Leptin
feeding behavior, whereas mice lacking NPY levels fall during periods of starvation and in-
receptors (NPY,-R, NPY,-R) develop late-on- crease during periods of excess energy, in pro-
set obesity. NPY appears to be critical for portion to adiposity. Any disruption in the
stimulating food intake during periods of en- centrally mediated signaling of either leptin or
ergy deprivation (starvation), but may not be insulin can cause obesity. Leptin-deficient (obl
necessary for normal body weight regulation. ob) mice are hyperphagic, obese, and diabetic
The primary phenotype of orexin gene knock- (108). The discovery of leptin underscored the
out mice is narcolepsy, not changes in body important role that molecular factors play in
weight. However, icv administration of anti- regulation of body weight homeostasis and set
bodies to orexin A or antagonists to the OX,-R off the search for other candidate genes.
decrease food intake (106, 107). Studies with The pancreatic hormone insulin is primar-
selective peptide or nonpeptide pharmacologi- ily involved in the regulation of glucose ho-
cal probes are necessary to fully decipher the meostasis. However, insulin inhibits food in-
complex roles of these neuropeptides and their take when administered directly into the
receptors. brain (110). Furthermore, insulin levels rise
4 Physiology and Pharmacology

with increasing adiposity, contributing to the satiety signals, generally released into sys-
pathophysiology of obesity-related comorbidi- temic circulation after food intake. CCK is also
-
ties. Neuron-specific deletion of either the in- synthesized in the brain where it is colocalized '

sulin receptor or insulin receptor substrate-2 with dopamine in selected neurons. The pe- -
in mice produces an obese phenotype (111, ripheral pharmacological activities of the CCK
112). peptides, which include stimulation of gastric
The recently identified gut/brain hormone emptying and release of digestive enzymes,
ghrelin may be another important integrator are mediated by a subtype of the CCK family of
of peripheral and central signals (113). Ghre- receptors called CCq-R, found mainly in
lin, an endogenous ligand for the growth hor- nerve terminals in the periphery. The anorec-
mone secretagogue receptor type la (GHS- tic effects of CCK fragments require an intact
Rla), is synthesized in the stomach, gut, and vagal nerve that serves as the main conduit
hypothalamus and is regulated by feeding and between the stomach and the brain, primarily
fasting. Ghrelin promotes hyperphagia, in- the NTS. Otsuka Long-Evans Tokushima
creased adiposity, and obesity in rodents Fatty (OLETF) rats lack CCK,-R and are hy-
(114). The orexigenic actions of ghrelin are perphagic and obese (117). Interestingly,
blocked by NPY antagonists and immuno-neu- CCK,-R knockout mice are not obese. A recent
traliiation of AGRP, supporting a role for ghre- review describes the biological activities of
lin in energy balance in rodent models (115). CCK and analogs (118).
Adipose tissue was once considered to be Several other gut peptides such as en-
primarily a storage site of triglycerides that terostatin or gastrin-releasing-peptide (and
could be released as free fatty acids upon sym- other bombesin-like peptides) are also in-
pathetic stimulation. However, it is now rec- volved in initiating satiation responses after
ognized that adipose tissue is an important food intake. The roles of these peptides in reg-
endocrine organ that secretes many hormones ulating food intake have been reviewed else-
and cytokines that are involved in energy ho- where (34).
meostasis, including leptin and other factors
such as angiotensinogen, resistin, adipsin, 4.1.4 Adrenergic and Serotonergic Regula-
ACRP30, tumor necrosis factor a, IL-6, and tion of Food Intake. Both the hypothalamus
plasminogen activator inhibitor 1. The roles of and NTShrain stem are innervated with NE
these adipogenic hormones in the regulation and 5-HT fibers that are involved in the regu-
of energy balance and carbohydrate metabo- lation of food intake. NE stimulates food in-
lism have been reviewed elsewhere (116). take through activation of a,-adrenergic re-
ceptors (a,-AR) in the PVN and decreases
4.1.3 Nucleus Tractus Solitaris (NTS) and feeding through a,-ARs that are also in the
Peripheral Satiety Signals. The nucleus tractis PVN (119). Many sympathomimetic agents
solitaris (nucleus of the solitary tract, NTS) is that increase synaptic NE release actually de-
a collection of neurons found in the region of crease appetite by indirectly stimulating al-
the brain stem (hindbrain) that integrates adrenoceptor pathways. Serotonin acts on
many signals from the GI tract that are re- postsynaptic 5-HT,, and 5-HT,, receptors in
leased into the circulatory system after food the LH, VMH, and NTShrain stem, to de-
intake. The NTS receives signals through va- crease food intake and alter meal size and
gal nerve afferents and then communicates meal number (120, 121). The anorectic effects
with the hypothalamus to modulate the activ- of 5-HT, however, are primarily mediated by
ities of important neuropeptides involved in 5-HT,, receptors located in the brain stem.
stimulating or inhibiting food intake. The For example, fourth ventricle administration
NTS is also activated by the neurotransmit- of small molecule 5-HT,, receptor agonists is
ters NE and 5-HT, which can stimulate satiety sufficient to mediate all the anorectic effects of
mechanisms and increase energy expenditure. such agents (122). Synaptic levels of 5-HT are
Cholecystokinin (CCK) and related peptide controlled by a variety of signals, including
fragments such as CCK-33 and CCK-8 are a such peripheral satiety factors as CCK. Acti-
class of gut peptides that act as short-term vation of hypothalamic 5-HT receptors results
Drugs to Treat Eating and Body Weight Disorders

in a downregulation of NPY secretion (121). secondary to the pathogenesis of the diseases.


Serotonergic pathways involved in food intake In anorexia nervosa, for example, plasma lev-
appear to operate independently of leptinergic els of stress hormones such as ACTH and c o ~
pathways. tisol are elevated compared to controls, sug-
gesting increased hypothalamic levels of CRH,
4.1.5 Genetics. Several examples of mono- a catabolic hormone (128). Plasma leptin lev-
genic single-nucleotide polymorphisms (SNPs) els are also decreased, although this is proba-
or mutations in human genes have been iden- bly related to depletion of adipose tissue,
tified that lead to obesity or a predisposition to whereas NPY and ghrelin levels are increased,
an obese phenotype. The most extensively probably as an adaptive response to decreased
characterized SNP is the TRP,, +ARG,, mu- food intake (129, 130). In bulimia nervosa,
tation in the human &-adrenergic receptor, CCK release is blunted because of delayed gas-
which has been associated with an increased tric emptying caused by stomach enlargement
prevalence of obesity or diabetes in certain (131).
populations (123).It is not clear whether there Cachexia may be driven by the increases in
are actually functional differences between various cytokines that are observed in many
the two isoforms (124, 125). A SNP in the wasting disorders (132). Cytokines such as
CCK-R promoter region is associated with in- IL-1 and IL-6 can promote negative nitrogen
creased fat mass in humans (126). Mutations balance and protein wasting by modulating
that inactivate the gene encoding the melano- the activities of various hypothalamic neu-
cortin-4 receptor subtype are found in approx- ropeptides involved in the regulation of energy
imately 5% of all morbidly obese humans and homeostasis, including NPY. These cytokines
represent one of the commonest known mono- can also increase leptin synthesis in adipose
genic causes of human obesity (127). tissue and stimulate downstream leptinergic
Several other monogenic mutations are pathways in the CNS, thus leading to severe
found in humans but are much less common. anorexia (133). Recent evidence suggests that
These include the leptin, leptin receptor, elevated 5-HT levels may play an important
POMC, and prohormone convertase I genes. role in the anorexia of certain cancers and
Patients with Prada-Willi syndrome also have other wasting disorders (134).
a gene deletion.
4.2 Eating DisordersKachexia 5 HISTORY
Although signals involved in the control of
5.1 Discovery of Sibutramine
food intake are well known, the pathophysiol-
ogy of anorexia nervosa and other wasting dis- The anorectic effects of sibutramine, one of
eases such as drug or disease-mediated ca- only two weight-loss drugs currently approved
chexia is less understood. Anorexia nervosa, for long-term use, were serendipitously dis-
binge eating disorder, and bulimia nervosa are covered during clinical trials. The compound
in part eating, body weight, and psychiatric was originally developed as an antidepressant
diseases. In all these conditions, symptoms of medication because of its potent NE and 5-HT
depression, obsessive compulsive behavior, reuptake inhibitory activities. However, the
and anxiety are common. These psychiatric drug failed to show any efficacy in Phase I1
symptoms are generally associated with de- human trials, despite demonstrating good ac-
creased central serotonergic activity. In an- tivity in animal models of depression. An-
orexia nervosa, for example, cerebrospinal orexia was observed as a side effect in many of
fluid (CSF) levels of a metabolite of 5-HT the depressed patients, which then led to a
called 5-hydroxyindoleacetic acid are low, but change in the clinical program (135). The an-
return to normal levels after weight regain orectic effects of sibutramine were later con-
(25). Several neurotransmitters, neuropep- firmed in animal models after both single and
tides, and peripheral hormones are also chronic dosing (136,137). The decrease in food
known to be up- or downregulated in eating intake was shown to occur through both NE
disorders, although these effects appear to be and 5-HT pathways, given that it was partially
6 Structure-Activity Relationships

blocked by administration of centrally active membrane transporters. Such compounds all con-

-
serotonin receptor antagonists (metergoline), tain a 2-phenethylamine moiety, in which a basic
a,-receptor antagonists (prazosin), and &-re- amino group is separated from a lipophilic aryl*
ceptor antagonists (metoprolol) (138). ring by an alk.yl spacer consisting of two carbon
Sibutramine failed to show antidepressant atoms. The unsubstituted derivative,2-phenethyl-
activity in humans, but was found to be a potent amine, shows weak sympathomimeticand serobP
anorectic agent. A structurally distinct com- nergic activity and exhibits no CNS exposure
pound, venlafaxine (811,with similar in vitro because of its rapid metabolism by MAOs. Intro-
duction of one or two -1 substituents at the C1.
position adjacent to the amino group decreases
metabolism by MAOs and enhances CNS expo-
sure (140).Both amphetamine (38)and phenter-
mine (3),which differ from 2-phenethylamine by
the addition of one or two methyl groups, exhibit
good CNS exposure.
The structure/activity relationships of
2-phenethylamines on serotonin uptake in-
hibitory activity have been investigated using
(81) Venlafaxine platelet-rich plasma from human volunteers
(141). The uptake activity of amphetamine is
pharmacology at both the NE and 5-HT re- enhanced by alkyl substituents on the amino
uptake transporters, proved to be an efficacious group and by the incorporation of methyl sub-
antidepressant drug, without displaying sigdi- stituents adjacent to the nitrogen atom (see
cant anorectic activity in humans. Venlafaxine Table 15.13). Tertiary m i n e s such as sibutra-
has been shown to inhibit food intake in rodent mine exhibit weak 5-HT uptake activity. In-
models, but only at very high doses. The reasons troduction of lipophilic electronegative sub-
for the disparities in the pharmacological activ- stituents (i.e., C1, CF,) on the aryl ring results
ities between the two structurally different com- in a significant increase in activity, whereas
pounds are not yet fully known. introduction of polar groups (i.e., OH) leads to
a decrease in activity. The dextrorotatory iso-
mers are more active than the corresponding
6 STRUCTURE-ACTIVITY RELATIONSHIPS levorotatory isomers.
Hansch and Caldwell have analyzed the
Structure-activity relationships (SARs) for quantitative structure/activity relationships
several drugs used in the treatment of body (QSAR) of a series of amphetamine and
weight disorders, including some 2-phenethyl- 2-phenethylamine analogs, to discern the role
m i n e derivatives and dronabinol, have been of steric and hydrophobic aryl substituents on
described in the literature. For other drugs the inhibition of 5-HT uptake (142). From the
such as sibutramine and diethypropion, the biological data of 19 compounds, including
only close-in compounds for which biological those in Table 15.13. and some additional an-
data exist are metabolites of the parent drug alogs, the following equation was derived for
(see Section 3). Analogs of sibutramine are de- inhibition of uptake activity, where C is the
scribed in the patent literature, but no data IC,, concentration, MR, is the molar refrac-
are provided (139). The SARs of antidepres- tivity value of the aryl substituent scaled by
sant medications have been described else- 0.1, and n3 is the hydrophobicity of the meta
where in this series. substituent on the aryl ring:
6.1 SAR of 2-Phenethylamines
Appetite suppressants such as amphetamine, fen-
fluramhe, and sibutramine stimulate 5-HT, NE,
and/or DA release or inhibit their reuptake by
i
876 Drugs to Treat Eating and Body Weight Disorders

Table 15.13 Inhibition of Human Platelet 6-HT Uptake by 2-Phenethylamine Derivativesa


5-HT Uptake Inhibition
Compound Structure IC,, (x 10-5/M)

(-)-Amphetamine (82)
Phentermine (3)

(2)-4-Chloromethylarnphetamine(85)

Chlorphentermine (86)

An indicator variable I was added to the was low (s = 0.219). The data suggest that
above equation to differentiate substituted lipophilic substituents at the meta position
2-phenethylamine derivatives such as am- on the aryl ring in phenethylamine analogs
phetamine from unsubstituted 2-phenethyl- fit into an important hydrophobic pocket in
amine compounds. The correlation coeffi- the 5-HT transporter and that the introduc-
cient ( r ) for the equation was high (r = tion of such groups should enhance the in-
0.965), whereas s, the standard deviation, hibitory activity.
6 Structure-Activity Relationships

Table 15.13 (Continued)


5-HT Uptake Inhibition
Compound Structure IC,, (x10-~/M)

"Ref. 141.

The SAR for norepinephrine uptake inhibi- poor CNS exposure. Substitution of the termi-
tion by amphetamine analogs is similar to that nal amino group with one alkyl group de-
for inhibition of 5-HT reuptake. The protypi- creases NE activity and substitution with two
cal unsubstituted derivative, 2-phenethyl- alkyl groups essentially eliminates activity
amine, is a weak uptake inhibitor in isolated (see Table 15.11). In general, as the size of the
rat heart membranes (ID,, = 1.1 CLM) (143). alkyl group on the basic nitrogen group in-
Introduction of a methyl group at the C1 posi- creases, the indirect syrnpathomimetic activ-
tion adjacent to the amino group results in a ity decreases. Serotonin release, in contrast, is
10-fold increase in potency (i.e., dexamphet- generally enhanced by electron-withdrawing
amine, (a), ID,, = 0.18 p M ) (143). Sibutra- substituents on the phenyl ring (see Table
mine, a tertiary amine, shows moderate NE 15.9). Thus, fenfluramine shows no NE releas-
uptake activity (Ki = 350 nM), but its des- ing activity but is a potent 5-HT releasing
methyl and di-desmethyl metabolites, (R)- agent. Likewise, amphetamine and phenter-
BTS 54 354 (44) and (R)-BTS 54 505 (461, mine do not stimulate 5-HT release but show
exhibit potent activity (Kivalues <20 nM)(see weak to moderate activity for stimulating NE
Table 15.10) (71). release. Sibutramine has little effect on either
The SAR for NE and 5-HT releasing activ- NE or 5-HT release.
ity of amphetamine derivatives is less well de-
6.2 SAR of Dronabinol Analogs
fined (144). NE release is increased by the
presence of hydroxyl groups on the aryl ring The structure-activity relationships of dron-
and decreased by substitution with halogen or abinol (32) on cannabinoid receptor activity
CF, groups. Phenolic and catechol derivatives have been investigated (see Table 15.14). Both
of 2-phenethylamine, however, generally un- the phenolic hydroxyl group and the C3 alkyl
dergo rapid glucuronidation and thus show chain in (32) are critical for binding affinity.
878 Drugs to Treat Eating and Body Weight Disorders

Table 15.14 Structure-Activity Relationships of Dronabinoid on CB,-R Binding Activity


CBl-R, Ki CB2-R, Ki
Compound Structure Name (nM) (nM)

A8-THC- 0.83' 0.83b


DMH

Transposition of the olefin from the A9-posi- not lead to a significant drop in potency. Sev-
tion to the As-position as in compound (91) eral bicyclic compounds such as (94) and (95)
(ARTHC)results in a threefold loss of potency have been prepared that exhibit moderate ac-
(145).Compound (92) with a C3 dimethylhep- tivity.
tyl (DMH) chain is 100-fold more potent than Dronabinol(32)and analog (92) exhibit lit-
the analogous compound with a C3 pentyl tle selectivity for CB,-R vs. CB,-R. These two
chain. The binding affinities of compounds receptors show 44% sequence homology, with
with either endocyclic or exocylic olefin groups modest homology in the transmembrane do-
in the cyclohexane ring of the tricyclic core mains (68%).Replacement of the phenolic hy-
template in the DMH series are similar. Aro- droxyl group in the aromatic ring of (92) by a
matization of the terpene ring in As-THC does phenyl methyl ether moiety as in L-759633
6 Structure-Activity Relationships 879

Table 16.14 (Continmd)


CBl-R, Ki CB2-R,Kl
Compound Structure Name (nM) (nM)
(76) CH3 Cannabinol 2.49" 1.9aa
I T

(96) results in a 10,000-fold decrease in CBl-R regions were found in the CBl-R, where steric,
activity, but only a 40-fold loss of CB2-Raffin- electronic, and lipophilic interactions between
ity, providing CB,-R-preferring compounds ligands and receptor appeared to be critical for
(146). CB2-R-selectivecompounds may show activity. Additional interaction regions were
anti-inflammatory and immunosuppressive identified that conferred selectivity for one of
properties. the receptors. All compounds used in the
Fichera et al. used a series of 20 different study, including the endogenous cannabinoids
cannabinoid compounds from several differ- such as anandamide, were aligned against
ent chemical series to develop 3D-QSAR mod- dronabinol.
els for activities at CB,- and CB,-receptors Several natural and synthetic dronabinol
(147). The QSAR study was performed by use analogs have been clinically evaluated as safer
of GOLPE methodology (148). Seven spatial alternatives to AS-THC, although primarily as
880 Drugs to Treat Eating and Body Weight Disorders

Table 15.14 (Continued)


CBl-R, Ki CB2-R,Ki
Compound Structure Name (nM) (nM) -

"Ref. 145.
*Ref. 146.

treatments for neurogenic pain and cancer-


induced emesis (vomiting and nausea after
chemotherapy). Nabilone (99), a nonselective

(100) Cannabidiol, R =
A
6.3 Mazindol Analogs
Mazindol is a potent inhibitor of both dopa-
(99) Nabilone, CB1-R Ki = 2.19 nM mine and serotonin uptake that was first de-
CB2-RKi = 1.84 nM scribed in 1975 (149). The compound exists in
two tautomeric forms, although it is believed
that most of the pharmacological activity lies
CB,-R and CB,-R agonist, contains a carbonyl in the closed, tricyclic form where the hy-
group at the C9 position and a C3 dimethyl- droxyl group can act as both a hydrogen-bond
heptyl group. Cannabidiol (loo), a bicyclic de- acceptor and donor. The open form has been
rivative of (32)in which the central pyran ring shown to exhibit much weaker anorectic activ-
has been opened up, is a natural constituent of ity in rat models compared to that of the closed
Cannabis sativa L that exhibits no psycho- form tautomer (150).In one report on the SAR
tropic properties, although it shows neuropro- of Mazindol analogs, replacement of the
tective activities. C4'-C1 substituent on the B-ring with a C4'-F
7 Future Directions 881

Table 15.15 Mazindol Structure-Activity Relationships

4'

IC50, nM
[3H]Dopamine
Compound W X Y Uptake"

"IC,, values measured in rat striatal tissue.

group results in a decrease in [3Hldopamine 6.4 Orlistat Derivatives


uptake activity, although there is no change in
Lipstatin (109) is a natural product isolated
activity when the C4'-C1 group is replaced by
either C4'-Br or C4'-Igroups (see Table 15.15) from Streptomyces toxyticini, which shows
moderate pancreatic lipase inhibitory activity
(46). An electronegative halogen substituent
on the B-ring is necessary for activity. Inter- (IC,, = 0.14 ~ g / m L (151).
) Hydrogenation of
(109) to give orlistat (1)results in only a slight
estingly, the dopamine uptake activity de-
loss of activity (151). However, replacement of
creases if the B-ring is substituted with a
the p-lactone ring in the drug with a 2-meth-
C2'-C1 group or if the A-ring is substituted
yleneoxetane group leads to a significant drop
with a C2-Cl group. Inserting one or two meth-
in potency (152).
ylene groups into the imidazoline ring to give
six- and seven-membered rings further im-
proves the inhibitory activities of the com-
pounds (46). These homologs, moreover, show 7 FUTURE DIRECTIONS
increased selectivity for the dopamine trans-
porter over the serotonin or NE transporters. Several novel CNS and peripherally acting
drugs are currently undergoing clinical evalu-
ation (Phases 1-111)for the treatment of obe-
sity and select eating disorders (see Tables
2=~N) N-
W 15.16-15.18). These drugs exhibit varied
mechanisms of action, most of which are clin-
ically unprecedented, such as decreasing food
intake through stimulation of gastrointestinal
satiety pathways, increasing energy expendi-
ture through thermogenesis of brown adipose
tissue, or preferentially enhancing fat oxida-
tion over carbohydrate oxidation. One new
W = @Hz), where n = 1, 2, 3 drug may be able to modulate specific path-
Drugs to Treat Eating and Body Weight Disorders

(109) Lipstatin, IC50 = 0.14 pg/mL (1) Orlistat, IC50= 0.4 pg/mL

ways involved in reward mechanisms, which


may prove effective in changing behaviors
such as overeating that often result in obesity.
A recombinant protein under development
prevents the body's adaptive response to star-

",
; vation that occurs after weight loss.
New weight loss drugs must meet certain
n-C9H19 guidelines established by the FDA before re-
ceiving marketing approval (153). These
(110) Compound, IC50 = 1.7 pg/mL guidelines require that weight-loss agents
Table 15.16 Antiobesity Drugs in Late-Stage Clinical Development
Mechanism of Development
Name Structure Action Stage
Axokine (111) 1-185-ciliary neurotropic factor (CNTF) Activation of STAT Phase I11
signaling
Rimonabant, CB,-R antagonism Phase I11
SR-141716A
(112)

C1

Topiramate, Unknown Marketed; Ph


Topimax mechanism III-obesity
(113) i

0, ,
S
No
7 Future Directions 883

Table 15.17 Centrally Acting Anorectic Drugs in Early Clinical Development


Development
Name Structure Mechanism of Action Stage
Wellbutrin (114) DA/NE reuptake Marketed; Ph II-

C1
JJ+ /
N
inhibition obesity
'Z

H
0

BW1555U88 F
I DA/NE reuptake

Leptin (116) Ob-R (leptin Ph W h I1


receptor) agonism

demonstrate efficacy for at least 1 year, de- given that withdrawal of treatment does not
fined as greater than 5% weight loss vs. pla- result in any rebound weight gain as is ob-
cebo, generally in double-blind clinical trials served with most other weight-loss agents. In
in patients with BMIs greater than 30 kg/m2 a 3-month clinical trial, obese patients who
or BMIs greater than 27 kg/m2 with at least were administered 2 pg kg-' day-' reportedly
one associated comorbidity. The clinical trials lost 10 extra pounds compared to the placebo
should preferably last at least 2 years, al- group (156). This weight loss was equivalent
though the second year need not be blinded. to that observed for sibutramine and orlistat
The guidelines also require that such drugs over the same time period. In earlier trials for
reduce comorbidities, especially in overweight another indication, amyotrophic atherosclero-
patients with BMIs less than 30 kg/m2. Any sis, lean patients reportedly lost 14% of their
drug used for the chronic treatment of a dis-
body weight. However, the dose in this trial
ease must also exhibit an exceptional safety
was much greater than that used in the obe-
profile, with acceptable benefit-to-risk pro-
sity trial (15or 30 pg/kg three times per week
files.
vs. a maximum dose of 2 pg kg-' day-') (157).
7.1 Antiobesity Compounds and New Drugs The precise mechanism of action of CNTF
to Treat Binge Eating in Clinical Development in the promotion of weight loss has not been
defined, but its effects appear to be mediated
7.1.1 Axokine. Axokine (111) is a recombi- by various hypothalamic pathways. The
nant form of ciliary neurotrophic factor weight loss from a low dose of CNTF in ro-
(CNTF), a 200 amino acid member of the cy- dents and humans does not appear to be
tokine family, which also includes proteins caused by cachectic cytokines such as interleu-
such as leptin, gp130, interleukins, prolactin, kin-1 because no muscle wasting was observed
and growth hormone (154). CNTF promotes in the CNTF-treated groups. CNTF may me-
weight loss in several different animal models diate some of its effects by coupling to down-
of obesity including oblob mice, diet-induced stream signaling events in the leptin pathway.
obesity, and fatfa Zucker rats (155). Interest- In a diet-induced model of obesity, CNTF, but
ingly, CNTF appears to change the set point not leptin, was shown to stimulate phosphor-
for body weight in both rodents and humans, ylation of the cytoplasmic transcription factor
Table 15.18 Peripheral Antiobesity Drugs
Mechanism of Development Stage
Name Structure Action (status)
P3-AR agonism Ph I1 (abandoned)

P3-AR agonism

CCK-R
agonism
7 Future Directions

called signal transducer and transcription fac- creases body weight is unknown, although its
tor 3 (STAT-3) in the arcuate nucleus and anticonvulsant properties are attributed in .
thereby activate downstream signaling path- part to increasing gamma-aminobutyric acid
.
ways. In lean control animals, however, both (GABA), a neurotransmitter that inhibits ex-
CNTF and leptin stimulated phosphorylation citation of nerve cells in the brain (163). Topi-
of STAT-3. These data support a hypothesis ramate may alter both energy intake and en- r
that diet-induced obesity causes "leptin resis- ergy expenditure, decrease food intake, and
tance" and that CNTF may overcome the re- increase energy utilization (164).
sistance observed in this model of obesity.

7.1.2 Rimonabant. The centrally-acting se- 7.1.4 Combined Norepinephrine/Dopamine


lective cannabinoid-1receptor (CBl-R) receptor Reuptake Inhibitors. Bupropion (114, Wellbu-
antagonist rimonabant (112, SR-141716A) has trin, Zyban), a close-in congener of diethylpro-
been reported to decrease body weight in Phase pion, is a weak and nonselective dopamine and
I1 clinical trials in a dose-dependent manner norephinephrine uptake inhibitor that is cur-
(158). The weight loss was comparable to that rently marketed for depression and smoking
observed with marketed weight-loss agents such cessation (165). It is also reportedly a noncom-
as either orlistat or sibutramine. In preclinical petitive nicotinic antagonist at some, but not
models, rimonabant was found to inhibit food all, of the nicotinic receptor subtypes (166).
intake in normal rats and NPY gene knockout The drug is currently undergoing clinical eval-
mice, but not in CBl-R-deficientmice (159,160). uation as an antiobesity agent. In an 8-week
The preclinical and clinical data with rimon- study in 50 obese women, bupropion was
a b a 2 cob a role for endogenous cannabi- found to be more effective than placebo in pro-
noids such as anandamide in the regulation of moting weight loss. The bupropion group, for
food intake. Recent studies have shown that hv- example, lost 6.2% of body weight, whereas
pothalamic
- levels of anandamide and 2-arack- the placebo group lost only 1.5% of body
donoyl glycerol, two of the endogenous ligands weight (167). The pharmacological mecha-
of the cannabinoid receptors, are decreased in nisms by which this drug decreases food in-
leptin-treated (hypophagic) rats (160). take are not full understood, but drugs that
Rimonabant may also alter reward path- increase dopamine levels oftens decrease ap-
ways that promote addictive behaviors such as petite (168).
overeating. This drug has been shown to at- BW1555U88 (1151, a 3,5-difluorophenyl-
tenuate the rewarding effects of alcohol in a 3,5-dimethyl-2-morpholinolderivative, is in
strain of alcohol-preferring rats (161) and may early clinical development for both smoking
similarly diminish the pleasurable effects of cessation and weight loss (169). This com-
food and overeating that can often play impor- pound is significantly more potent than bupro-
tant roles in the etiology of obesity. pion as both a NE and DA reuptake inhibitor
and has been shown to decrease food intake
7.1.3 Topiramate. Topiramate (113, To- and body weight in rodent models of obesity
pamax) is a sulfamate-substituted D-fructose (170).
derivative that is currently marketed as an an-
tiepileptic drug (AED). Topiramate promotes 7.1.5 Leptin. Leptin (116), the product of
weight loss, whereas AEDs in general increase the ob gene, is a member of the cytokine family
body weight gain. Topiramate has progressed of hormones. Leptin plays a critical role in the
into Phase 111clinical trials for the treatment regulation of body weight, given that its com-
of both binge eating disorder and obesity. In plete absence in both animals and humans
an open-label trial involving 13 patients diag- leads to profound morbid obesity (108, 171).
nosed with a DSM IV binge eating behavior, Initial clinical results from small placebo-con-
topiramate caused an average weight loss of trolled studies have been disappointing, with
12% among all patients and decreased binge moderate weight loss of 6 kg in 24 weeks re-
eating symptoms in 75% of the patients (162). ported for obese subjects on high doses of drug
The mechanism by which topiramate de- (0.3 mg kg-' day-') (172). Recently, it has
Drugs to Treat Eating and Body Weight Disorders

been shown that many obese patients actually 7.2 New Targets
have elevated plasma, but low CSF levels of In the past decade, many new genetic targets
leptin, suggesting defects in leptin transport' involved in regulation of energy homeostasis, '

across the blood-brain barrier, possibly be- especially in rodent models, have been identi-
cause of saturation of the transporter (173). fied. A number of these molecular targets are
considered "druggable" or suitable for phar- ,
7.1.6 p,-Adrenergic Receptor Agonists. P3- macological modulation, including the 5-HT,,-R
Adrenergic receptor agonists (P3-AR) are pe- that mediates the anorectic effects of fenflur-
ripherally acting thermogenic agents that are amine, the NPYl- and NPY,-receptor sub- .

currently undergoing clinical evaluation for types that are involved in the stimulation of
the treatment of obesity and diabetes. P3-AR food intake, the melanocortin-4 receptor sub-
agonists increase thermogenesis by activation type, and the orexin-1 receptor subtype. Stim-
of P3-ARson brown adipocytes, which leads to ulation of NPYl-R, NPY,-R, and OXl-R may
increases in intracellular CAMPlevels, stimu- be useful in the treatment of wasting diseases
lation of uncoupling proteins, and increases in (anorexia nervosa, cachexia), whereas inhibi-
fatty acid acid oxidation and nonshivering tion of these receptors may show utility in the
therrnogenesis. These compounds also show a management of body weight disorders such as
pronounced insulin-sensitizing, antidiabetic obesity. Activation of the melanocortin sys-
effect in diabetic rodent models, an effect that tem, in particular the MC,-R subtype, should
is independent of weight loss. A first-genera- decrease food intake and antagonism of the
system should increase food intake.
tion P3-ARagonist, CL-316243 (117),has been
Selective ligands for 5-HT,,, NPY, and
reported to increase glucose disposal, whole
orexin receptors are currently undergoing
body fat oxidation and plasma free fatty acids
preclinical and clinical evaluation for the
after 4 weeks in lean males (174). CL-316243 treatment of body weight disorders, primarily
also has been found to increase whole body obesity. Ro 60-0175 (120) and ORG-12962
lipolysis in obese subjects after 3 months. No (121) are potent 5-HT,, receptor agonists cur-
increase in thermogenesis, however, was ob-
served in the study. Another P,-AR agonist,
LY-377604 (lls),has been shown to increase
energy expenditure and decrease respiratory
quotient. The decrease in respiratory quotient
indicated a shift from carbohydrate oxidation
to fat oxidation. Several P3-AR agonists also
reported to increase energy expenditure in
monkeys (175).

7.1.7 CCK, Receptor Agonists. CCK is a


short-term satiety signal that is released
upon food ingestion by endocrine cells in the
small intestine. In human studies, exoge-
nous administration of CCK has been shown
to reduce food intake in both lean and obese
subjects (176, 177). A nonpeptidic CCK,-R
agonist, GI 181771 (119),is reportedly un-
dergoing clinical evaluation as an anorectic
agent. No long-term studies have been re-
ported for CCK or CCK,-R agonists in hu- rently in preclinical development. 5-115814
mans. A possible side effect of this class of (122) is a selective NPY Yl-R antagonist with
anorectic agents is pancreatitis, or inflam- reportedly good brain exposure that decreases
mation of the pancreas. food intake in dbldb and C57BL6 mice after
7 Future Directions

(123) CGP 71683A

intraperitoneal administration, but does not activity at several receptors that may influ-
affect food intake in NPY,-R knockout mice ence food intake(179-181).L-152804 inhibits
(178).CGP 71683A(123)and L-152804(124) the orexigenic effects of NPY5-R, preferring
are potent NPY Y5-R antagonists, although peptidic agonists, but not the effects of NPY
CGP 71683A is not particularly selective, with itself. An interesting series of pyrrolo[3,2-
dlpyrimidine derivatives such as compound
(125)have been reported as Y,-R antagonists,
with nanomolar affinity for the receptor(182).
A selective OX,-R antagonist, SB-334867-A
Drugs to Treat Eating and Body Weight Disorders

(126),has been identified that decreases food 9 ABBREVIATIONS


intake in rat models (107,183).
AN anorexia nervosa
BE binge eating
BMI body mass index
BN bulimia nervosa
DA dopamine P
5-HT 5-hydroxytryptamine
MA0 monoamine oxidase -
NE norepinephrine
SSRI selective serotonin reuptake inhibitor
TCA tricyclic m i n e antidepressants

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Health Organization, Geneva, 1998.
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These disorders are currently managed by use Med. Assoc., 282,1519-1522 (1999).
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Index
P
Terms that begin with numbers Acetaminophen (APAP) with for neurodegenerative condi-
are indexed as if the number were codeine, 335 tions, 675
spelled out; e.g., "3D models" is Acetaminophen (APAP) with phosphorus-derived cholin- -
located as if it were spelled hydrocodone, 335 ergics, 90-93
"ThreeD models." Acetaminophen (APAP) with reversible noncovalent cholin-
oxycodone, 335 ergics related to 1,2,3,4-tet-
A-68930 Acetaminophen (APAP) with
for Parkinson's disease, 727, propoxyphene, 335
728 Acetorphan reversible quaternary ammo-
A-77636 opioid peptide metabolism in- nium cholinergics, 84-86
for Parkinson's disease, 727, hibitor, 442 Acetylcoenzyme A, 40
728 Acetyl-L-carnitine Actiq, 334
A-84543 for Alzheimer's disease, 768 Acyclic analgesics, 334
cognition enhancer, 802-803 Acetylcholine, 110. See also An- structure-activity relationship,
A-85380 ticholinergics; Cholinergics; 385-387
cognition enhancer, 802,804 Muscarinic acetylcholine Adatanserin, 572
A-86929 receptors; Nicotinic acetyl- Adderall, 3,170
for Parkinson's disease, 727, choline receptors Addiction
728 cholinergics based on, 43-49 narcotic analgesics, 336
Abercarnil, 558 and constrictor muscle fibers, Adenosine antagonists
binding affinity with GABA,I 114 for Parkinson's disease, 733
Bz, 788 dissociation constant, 151 Adinazolam, 552
Absorption, distribution, metab- role in nerve transmission, 40 Adipex, 844
olism, and excretion substitution of ester group by Adipex-P, 171
(ADME) other groups, 47-49 Adiphenine
adrenergics and adrenergic- variations of acyl group, anticholinergic, 134
blocking agents, 16-21 45-46 influence of cyclic radicals on
anticonvulsants, 273-291 variations of ethylene bridge, anticholinergic activity, 143
opioid analgesics, 339-341 46-47 local anesthetic activity, 154
sedative-hypnotics, 211-233 variations of quaternary am- relative anticholinergic activ-
ABT-089 monium group, 43-45 ity, 156
cognition enhancer, 805 Acetylcholine-atropine antago- Adipose tissue, 873
ABT-418 nism, 152-153 Adipost, 171
cognition enhancer, 799-800 Acetylcholine receptors, 41-43. ADME studies, See Absorption,
ABT-431 See also Muscarinic acetyl- distribution, metabolism,
for Parkinson's disease, 727, choline receptors; Nicotinic and excretion (ADME)
728 acetylcholine receptors Adrenaline, 2
ABT-594 Acetylcholinesterase, 40 applications, 9-10
I cholinergic, 53 catalytic site, 84-85 general adrenergic agonist, 3
! cognition enhancer, 804-805 Acetylcholinesterase inhibitors, history, 26-27
Abyssinian tea, 168 40 metabolism, 16-17
Acebutolol for Alzheimer's disease, synthesis, 23-25
P-antagonist, 5 761-762, 781 Adrenergic agonists, 2, 3
applications, 16 carbamate-derived cholin- ADME, 16-21
Aceclidine ergics, 88-90 applications of a,-agonists,
cholinergic, 65, 78-79 for cognition enhancement, 12-13
Acetaminophen, 331 781 applications of a,-agonists,
first tier of cancer pain treat- miscellaneous cholinergics, 13-14
ment, 332-333 93-97 applications of P-agonists, 14
895
Index

Adrenergic agonists (Continued) applications of nonselective, Adrenergic regulation of food


applications of agonistslantag- 15 intake, 873-874
onists, 16 alp-Adrenergic receptor antago- Adrenocorticotropic hormone
applications of general, 9-12 nists, 5 (ACTH)
applications of selective p,- applications of, 16 ulcers from, 118
agonists, 34-35 aa-Adrenergic receptor antago- Adrenoreceptors, See Adrenergic
-T
current drugs,3-9 nists receptors
history, 26-28 applications of selective, 33-34 AF-DX-116
physiological significance, a,-Adrenergic receptor antago- anticholinergic, 129
21-22 nists Afenta. 334
recent developments, 33-35 applications of selective, 15-16 Age-associated memory impair-
structure-activity relation- ment, 780
a,-Adrenergic receptor antago-
ships, 28-33 agouti Gene-related peptide, 870
nists, 2
Adrenergic-blocking agents, 2,4, Akineton
14-15 selective, 4
for Parkinson's disease, 731,
ADME, 16-21 p-Adrenergic receptor antago-
732
applications of agonistslantag- nists, See p-Blockers Albuterol, 2
onists, 16 Adrenergic receptors, 2 p-agonist, 4
applications of alp-antago- effector mechanisms, 25 applications, 14
nists, 16 selected tissue response to, 23 metabolism, 17-18
applications of p-antagonists, subtype characterization, structure-activity relationship,
16 25-26 29
applications of nonselective a-Adrenergic receptors, 2 Aldomet, 3
a-antagonists, 15 and depression, 506-507 Alert wakefulness, 224
applications of selective a,,- effector mechanisms, 25 Alfentanil, 383
antagonists, 33-34 selected tissue response to, 23 cytochrome P,,, isozyme sub-
applications of selective a,- a,,-Adrenergic receptors, 2 strate, 339
antagonists, 15-16 characterization, 26 dose, 334
current drugs,3-9 alB-Adrenergicreceptors, 2 Aliphatic acid anticonvulsants,
history, 26-28 characterization. 26 270
physiological significance, alD-Adrenergicreceptors, 2 ADME, 275-282
21-22 a,,-Adrenergic receptors, 2 Allegron, 485
recent developments, 33-35 aZB-Adrenergicreceptors, 2 Allobarbital, 205
structure-activity relation- aZc-Adrenergicreceptors, 2 Allococaine, 191
ships, 28-33 a,-Adrenergic receptors, 2 Allomuscarine, 57
Adrenergic nerves, 27 effector mechanism, 25 Allylprodine, 376
Adrenergic receptor agonistt selected tissue response to, 23 Alnespirone, 581
antagonists, 5 subtype characterization, Alor 51500, 335
applications,.16 25-26 Alosetron
a,-Adrenergic receptor agonists, a,-Adrenergic receptors, 2 cognition enhancer, 816
2,3 effector mechanism, 25 Alphagan, 3
applications of, 12-13 selected tissue response to, 23 Alphaprodine, 718
a,-Adrenergic receptor agonists, subtype characterization, Alpidem, 561562
2,3 25-26 Alprazolam, 530
applications,13-14 p-Adrenergic receptors, 2 dose for anxiety, 529
p-Adrenergic receptor agonists, effector mechanisms, 25 dose for eating disorders, 852
2,4 selected tissue response to, 23 for eating disorders, 858
applications, 14 PI-Adrenergic receptors, 2 ALS drugs, 675
p,-Adrenergic receptor agonists, characterization, 26 Alupent, 4
2 selected tissue response to, 23 Alzheimer's disease, 674-675,
applications of selective, p,-Adrenergic receptors, 2 744-745
34-35 characterization, 26 amyloid cascade hypothesis,
for eating disorders, 886 selected tissue response to, 23 749-761
a-Adrenergic receptor antago- &Adrenergic receptors, 2 cholinergics for, 40
nists characterization, 26 epidemiology, 745
applications of alp-antago- selected tissue response to, 23 etiology, 745-749
nists, 16 p,-Adrenergic receptors, 2 genetic determinants, 745-746
genetic risk factors, 746-748 3-Aminobenzamide
nongenetic risk factors, NAD glycohydrolase inhibitor, role in Alzheimer's disease,
748-749 686 744-768
susceptibility locus on chro- PARP inhibitor, 680 Amyloidoses, 744
mosome 10,747 Amino-carbofluorene Amyloid P-peptides, 744-768
susceptibility locus on chro- anticholinergic, 134 Amyloid precursor protein
mosome 12,747-748 Aminopentamide and Alzheimer's disease, 746 P
Alzheimer's disease therapeutics anticholinergic, 135 gene-knockdown agents, 761
acetylcholinesterase inhibi- relative anticholinergic activ- Amyotrophic lateral sclerosis,
tors, 761-762, 781 ity, 157 674 .

AMPA response modulation, Aminorex, 843 Amytal, 204


765 dose, 847
Anabaseine, 764
i amyloid P-peptide aggregation Amisulpride, 641
analogs as cognition enhanc-
I discovery, 618
ers, 808-809
tg inhibitors, 758-760 Amitriptyline
i amyloid P-peptide catabolism affinities for monoamine re- cholinergic, 54-55
1 and removal, 760
ceptors, 495 Anabasine, 49
amyloid p-peptide disaggrega- antidepressant, 485,486,487 Anafranil, 485
I tion accelerators. 760 Analgesics, 331. See also Nar-
dose for eating disorders, 851
amyloid P-peptide neurotoxic- for eating disorders, 858 cotic analgesics
ity modulators, 760-761 inhibition of serotonin, norepi- (+)-Anatoxin-A
amyloid precursor protein nephrine, and dopamine cholinergic, 56,93
gene-knockdown agents, transporters, 500 Androgens
761 pharmacokinetic parameters, for Alzheimer's disease,
anti-inflammatory agents, 767 497 765-766
antioxidants, 758, 767-768 side effects profile, 493 Anesthesia
apoptosis inhibitors, 766-767 Amobarbital, 204 anticholinergic premedication,
cholinergic transmission at- Amoxapine 115
tenuation, 761-765 affinities for monoamine re- Anhisan, 214
compounds affecting fibril for- ceptors, 495 4-Anilidopiperidine analgesics,
mation, 758 antidepressant, 485, 486, 488 334
estrogens and androgens, inhibition of serotonin, norepi- structure-activity relation-
765-766 nephrine, and dopamine ships, 381-385
y-secretase inhibitors, transporters, 500 Animal models and studies
754-756 pharmacokinetic parameters, antipsychotic agents, 611-617
497 anxiety, 548-549
immunosuppression, 766
side effects profile, 493 cognition, 780-781
immunotherapy, 766
AMP397A Anisotropine
muscarinic acetylcholine re- anticonvulsant, 315316 therapeutic use, 117
ceptor agonists and antago- Amphetamine, 170, 172, 174, Anorexia nervosa, 840-841,874
nists, 762-764 855 Anorexia nervosa drugs, 171,
nicotinic acetylcholine recep- applications, 10 843,849-853
tor agonists and antago- general adrenergic agonist, 3 Anracetam
nists, 764-765 metabolism, 176-177 for Alzheimer's disease, 764
a-secretase inhibitors, physiology and pharmacology, Antiadrenergics, See Adrenergic-
752-753 180,183 blocking agents
p-secretase inhibitors, stereotyped behaviors induced Antianxiety agents
753-754 by, 615 adverse effects, 532-533
a-secretase shift, 761 structure-activity relation- clinical applications, 527-537
statins, 756-758 ships, 184-187 current and future develop-
Amantadine Amphibian skin, opioid peptide ments, 578-581
for Parkinson's disease, analogs from, 409-410 currently used drugs, 527-532
733-734 Amprotropine for eating disorders, 852,858
Ambien, 211, 561 anticholinergic, 134 history, 546-548
Amino acids local anesthetic activity, 154 metabolism, 533-537
nitric oxide synthase inhibi- relative anticholinergic activ- nonbenzodiazepine ligands,
tors, 699-700 ity, 156 555466
Index

Antianxiety agents (Continued) stereoisomerism and activity, recent and future develop-
physiology and pharmacology, 147-150 ments, 516-518
537-546 structure-activity relation- side effects, 490-496 -
structure-activity relation- ships, 133-151 structure-activity relation:
ships, 548-578 synthetic, 126-133 ships and metabolism,
Anticholinergics, 110-111 therapeutic uses, 153-154 510-516
anticholinergic activity as side tricyclic benzodiazepines, Antihistamines F
effect of drugs, 115 128-129 ADME, 223
antispasmodic activity assay, Anticholinergic syndrome, currently used drugs, 212-214
116-118 115-116 discovery, 236 -
as antispasmodics, 111 Anticholinersterases,40. See pharmacologic effects, 230
antiulcer activity assay, also Acetylcholinesterase side effects and drug interac-
118-119 inhibitors tions, 211
as antiulcer agents, 111-114 a,-Antichymotrypsin (ACT), 767 Antihypertensives
atropine analogs, 126-128 Anticonvulsant receptor models, adrenergics, 2
benzothiazepines, 129 319-320 Anti-inflammatory agents
biocomparative assay, Anticonvulsants, 264-265 for Alzheimer's disease, 767
116-120 ADME, 273-291 Antimalarial agents
classification based on sub- currently used drugs, 265 for Alzheimer's disease, 767
types of muscarinic recep- future developments, 315320 Anti-obesity drugs, 844-849
tors, 115-116 GABA, receptors, 295-296 absorption and metabolism,
developed for specific uses, GABA,receptors, 296 860-866
154-158 glutamate receptors, 296-297 clinical applications, 843-860
diphenylacetyloxy derivatives, history, 297-304 CNS stimulants for, 173, 193
132-133 ion channels, 292 new drugs in development,
dissociation constants, 150 NMDA receptor antagonists, 881-886
dual cholinergic/anticholin- 694,696-697 new targets for drugs,
ergic compounds, 150-151 with opioid analgesics, 333 886-888
himbacine, 133 physiology and pharmacology, structure-activity relation-
indene derivatives, 131-132 291-297 ships, 875-881
interaction at muscarinic re- recently developed agents, Antioxidants
ceptors, 151-153 311315 for Alzheimer's disease, 674,
kinetic basis for mechanism of side effects, adverse effects,
675, 758,767-768
action, 152 and drug interactions,
Antipsychotic agents, 600-602
miscellaneous activity assays, 265-273
120 animal models of efficacy and
structure-activity relation-
mydriatic and cycloplegic ac- ships, 304-311 side effects, 611-617
tivity assay, 119-120 T-type calcium channels, 297 anticholinergic effects,
as mydriatics and cycloplegics, Antidepressants, 484. See also 608- 609
114-115 Monoamine oxidase inhibi- cardiovascular effects, 609
for Parkinson's disease, tors; Serotonin-selective cognitive impairment, 608
731-733 reuptake inhibitors; Tricy- dermatologic effects, 611
polymethylene tetramines, clic antidepressants discovery, 617-619
131 clinical efficacy, 486-490 drug discovery strategies
in premedication during anes- CNS stimulants in terminal based on dopaminergic ap-
thesia, 115 illness, 173 proaches, 640- 651
quinuclidine-based antago- currently used drugs and clas- drug discovery strategies
nists, 129-131 sification, 484-486 based on non-dopaminergic
receptor-subtype-selective, for eating disorders, 843, approaches, 651-655
128-133 849-851 extrapyramidal symptoms,
relative activities, 156 efficacy relative placebo, 489 600,605-607
side effects, 154 history, 508-510 hematologic effects, 610
sila-difenidols, 132 for Parkinson's disease, 725 hepatic effects, 610-611
solanaceous alkaloids, pharmacokinetics, 496-498 neuroleptic malignant syn-
120-126 physiology and pharmacology, drome, 607-608
specificity of antagonism, 152 498-508 for Parkinson's disease, 725
Index

pharmacokinetics, biotrans- Appetite suppressants, 843, molecular factors in absorp-


formation, and drug interac- 844-846,847-848 tion, fate, and excretion,
tions, 632-640 absorption and metabolism, 122-124
sedation, 608 860-866 mydriatic and cycloplegic ac- .
seizures, 608 clinical applications, 843, tivity, 153
sexual side effects and hyper- 855-856 relative anticholinergic activ-
prolactinemia, 609- 610 structure-activity relation- ity, 156 7
structure-activity relation- ships, 875-881 in solanaceous alkaloids,
ships, 619-632 Apraclonidine 120-126
tardive dyskinesia, 607 a,-agonist, 3 stereoisomerism, 147-149 .
therapeutic indications, applications, 13 therapeutic use, 117
604-605 Aprobarbital, 204
tropine-modified, 123
weight gain, 610 AQ-RA 741
Antisense oligonucleotides Atropine-acetylcholine antago-
anticholinergic, 129
amyloid precursor protein Aramine, 3 nism, 152-153
gene-knockdown agents, 761 Arecoline analogs Atropine analog anticholin-
Antispasmodics as cholinergics, 62-71 ergics, 126-128
anticholinergic activity assay, Aricept Atropinesterase, 124
116-118 for Alzheimer's disease, 762 Atrovent, 117, 158
anticholinergics, 111 for cognition enhancement, Attention-deficit hyperactivity
Antiulcer agents 781 disorder (ADHD),855. See
anticholinergic activity assay, Aripiprazole, 650 also Methylphenidate
118-119 ARL17477 (Ritalin)
nonanticholinergics as, nitric oxide synthase inhibi- CNS stimulants for, 172-173,
155-158 tor, 706 193
Antrenyl, 137 Artane Aventyl, 485
Anxiety, 526 for Parkinson's disease, 731, dose for eating disorders, 851
animal models, 548-549 732
Anxiety disorders, 526-527. See AWD-131-138
Aryloxypropanolamines, 5, 16
also Antianxiety agents metabolism, 19-21 anticonvulsant, 311
physiology and pharmacology, structure-activity relationship, Axokine, 882,883-885
537-5546 30-31 AX-RA 513
Anxiolytic agents, See Antianxi- ASA with codeine, 335 anticholinergic, 129
ety agents Asendin, 485
AO-33 Asendis, 485 Banthine
anticonvulsant, 314 Asimadoline anticholinergic, 128, 137
Apadoline analgesic, 394, 395 Baogongteng-A
analgesic, 392 Aspirin, 331 cholinergic, 79
Apnea of prematurity first tier of cancer pain treat- Barbital, 204
CNS stimulants for, 173-174 ment, 332333 Barbitalum, 204
Apolipoprotein E Atarax, 214 Barbiturate antianxiety agents,
and Alzheimer's disease, Atenolol 527
748-749 P-antagonist, 2, 5
Apomorphine Barbiturate anticonvulsants,
applications, 16
for Parkinson's disease, 723, 271
metabolism, 21
726,728-729 Ativan, 207,529,551 ADME, 282
stereotyped behaviors induced ATP structure-activity relationship,
by, 615 and cellular energetics, 306-307
Apoptosis 679-680 Barbiturate sedative-hypnotics,
and Alzheimer's disease, 749 Atratran, 117 203
inhibitors for Alzheimer's dis- Atropine, 110-111. See also An- ADME, 211-217
ease, 766-767 ticholinergics currently used drugs, 204-205
in stroke, 676-677 anesthesia application, 115 discovery, 235
Appetite stimulants, 843, 854 and constrictor muscle fibers, pharmacologic effects, 229
absorption and metabolism, 114 receptor interactions, 237
866-867 and gastrointestinal spasms, side effects and drug interac-
clinical applications, 858 111 tions, 203-206
Index

Barbiturate sedative-hypnotics Benzodiazepine sedative-hypnot- Binge eating drugs, 849-853


(Continued) ics, 206 new drugs in development,
structure-activity relation- ADME, 217-220 881-886
ships, 237 clinical pharmacology, Biogastrone, 158
structure-function relation- 230-234 Biperiden
ships, 246-247 cuurently used drugs, 207 for Parkinson's disease, 731,
Basal ganglia discovery, 235-236 732 P
and Parkinson's disease, 713, pharmacologic effects, Bisoprolol
714 229-230 p-antagonist, 5
Batimastat receptor interactions, 237 applications, 16
for Alzheimer's disease, 752 side effects and drug interac- Bitolterol
Belladonna alkaloids, 120-126 tions, 206-208 P-agonist, 4
Benactyzine structure-activity relation- applications, 14
relative anticholinergic activ- ships, 237-242 structure-activity relationship,
ity, 156 structure-function relation- 28
Benadryl, 214 ships, 247-251 BMS-194449,33
for Parkinson's disease, 731, Benzoisothiazole antipsychotics BMS-196085,33
732 pharmacokinetics, biotrans- BN80933
Benserazide formation, and drug interac- nitric oxide synthase inhibi-
for Parkinson's disease, 724, tions, 639 tor, 706
730 Benzomorphan analgesics Body mass index, 839,842
Bentazepam, 554 structure-activity relation- Body weight, 867-869
Bentyl, 134 ships, 373-376 adrenergic and serotonergic
Benzacetamide Benzothiazepine anticholin- regulation of food intake,
analgesic, 387-388 ergics, 129 873-874
Benzamide Benzoxazole PARP inhibitors, genetic factors, 874
PARP inhibitor, 680 681-682 and neuroendocrine regula-
Benzamide antipsychotics Benzphetamine, 171 tion of energy homeostasis
structure-activity relation- absorption and metabolism, by hypothalamus, 869-872
ships, 627-631 861-863 nucleus tractus solitaris and
Benzedrine, 172 dose, 845 peripheral satiety signals,
Benzhexol structure-activity relationship, 873
relative anticholinergic activ- peripherdcentral adiposity
186
ity, 157 signals, 872-873
Benztropine mesylate
stereoisomerism, 149 Body weight disorders, 838-839
for Parkinson's disease, 731, Bonadorm, 209
Benzisoxazole antipsychotics
pharmacokinetics, biotrans- 732 Bontril, 171, 846
formation, and drug interac- Besipirdine Brallo barbital, 205
tions, 639 cholinergic, 79 Bretazenil, 563-564
Benzodiazepine antianxiety P,-Antagonists, See p-Blockers Brethine, 4
agents, 528-531 p-Blockers, 2 Brevibloc, 5
discovery, 546-548 applications, 16 Brevital, 204
metabolism, 533-536 currently used drugs, 5 Brimonidine
structure-activity relation- Betagan, 5 a,-agonist, 3
ships, 548-578 Betapace, 5 applications, 13-14
Benzodiazepine anticholinergics, P-Site APP cleaving enzyme 1 structure-activity relationship,
128-129 (BACEl),753 31
Benzodiazepine anticonvulsants, P-Site APP cleaving enzyme 2 BRL 52974
271 (BACEZ), 753 analgesic, 394
ADME, 282 Betaxolol BRL 52537A
structure-activity relationship, P-antagonist, 5 analgesic, 391, 392
307-310 applications, 16 BRL 52656A
Benzodiazepine receptors Betaxon, 5 analgesic, 391, 392
GABAA/benzodiazepinerecep- Betoptic, 5 Brofaromine
tor complex, 538-541, Binge eating disorder, 840-841, for Parkinson's disease, 729,
782-797 842 730
Index

Bromazepam, 207,530 Cabergoline Carte0101


dose for anxiety, 529 for Parkinson's disease, 722, p-antagonist, 5
Bromocriptine 725 applications, 16
for Parkinson's disease, 722, Cachexia secondsuy to other dis- Cartrol, 5
725 eases, 838,840,874 Carvedilol
5-Bromo-2'-deoxyuridine guidelines for treatment, alp-antagonist, 5
PAFZP inhibitor, 681 842-843 applications, 16 .T

5-Bromouracil Cachexia therapeutics, 854 Carvediol


PARP inhibitor, 681 absorption and metabolism, structure-activity relationship,
Bronchodilators, 172 866-867 32 -
clinical applications, 858 p-Casomorphin analogs,
adrenergics, 2
structure-activity relation- 422-425
currently used drugs, 171
ships, 877-880 Caspase-3
Bronkosol, 4 Caffedrine, 170 and cellular energetics, 680
Brotizolam, 207,554 Caffeine, 169-172,174 Catapress, 3
BTM-1086 dose as anti-obesity agent, 846 Catecholamines
anticholinergic, 129 lipolytic agent, 857,859 auto-oxidation, and Parkin-
BU48,371 PAW inhibitor, 681 son's, 716
Bulimia nervosa, 840-842 physiology and pharmacology, Catechol-0-methyltransferase
Bulimia nervosa drugs, 843, 184 (COMT) inhibitors
849-853 side effects, adverse effects, for Parkinson's disease, 731
Buprenex, 335 and drug interactions, 176 (-)-Cathinone,169
Buprenorphine, 335, 371 Calcium channel blockers structure-activity relationship,
Bupropion, 494,885 N-channel anticonvulsants, 185
affinities for monoamine re- 318-319 CCD 1042
ceptors, 495 Calcium channels, T-type anticonvulsant, 314-315
antidepressant, 485,486,489 and anticonvulsants, 297 CCK-A receptor agonists
CAMP for eating disorders, 886
inhibition of serotonin, norepi-
and G protein coupling to ad- CCK-A receptors, 544
nephrine, and dopamine
renergic receptors, 25 CCK-B receptor antagonists,
transporters, 500 Cantil, 137 573575
pharmacokinetic parameters, Caproctamine CCK-B receptors, 544
497 anticholinesterase, 95 CCK-4 receptors, 544
side effects profile, 493 Carbamate anticonvulsants CCK-8s receptors, 544
BuSpar, 529 ADME, 284-285 Celexa, 485, 529
Buspirone, 530,566 Carbamate-derived cholinergics, Cell suicide, See Apoptosis
for anxiety disorders, 531 88-90 Cellular energetics, 679-689
dose for anxiety, 529 Carbamazepine and NAD precursors, 687-690
metabolism, 536-537 ADME, 275 Central nervous system, 264
Butabarbital, 205 anticonvulsant, 265, 266, 267, and body weight disorders, 838
Butalbital, 205 298,306,319 opioid effects, 341
Butallylonal, 205 clinical efficacy, 273 Centrine, 135
Butethal, 205 dose, 270 Cerebral infarction, 676
Butisol, 205 side effects, 276 Cerivastatin
Carbenoxolone for Alzheimer's disease,
Butorphanol, 335,372
antiulcer application, 158 756-757
Butyrophenone antipsychotics CGP 33101
Carbidopa
pharmacokinetics, biotrans- for Parkinson's disease, 724, anticonvulsant, 313-314
formation, and drug interac- 730 CGP 71683A, 887
tions, 637-639 Carbochloral, 208,209 CGS 8216,560
structure-activity relation- Carbofluorene CGS 9896,560
ships, 625-627
B2 Butyrylcholinesterase, 40,87
relative anticholinergic activ-
ity, 156
CGS 19755,653
Chemical warfare agents, 90-93
I BW-723C86,572 Carbrital, 209 Chloralbetain, 208
i Carbromal, 208,209 Chloral hydrate, 209
t BW-373U86,395-399
1 BW-1555U88 Cardura, 4 ADME, 220-221
I anorectic agent, 883,885 Carfentanil, 382 for anxiety, 527
i
Index

Chloralodol, 208,209 oxotremorine, its analogs and Clonazepam, 529


Chloralol, 209 congeners, 71-78 ADME, 282
Chlorazepate, 207,530 phosphorus-derived anticho- anticonvulsant, 266,267,307
dose for anxiety, 529 linesterases, 90-93 dose, 270
Chlordiazepoxide, 530,549 pilocarpine, its analogs and dose for anxiety, 529
discovery, 548 congeners, 61-62 side effects, 276
-2'
dose for anxiety, 529 reversible noncovalent anti- Clonidine
Chlorhexadol, 208,209 cholinesterases related to a,-agonist, 3
2-Chloronicotine,51 1,2,3,4-tetrahydro-9-amino- applications, 14
Chlorpromazine acridine, 86-88 metabolism, 18 .

discovery, 617 reversible quaternary ammo- structure-activity relationship,


dose, 601 nium anticholinesterases,
31
pharmacokinetics, biotrans- 84-86
Clorazepate, 551
structure-activity relation-
formation, and drug interac- ADME, 282
ships, 80-84
tions, 633-635 anticonvulsant, 266,307
Cholinesterase, 40
receptor binding and side ef- CI-977 dose, 270
fects, 606 analgesic, 391 side effects, 277
Chocolate, 169 CI-988,544,
575 Clotiazepam, 554
Cholecystokinin CI-1008 Cloxazolam, 551-552
and anxiety, 544 anticonvulsant, 312-313 Clozapine
and gastric secretion, 112 CI-1015,575 discovery, 618
and satiety signals, 873 Ciliary neutrophic factor doesn't cause extrapyramidal
Cholesterol and axokine,883 symptoms, 600-601
and Alzheimer's disease, Cimetidine dose, 601
748-749 antiulcer application, 155,158 for Parkinson's disease, 725
Choline Cinolazepam, 207 pharmacokinetics, biotrans-
representative esters, 44 Cipramil, 485 formation, and drug interac-
transport process for, 40 Citalopram, 531 tions, 636-637
Choline acetyltransferase,40 affinities for monoamine re- receptor binding and side ef-
Cholinergic receptors, 41-43. ceptors, 495 fects, 606
See also Muscarinic acetyl- antidepressant, 485,486,488, Clozaril, 601
choline receptors; Nicotinic 508 CNS stimulants, 168-172
acetylcholine receptors dose for anxiety, 529
ADME, 176-179
Cholinergics,40-41 inhibition of serotonin, norepi-
acetylcholine and analogs, clinical use of agents, 172-179
nephrine, and dopamine
43-49 transporters, 500 history, 172
acetylcholine-release modula- pharmacokinetic parameters, physiology and pharmacology,
tors, 97-98 497 179-184
arecoline, its analogs and con- side effects profile, 493 recent and future develop-
geners, 62-71 CL-316243,884,886 ments, 192-194
carbarnate-derived anticho- Clobazam, 551 receptor types and actions,
linesterases, 88-90 ADME, 282 180-184
dissociation constants, 150 anticonvulsant, 266,267,307 side effects, adverse effects,
dual cholinergic/anticholin- side effects, 277 and drug interactions,
ergic compounds, 150-151 Clomethiazole, 210,211 174-176
miscellaneous, structurally ADME, 221 structure-activity relation-
unique muscarinic agonists, .
Clomi~ramine ships, 184-187
78-80 affinities for monoamine re- CNS stimulation, 172
miscellaneous anticholinester- ceptors, 495 Cocaethylene, 177
ases, 93-97 antidepressant, 485,486,487 Cocaine, 169,170
muscarine, muscarone, and inhibition of serotonin, norepi- and kappa opioid receptor, 356
related compounds, 57-61 nephrine, and dopamine metabolism, 177
nicotine, its analogs and con- transporters, 500 Parkinson's disease diagnostic
geners, 49-57 pharmacokinetic parameters, radioligand, 735
not closely related structurally 497 physiology and pharmacology,
to acetylcholine,49-80 side effects profile, 493 179-180,182,183
Index

side effects, adverse effects, CP-212,454,574-575 Datura, 120


and drug interactions, CP-310,713, 575 DBO-83
175-176 Crotyl barbital, 205 cholinergic, 54-55
structure-activity relation- Curariform drugs, 110 Decongestants
ships, 188-192 Curral, 205 adrenergics, 2
Cocaine and amphetamine-re- CX509 currently used drugs, 171
lated transcript (CART), for Alzheimer's disease, 764 Id-Dehydromuscarine,58 -?
870 CX516 Delorazepam, 207
Coca leaves, 172 for Alzheimer's disease, 764 Delta opioid receptors, 331,
Cocoa, 169 CX614 341-355 .
Codeine, 332, 633 for Alzheimer's disease, 764 and addiction, 336-337
cytochrome P,,, isozyme sub- CY-208-243 ligands used to characterize,
stratelinhibitor, 339 for Parkinson's disease, 727 342,343-347,451
dose, 334 Cyclazocine, 375 signal transduction, 342-343
Cogentin Cyclic AMP response element structure and molecular biol-
for Parkinson's disease, 731,732 protein, 508 ogy, 350-354
Cognex Cyclobarbital, 205 Delta-selective opioid receptor
for Alzheimer's disease, 762 Cyclogyl, 134 agonists, 348, 354-355,
for cognition enhancement, 781 Cyclopal, 205 395-400
Cognition, 780-781 Cyclopentenylallylbarbituric Delta-selective opioid receptor
measurement, 781 acid, 205 antagonists, 348,367-370
Cognition enhancers, 780-781 Cyclopentolate Deltorphin analogs
clinically approved agents, 781 anticholinergic, 134 constrained, 435-437
exploratory approaches, mydriatic and cycloplegic ac- linear, 432-435
781-782 tivity, 153 Delvinal, 205
GABAA/Bzreceptor complex, relative anticholinergic activ- Dementia, 780. See also Alzhei-
782-797 ity, 156 mer's disease; Alzheimer's
nicotinic acetylcholine recep- Cycloplegics disease therapeutics; Cogni-
tor, 797-811 anticholinergic activity assay, tion enhancers
potassium M-channel, 817-820 119-120,153 in Alzheimer's, 744, 745
serotonin receptor, 811-817 anticholinergics, 114-115 Demerol, 334
therapeutic approaches, 781 Cyclorphan, 372 Demser, 4
Combinatorial libraries Cyclosporine A Dependence
peptides with high affinity for for Alzheimer's disease, 766 narcotic analgesics, 336
opioid receptors, 438-440 Cylert, 170 Depepsin, 158
Compazine, 601 Cytochrome P450 Depression, 484. See also Anti-
Comtan narcotic analgesic interac- depressants
for Parkinson's disease, 730, tions, 338-339 CNS stimulants in terminal
731 illness, 173
Conantokin-G, 693 D 2916 Deracyn, 552
Concerta, 170 anticonvulsant, 315 Deramciclane, 581
Coreg, 5 Dactil, 136 Dermorphin analogs
Corgard, 5 Dalgan, 335 constrained, 430-432
Cortical microvascular amyloid, Dalmadorm, 207 linear, 428-430
744 Dapiprazole Desethermuscarine, 61
Corticotropin-releasing factor a-antagonist, 4 Desipramine
and anxiety, 544-545 applications, 15 affinities for monoamine re-
Corticotropin-releasingfactor Darbid, 135 ceptors, 495
antagonists Daricon, 136 antidepressant, 485,486,487
antidepressants, 517-518 Darmonoct, 207 dose for eating disorders, 850
Coumarin Darstine, 139 for eating disorders, 858
PARP inhibitor, 681 Darvocet-N, 335 inhibition of serotonin, norepi-
COX-2 inhibitors Darvon, 335 nephrine, and dopamine
for Alzheimer's disease, 767 Darvon-N, 334 transporters, 500
CP-154,526, 577 DATScan phannacokinetic parameters,
CP-164,526 Parkinson's disease diagnostic 497
antidepressant, 518 radioligand, 735 side effects profile, 493
Index

Desmethylephedrine Dibenz(l,4)thiazepineantipsy- Diphemanil


metabolism, 17 chotics anticholinergic, 136
2-Desoxyabarbiturate anticon- pharmacokinetics, biotrans- relative anticholinergic activ-.
vulsants, 271 formation, and drug interac- ity, 157
ADME, 282-284 tions, 637 Diphenoxylate, 333
Desoxyn, 170 Dibenzylime, 4 antidiarrheal, 338
Desyrel, 485 Dibuline, 139 dose, 334 7
Dexamphetamine,843,855 Dibutoline, 139 Diphenyhydramine
dose as anti-obesity agent, mydriatic and cycloplegic ac- for Parkinson's disease, 731,
847 tivity, 153 732
Dexedrine, 3, 170 relative anticholinergic activ- Diphenylacetyloxy-derivative -
ity, 157 anticholinergics, 132-133
dose as anti-obesity agent, 847
Diphenylhydramine, 212,214
Dexfenfluramine Dichloralphenazone, 208,209
Dipivefin
dose, 848 Dicholoroisoproterenol, 27
applications, 10
removedlrestricted by FDA, Dicyclomine general adrenergic agonist, 3
843,856 anticholinergic, 134 Diprenorphine, 371
Dextroamphetamine, 170 influence of cyclic radicals on Disipal
Dextromethorphan, 372 anticholinergic activity, for Parkinson's disease, 731,
Dextropropoxyphene 143 732
cytochrome P,,, isozyme sub- relative anticholinergic activ- Dital, 171
stratelinhibitor, 339 ity, 156 Divalproex
Dextrorphan, 372 Didrex, 171,186,845 anticonvulsant, 266
Dextrostat, 170 Diels-Alder adduct analgesics Dizocilpine
Dezocine, 335 structure-activity relation- anticonvulsant, 306
analgesic, 308 ships, 370-372 DMP-696,578
DHC Plus, 335 Diethylpropion, 171,856 antidepressant, 518
Diabetes mellitus, type 2 absorption and metabolism, DMP-904,577-578
obesity increases risk, 839 863-866 DNA damage, 677
Diadenosine-tetraphosphaete dose, 845 and apoptosis, 677
PARP inhibitor, 681 metabolism, 177-179 DNA fragmentation, 677
Dial, 205 pharmacological activities, DNA ligase, 677
DNA polymerase epsilon, 677
Diampromine 865
DNA polymerases, 677
analgesic, 385 structure-activity relationship,
DNA repair
Diarylbutylamine antipsychotics 185,186,187
and apoptosis after stroke, 677
pharmacokinetics, biotrans- Difenoxin and PARP (poly(adenosine
formation, and drug interac- dose, 334 5'-diphosphateribose)poly-
tions, 639-640 Digestion, 111-114 merase), 677-679
Diazepam, 530 Dihydrexidine Dobutamine
ADME, 273 for Parkinson's disease, 727, agonist/antagonist, 5
anticonvulsant, 266, 267, 298, 728 applications, 16
307 Dihydrocodeine, 363 structure-activity relationship,
discovery, 547 Dihydromorphine, 363 29
dose, 270 Diisopropyl fluorophosphate Dobutrex, 5
dose for anxiety, 529 (DFP),92 Donepezil
side effects, 276 Dilaudid, 334 for Alzheimer's disease, 762
Dibenzo(l,4)diazepineantipsy- Dimethindene anticholinesterase, 96
chotics anticholinergic, 131 for cognition enhancement,
pharmacokinetics, biotrans- 1-Dimethyl-4-phenylpipera- 781,782
formation, and drug interac- zinium (DMPP) L-Dopa, 674
tions, 636-637 cholinergic, 56 metabolism and Parkinson's
Dibenz(l,4)oxazepineantipsy- Dimethylpyrindine therapy using, 720,721-725
chotics anticholinergic, 131 and norepinephrine synthesis,
pharmacokinetics, biotrans- Dinapsoline 22
formation, and drug interac- for Parkinson's disease, 727, for Parkinson's disease,
tions, 635-636 728 712-736
Index

Dopamine metabolism, 19 EMD 60400


and addiction, 336-337 selective a,-antagonist, 2, 4 analgesic, 394
antipsychotic drug discovery structure-activity relationship, EMD 61753
strategies based on, 31 analgesic, 394, 395
640-651 Doxefazepam, 207 EMD 128130
and body weight, 855 Doxepine for Parkinson's disease, 733,
inhibition by depressants, 500 affinities for monoamine re- 734 Z
and Parkinson's disease, ceptors, 495 En, 207
712-736 antidepressant, 485,486,487 Enactin
role in CNS stimulant effects, inhibition of serotonin, norepi- inhibitor of amyloid P-peptide -
180-182 nephrine, and dopamine aggregation, 759
and schizophrenia, 602-603 transporters, 500 Endogenous opioid peptides,
Dopamine agonists, 725 pharmacokinetic parameters,
356-358
structural modeling, 728-729 497
Dopamine Dl receptor agonists, Endomorphins, 357, 358,
side effects profile, 493
726-728 Doxylamine, 212,214 422-425
Dopamine D, receptor agonists, DPC-368,581 P-Endorphin, 331,356,357,358
725-726 DP-VPA Endorphins, 356-358
Dopamine Dl receptors, 713, 726 anticonvulsant, 311 Endothelial cells
Dopamine D, receptors, 713, 725 Dronabinol and blood-brain barrier, 676
Dopamine D, receptors, 713 dose, 854 Endothelial nitric oxide syn-
Dopamine D, receptors, 713 metabolism, 866 thase, 695-708
Dopamine potentiating agents structure-activity relation- Endothelin-converting enzyme
for Parkinson's disease, ships of analogs, 877-880 degrades amyloid P-peptide,
729-731 for wasting, 858,860 760
Dopamine-selective reuptake DuP 747 Energy homeostasis, 869-872
inhibitors analgesic, 389, 391 Enejets, 170
antidepressants, 494,515 DuP 996 Enkephalin analogs
combined with norepineph- acetylcholine-release modula- with antagonist activity at
rine-selective, for eating dis- tor, 97-98 delta receptors, 416-417
orders, 885 Duragesic, 334 delta-selective constrained,
Dopamine transporter, 498,499 Dutonin, 485 414-416
inhibition by antidepressants, Dynorphin A, 356,357,358,418 delta-selective linear, 412-414
500 Dynorphin A analogs, 418-422 dimeric, 417-418
Dopascan Dynorphin analogs mu-selective constrained,
Parkinson's disease diagnostic constrained, 420-421 411-412
radioligand, 735 linear, 418-420 mu-selective linear, 410-411
Doral, 207,549-550 Dynorphin B, 358 Enkephalins
Doriden, 211 Dynorphins, 331,656-658 discovery, 331
Dorimide, 211 Dyrexan-OD, 171 and Parkinson's disease, 715
Dormicum, 207 Entacapone
Dormonocot, 553 Eating disorders, 838-839, for Parkinson's disease, 730,
Dostinex 840-842 731
for Parkinson's disease, 722 guidelines for treatment, Ephedra, 10, 168-169,857
Dothiepen 842-843 Ephedrine, 168-169,171
afiinities for monoamine re- physiology and pharmacology, applications, 10, 12, 172
ceptors, 495 874 dose as anti-obesity agent, 846
antidepressant, 485,486,487 Ecothiophate, 91,93 general adrenergic agonist, 3
inhibition of serotonin, norepi- Edronax, 485 as lipolytic agent, 857
nephrine, and dopamine Edrophonium metabolism, 17
transporters, 500 anticholinesterase, 85 structure-activity relationship,
pharmacokinetic parameters, Effexor, 485,529 30,187
497 Elavil, 485 Epiallomuscarine, 57
Double-strand breaks, 677 dose for eating disorders, 851 Epibatidine
Doxans, 207 Eldepryl analogs as cognition enhanc-
Doxazosin for Parkinson's disease, 730 ers, 806-808
applications, 15-16 Elorine, 139 cholinergic, 52-53
Index

Epilepsy, 264-265. See also An- Ethynyl estradiol Fight or flight response, 526
ticonvulsants dose for eating disorders, 853 FK 506
new causative agent for, 320 for eating disorders, 858 for Alzheimer's disease, 766 .
porcine embryonic GABAergic 5-Ethynylnicotine, 52 Flesinoxan, 568-569
cell transplants, 320 Etizolam, 554 Flomax, 4
Epimuscarine, 57 Etodroxizine, 212,214 Flumazenil, 563-564
Epinephrine, See Adrenaline Etonitazene cognition enhancer, 796 T

4,5P-Epoxymorphinananalge- analgesic, 308 Flunitrazepam, 207,550


sics, 334 Eucatropine para-Fluoroamphetamine, 187
structure-activity relation- anticholinergic, 136 Fluorodonepezil
ships, 361-364 mydriatic and cycloplegic ac- anticholinesterase, 96
tivity, 153 Fluoxetine, See Prozac
structure-activity relation-
Fluphenazine
ships of N-substituted, relative anticholinergic activ-
dose, 601
364370 ity, 157
receptor binding and side ef-
Equilin Euphthalmine, 136 fects, 606
dose for eating disorders, 853 Eurodin, 207 Flurazepam, 207
for eating disorders, 858 Exelon Fluvoxamine, 530
Erimin, 207 for Alzheimer's disease, 762 affinities for monoamine re-
Eserine blue for cognition enhancement, ceptors, 495
anticholinesterase, 88 781 antidepressant, 485,486,488
Eseroline Extrapyramidal symptoms, of dose for anxiety, 529
anticholinesterase, 88 antipsychotics, 600, dose for eating disorders, 850
Esilgan, 207 605-607 for eating disorders, 857
Esmolol inhibition of serotonin, norepi-
P-antagonist, 5 FAD nephrine, and dopamine
applications, 16 nitric oxide synthase binding transporters, 500
Estazolam, 207 site, 698 pharmacokinetic parameters,
Estrogen-replacement therapy Fananserin, 651 497
for eating disorders, 858 Fastin, 171 side effects profile, 493
Estrogens Fat-absorption inhibitors, 844 FMN
for Alzheimer's disease, clinical applications, 843 nitric oxide synthase binding
765-766,768 Faverin, 485 site, 698
for eating disorders, 853,858 Fedotozine Foradil, 4
Estrone analgesic, 394, 395 Formoterol
dose for eating disorders, 853 Felbamate P-agonist, 4
for eating disorders, 858 ADME, 284-285 applications, 14
Eterobarb anticonvulsant, 265,268,269, Fosphenytoin
anticonvulsant, 306-307 295,298 ADME, 275
Ethclorvynol, 208,209 clinical efficacy, 273 anticonvulsant, 266, 304
ADME, 221 development, 302 dose, 270
Ethopropazine dose, 270 Frontotemporal dementia and
for Parkinson's disease, 731, pediatric indications, 274 parkinsonism linked to
732 side effects, 278 chromosome 17 (FTDP-171,
Ethosuximide Fenfluramine 745
ADME, 282 dose, 847
anticonvulsant, 265, 267, 297, removed from market, 843, GABA
298 856 and anticonvulsants, 292-297
clinical efficacy, 273 Fedphen, 856 and anxiety, 537-541
dose, 270 Fentanyl, 332,333 and Parkinson's disease, 713
side effects, 277 analogs, 381-384 GABAA/benzodiazepinereceptor
Ethotoin cytochrome P,,, isozyme sub- complex, 538-541
ADME, 273 strate, 339 and cognition enhancement,
anticonvulsant, 266 dose, 334 782-797
dose, 270 Fentanyl Oralet, 334 GABA analog anticonvulsants,
Ethylpropion, 863-864 FG 7142 271
pharmacological activities, 865 cognition enhancer, 794-795 ADME, 282-284
index

GABA, receptor, 295,537 release during ischemia, 689 Halcion, 207


and anticonvulsants, 295-296 and schizophrenia, 603-604 Haldol, 601
GA13AA/benzodiazepinecom- Glutamate antagonists Halogenated sedative-hypnotics
plex, 538-541 for Parkinson's disease, ADME, 220-221
GABA, receptor, 295,537 733-734 curently used drugs, 208-209
and anticonvulsants, 296 Glutamate transporter, 498 discovery, 235
'Z
GAB& receptor, 295,537 (S)-Glutamic acid, 296 side effects and drug interac-
Gabapentin Glutethimide, 210,211 tions, 208-210
ADME, 284 ADME, 221 Haloperidol .
for ALS, 674 Glycine transporter, 498 discovery, 617-618
anticonvulsant, 265, 268, 296, Glycopyrrolate dose, 601
298 anticholinergic, 137 pharmacokinetics, biotrans-
clinical efficacy, 273 relative anticholinergic activ- formation, and drug interac-
development, 300301
ity, 156 tions, 637-639
dose, 270
GPCRs (G-protein-coupledre- receptor binding and side ef-
pediatric indications, 274
side effects, 278 ceptors) fects, 606
GABA receptors, 95-297 adrenergic receptors, 25 Harkoseride
GABA transporter, 498 opioid receptors, 342343 anticonvulsant, 311-312
Galantamine (galanthamine) G proteins, See GPCRs (G-pro- HDL, See High density lipopro-
for Alzheimer's disease, 762 tein-coupled receptors) teins
for cognition enhancement, GR 10361,643 Head injury
781, 782 GR 68755 and Alzheimer's disease,
Gallotannin cognition enhancer, 816 748-749
NAD glycohydrolase inhibitor, GR 89696 Helicobacter Pylori
686 analgesic, 391, 392 and ulcers, 119
Gamanil, 485 GR 103545 Heminevrin, 211
y-Secretase, 754 analgesic, 391, 392 Hepabarbital, 205
Ganaxolone Grand mal seizures, 264 Heptylphysostigmine
anticonvulsant, 314-315 GTS-21 anticholinesterases related to,
Ganglionic blocking drugs, 110 for Alzheimer's disease, 764 89
Gastric juice, 111-112 cognition enhancer, 808-809 Heroin
Gastric secretion, 110, 111-114 Guanabenz synthesis, 360, 362
Gastrin, 112 cqagonist, 3
Heterocyclic antidepressants,
Gemonil, 205 applications, 14
486
Genatropine, 117 metabolism, 18-19
Heterocyclic sedative-hypnotics
Generalized anxiety disorder, structure-activity relationship,
526 31 ADME, 221-223
Genescopolamine Guanadrel clinical pharmacology,
therapeutic use, 117 antiadrenergic, 4 234-235
Geodon, 601 applications, 14 currently used drugs,
Gepirone, 581 Guanethidine 210-211
Gerodorm, 207 antiadrenergic, 4 discovery, 235
Ghrelin, 873 applications, 14 pharmacologic effects, 230
GI-181771,884,886 Guanfacine side effects and drug interac-
Gingko a,-agonist, 3 tions, 210-211
for Alzheimer's disease, 674, applications, 14 Hexahydrosiladifenidol
675, 768 structure-activity relationship, anticholinergic, 132
Ginkolides, 674 31 Hexobarbital, 204
Glatiramer Guanidines, 4 Hexocyclium, 139
for MS, 674,675 metabolism, 18-19 relative anticholinergic activ-
Glaucoma structure-activity relationship, ity, 157
cholinergics for, 40 3031 High density lipoproteins (HDL)
Glucagon GW-150013,574 and Alzheimer's disease,
and gastric secretion, 112 GW-150,013,581 748-749
Glutamate GYKI-46903 Himbacine
and anxiety, 546 cognition enhancer, 816 anticholinergic, 116, 133
Index

Histamine Hypercholesterolemia Indene-derived anticholinergics,


role in gastric secretion, and Alzheimer's disease, 131-132
112-113 748-749 Inderal, See Propranolol
role in spasms, 111 Hypnotics, See Sedative-hypnot- Inducible nitric oxide synthase,
and ulcers, 119 ics 695-708
Histamine H2 receptor antago- Hypothalamus Indunox, 214
nists, 112-113 regulation of energy ho- Insulin P
antiulcer application, 155, 158 meostasis by, 869-872 and adiposity signals, 872-873
Histaminel receptors, 112 Hytrin, 4 meta-Iodobenzylguanadine
Histamine2 receptors, 112 HZ2 NAD glycohydrolase inhibitor,
Histamine3 receptors, 112 analgesic, 393 686
HMG-CoA reductase inhibitors, Ionamin, 171,844
See Statins Ibuprofen Ion channels
for Alzheimer's disease, 767 and anticonvulsants, 292
Homatropine, 124-125
first tier of cancer pain treat- Iopidine, 3
mydriatic and cycloplegic ac-
ment, 332-333 Ipral, 204
tivity, 153 ICI 197067 Ipratropium, 125,158
relative anticholinergic activ- analgesic, 392 therapeutic uses, 117
ity, 156 ICI 199,441 Ischemia, See Stroke
therapeutic use, 117 analgesic, 392,406-407 Ismelin, 4
5-HT, See Serotonin ICI 204,448 Isoetharine
HT-SOB, 572 analgesic, 394 P-agonist, 4
Human growth hormone, recom- Idebenone applications, 14
binant for Alzheimer's disease, structure-activity relationship,
dose for wasting diseases, 854 758-759,768 28-29
for wasting diseases, 858 Imidacloprid, 51-52 Isomethadone, 385
Huperzine-A Imidazoles Isometheptene, 158
anticholinesterase, 97 nitric oxide synthase inhibi- Isopropamide
Hydantoin anticonvulsants, 270 tors, 704-705 relative anticholinergic activ-
ADME, 273-275 Imidazolines, 3 , 4 ity, 157
structure-activity relationship, metabolism, 18-19 Isopropramide
304-305 structure-activity relationship, anticholinergic, 135
Hydrocodone, 363 30-31 Isoproterenol, 27
Iminostilbene anticonvulsants, P-agonist, 4
dose, 334
270 applications, 14
Hydrocordone
ADME, 275 structure-activity relationship,
cytochrome P,,, isozyrne sub-
structure-activity relationship, 29
strate, 339 305-306 Isoquinazolinone PARP inhibi-
Hydromorphone, 332,363 Imiprarnine tors, 686
dose, 334 affinities for monoamine re- Isothioureas
Hydroxychloroquine ceptors, 495 nitric oxide synthase inhibi-
for Alzheimer's disease, 767 antidepressant, 485,486,487 tors, 705-706
Hydroxymethylglutaryl-CoA dose for eating disorders, 850 Isoxazole
(HMG-CoA)reductase in- for eating disorders, 858 cognition enhancer, 801
hibitors, See Statins inhibition of serotonin, norepi- Isoxsuprine
2-Hydroxy-2-phenylnonanamide, nephrine, and dopamine agonistlantagonist, 5
304-305 transporters, 500 applications, 16
Hydroxyzine, 212,214 pharmacokinetic parameters, Isuprel, 4
Hylorel, 4 497 Itasetron
Hyoscyamine side effects profile, 493 cognition enhancer, 816
dissociation constant, 151 Immunosuppressive drugs
relative anticholinergic activ- for Alzheimer's disease, 766 5-113397
ity, 156 Immunotherapy opioid analgesic, 447,449
in solanaceous alkaloids, inhibitors for Alzheimer's dis- 5-115814,886-887
120-126 ease, 766 Jimsonweed, 120
stereoisomerism, 148, 149 Imodium A-D, 334 JTC-801
therapeutic use, 117 Imovane. 211 opioid analgesic, 447
I Index

Kappa opioid receptors, 331, Lacrimation, 110 Ligands


341354,355-356 Lactoylcholine, 150 for opioid receptor character-
and addiction, 336-337 dissociation constant, 151 ization, 342,343-347
ligands used to characterize, Laminin Limbitrol
342,343-347,451. inhibitor of amyloid p-peptide dose for eating disorders, 851
signal transduction, 342-343 aggregation, 759 Linopirdine
structure and molecular biol- Lamotrigine acetylcholine-release modula-
ogy, 3 5 0 3 5 4 ADME, 285-286 tor, 97-98
Kappa-selective opioid receptor anticonvulsant, 265, 268, 269, cognition enhancer, 818-820
agonists, 348,355-356 298,319 Lipolytic agents, 843, 846
centrally acting, 387-393 clinical efficacy, 273 clinical applications, 857
peripherally acting, 393-395 development, 302 Lipstatin, 881
Kappa-selective opioid receptor Lisuride
dose, 270
antagonists, 348,365-367 for Parkinson's disease, 722,
pediatric indications, 274
Kelatorphan 725
side effects, 279
opioid peptide metabolism in- Lobeline
hibitor, 441,442 Larodopa, See L-Dopa cholinergic, 56
Kemadrin Lendormin, 207 Lodosyn
anticholinergic, 132, 135 Lentizol, 485 for Parkinson's disease, 724
for Parkinson's disease, 731, Leptin, 872,873 Lofepramine
732 anorectic agent, 883,885 affinities for monoamine re-
Kerlone, 5 Lergotrile ceptors, 495
Ketanserin, 570-571 for Parkinson's disease, 722, antidepressant, 485,486,487
Ketazolam, 551-552 725 inhibition of serotonin, norepi-
Ketobemidone, 376 Lescopine, 117 nephrine, and dopamine
Ketocyclazocine Lesopitron, 570, 581 transporters, 500
ligand to characterize kappa Leu-enkephalin, 331,356358 pharmacokinetic parameters,
receptor, 342 Levabuterol 497
Khat, 168-169,172 applications, 14 Lomotil, 334
Klonopin, 529 Levatol, 5 Long term potention, 780
KMD-3213,33 Levetiracetam Loperamide, 333
Kriptin, 214 ADME, 291 antidiarrheal, 338
KW 6002 anticonvulsant, 265,268, 269, dose, 334
for Parkinson's disease, 733 Lopirazepam, 554
298
Loprazolam, 207,553
development, 304
L-152,804,887 Lopressor, 5
L-365,260,544,573-574 dose, 270
Lora, 209
L-685,458 pediatric indications, 274 Loramet, 207,551
for Alzheimer's disease, 755 side effects, 279 Lorazepam, 207,530,551
L-687,306 Levobetaxolol dose for anxiety, 529
for Alzheimer's disease, 763 P-antagonist, 5 Lormetazepam, 207,551
L-689,660 applications, 16 Losigamone
for Alzheimer's disease, 763 Levobunolol anticonvulsant, 314
L-740,093,581 P-antagonist, 5 Lotusate, 204
L-745,870,40,42 applications, 16 Loxapine
L-754,030,581 Levo-Dromoran, 334 dose, 601
L-792,782 Levomethadyl, 333 pharmacokinetics, biotrans-
binding affinity with GABAA/ dose, 334 formation, and drug interac-
Bz, 795 Levonordefrin tions, 635-636
Labetalol a,-agonist, 3 receptor binding and side ef-
alp-antagonist, 5 applications, 12 fects, 606
applications, 16 Levophed, 3 Loxitane, 601
structure-activity relationship, Levorphanol, 372 Ludiomil, 485
28,32 dose, 334 Luminal, 204
Lachesine Lewry bodies, 712,716 Lustral, 485
relative anticholinergic activ- Lexotan, 207,529 Luvox, 485,529
ity, 156 Librium, 529 dose for eating disorders, 850
Index

LY-164929 McN-A-343 Mesoridazine


analgesic, 411 cholinergic, 77 dose, 601
LY-227053 MDL28170 receptor binding and side ef- -
analgesic, 378 for Alzheimer's disease, 755 fects, 606
LY-246708 Mebaral, 204 Metadate ER, 170
for Alzheimer's disease, 763 Medazepam, 549 Metaprel, 4
LY-246736 Medomin, 205 Metaproterenol T
analgesic, 378 Megace, 854 P-agonist, 4
LY-253886 Megestrol applications, 14
analgesic, 378 dose, 854 structure-activity relationship, -
LY-255582 metabolism, 866 29
analgesic, 378 for wasting, 858 Metaraminol
LY-300164 Melanin-concentrating hormone, a,-agonist, 3
anticonvulsant, 312 870 applications, 12
Melanocortin, 870 structure-activity relationship,
LY-341495,654
a-Melanocyte stimulating hor- 30
LY-354740,581,654
mone Metazocine, 375
LY-377604,884,886 and appetite regulation, 870 Met-enkephalin, 331,356-358
LY-379268,654-655 Melatonergic agents, 251-254 a-Methadol, 385
LY-392098 Melatonin, 214, 215 P-Methadol, 385
for Alzheimer's disease, 765 for Alzheimer's disease, 758, Methadone, 332,333
LY-404187 768 analogs, 385-387
for Alzheimer's disease, 765 Melfiat-105 Unicelles, 171 cytochrome P ,,, isozyme sub-
Melidorm, 205 stratelinhibitor, 339
Madar, 207 Mellaril, 601 dose, 334
Ma huang, 10,12,168,172 MEM 1003 Methamphetamine, 171,177,185
Major tranquilizers, 600. See cognition enhancer, 820 Methantheline
also Antipsychotic agents Memantine anticholinergic, 137
Manerix, 485 for Parkinson's disease, 733, relative anticholinergic activ-
for Parkinson's disease, 729, 734 ity, 156
730 Memapsin 2, 753 Metharbital, 205
MA0 inhibitors, See Monoamine Meningeal vascular amyloid, 744 Methitural, 205
oxidase inhibitors Mepenzolate Methiiene
Maprotiline anticholinergic, 137 relative anticholinergic activ-
affinities for monoamine re- relative anticholinergic activ- ity, 157
ceptors, 495 ity, 156 Methoctramine
antidepressant, 485,486,487 Mepergan Fortis, 335 anticholinergic, 131
inhibition of serotonin, norepi- Meperidine, 332 Methoxamine
nephrine, and dopamine cytochrome P450isozyme sub- a,-agonist, 3
transporters, 500 strate, 339 applications, 12
pharmacokinetic parameters, dose, 334 structure-activity relationship,
497 Mephentermine 30
side effects profile, 493 applications, 12 Methscopolamine, 124
Marijuana, 858 general adrenergic agonist, 3 relative anticholinergic activ-
Marimastat Mephenytoin ity, 156
for Alzheimer's disease, 752 ADME, 273 therapeutic use, 117
Marinol, 854 anticonvulsant, 266 Methsuximide
Maxair, 4 dose, 270 ADME, 282
Maximal electroshock seizure, Mephobarbital, 204 anticonvulsant, 267
292 Mephohexital, 204 dose, 270
Mazapertine, 567-568, 569 Mepiperphenidol, 123, 139 N-Methyl-D-aspartatereceptor
Mazindol, 856 relative anticholinergic activ- antagonists, See NMDA re-
absorption and metabolism, ity, 157 ceptor antagonists
866 Meptazinol, 379 Methylatropine, 124
dose, 845 Mepyramine, 214 relative anticholinergic activ-
structure-activity relation- Meridia, 844 ity, 156
ships of analogs, 880-881 Mesopin, 117 therapeutic use, 117
Index

Methyldopa Mini-Mental State Examination, Monoaminergic antidepressants,


a,-agonist, 3 781 516
applications, 14 Minpress, 4 Monoamine transporters,
structure-activity relationship, Miosis, 110 498-502
29 Mirapex Monodral, 137
a-Methylfentanyl, 383 for Parkinson's disease, 722, Morphinan analgesics, 334
Z
Methylhomatropine 725 structure-activity relation-
relative anticholinergic activ- Mirisetron ships, 372-373
ity, 156 cognition enhancer, 816 Morphine, 331-332,333 -
Methylhyoscyamine Mirtazapine cytochrome P,,, isozyme sub-
relative anticholinergic activ- antidepressant, 485,486,489 strate, 339
ity, 156 inhibition of serotonin, norepi- dose, 334
stereoisomerism, 148,149 nephrine, and dopamine history of use, 358-360
Methylin, 170 transporters, 500 ligand to characterize mu re-
Methylleucatropine pharmacokinetic parameters, ceptor, 342
relative anticholinergic activ- 497 nonpeptide affinity labels used
ity, 156 side effects profile, 493 to study, 403-405
Methylphenidate (Ritalin) Mithixene structure-activity relationship,
dose, 170 anticholinergic, 135 361-362
metabolism, 177 MK-801 structure-activity relation-
physiology and pharmacology, anticonvulsant, 306 ships of derivatives,
179,181-182 MK-869 362-364
side effects, adverse effects, antidepressant, 517 Motofen,334
and drug interactions, 174 Moban, 601 MPTP (designer drug), 380
structure-activity relation- Moclobemide and Parkinsonism, 717-721
ships, 187-199 antidepressant, 485,486,488 Mr2034,375
N-Methyl-4-phenyl-l,2,3,6-tetra- for Parkinson's disease, 729, Mr2266,375
hydropyridine (MPTP; de- 730 MS drugs, 675
signer drug), 380 pharmacokinetic parameters, Multi-infarct dementia, 780
and Parkinsonism, 717-721 497 Multiple sclerosis, 674-675
N-Methyl-4-propionoxy-4-phe- side effects profile,493 Mu opioid receptors, 331,
nylpiperidine (MPPP; de- Modafinil, 170,193 341-354
signer heroin) Mogadon, 207
and addiction, 336-337
and Parkinsonism, 718 Molindone
ligands used to characterize,
Metipranolol dose, 601
@-antagonist,5 pharmacokinetics, biotrans- 342,343-347
applications, 16 formation, and drug interac- signal transduction, 342-343
Metoclopramide tions, 640 structure and molecular biol-
dose for eating disorders, 852 receptor binding and side ef- ogy, 350-354
for eating disorders, 858 fects, 606 Murel, 138
Metoprolol Molipaxan, 485 Muscarine, 41
@-antagonist, 5 Monoamine oxidase as cholinergic, 57-61
applications, 16 and depression, 507 Muscarinic acetylcholine recep-
metabolism, 21 and Parkinson's disease, 716 tor agonists
Metropine, 117 Monoamine oxidase inhibitors, for Alzheimers' disease,
Metyrosine 485,486 762-764
antiadrenergic, 4 for anxiety disorders, 528 miscellaneous structurally
applications, 15 for eating disorders, 851,858, unique cholinergics, 78-80
Mianserin, 57570-571 859 Muscarinic acetylcholine recep-
Micturation, 110 efficacy relative placebo, 489 tor antagonists
Midazolam, 207,553 for Parkinson's disease, for Alzheimers' disease,
Midodrine 729-731 762-764
a,-agonist, 3 pharmacokinetics,497-498 Muscarinic acetylcholine recep-
applications, 12-13 side effects, 491-492 tors, 41-43
Milameline structure-activity relationship, interaction of anticholinergics
for Alzheimer's disease, 763 512-513 with, 151-153
Index

Muscarinic M, acetylcholine re- NADPH Neprilysin


ceptors, 41-42 nitric oxide synthase binding for Alzheimer's disease, 760
agonists and antagonists, site, 698 Neravil, 205
115-116 Nafadotride, 643 Nerve gases, 90-93
Muscarinic M, acetylcholine re- Nalbuphine, 335,363 Neurodegenerative conditions,
ceptors, 41-42 Nalmefene, 363 674-676
agonists and antagonists, Naloxone, 333 and cellular energetics, 'Z
115-116 Naltrexone, 333 679-689
Muscarinic M, acetylcholine re- nonpeptide affinity labels used DNA damage and repair,
ceptors, 41-42 to study, 403-405 677-679 -
agonists and antagonists, Naphazoline necrosis and apoptosis,
115-116 a,-agonist, 2 , 3 676-677
Muscarinic M, acetylcholine re- applications, 13 nitric oxide synthase inhibi-
structure-activity relationship, tors, 695-706
ceptors, 41-42
30-31 NMDA receptor antagonists,
agonists and antagonists,
Naproxen 689 - 695
115-116 for Alzheimer's disease, 767 Neurofibrillary tangles, 744
Muscarinic M, acetylcholine re- Narcobarbital, 205 Neuroleptic malignant syn-
ceptors, 41-42 Narcolepsy drome, 607-608
agonists and antagonists, CNS stimulant for, 173, 193 Neuroleptics, 600. See also Anti-
115-116 Narcotal, 205 psychotic agents
Muscarone Narcotic agonists, 335 Neuronal nicotinic acetylcholine
cholinergic, 57-61,80 opioid receptor affinities, 348 receptors, See Nicotinic ace-
Muscle-type nicotinic acetylcho- Narcotic analgesics. See also tylcholine receptors, neuro-
line receptors, See Nicotinic Opioid analgesics; Opioid nal
acetylcholine receptors, receptors Neuronal nitric oxide synthase,
muscle-type future developments, 448-450 695-708
Mu-selective enkephalin ana- history, 358-360 Neuropeptide receptor-acting
log~,410-412 recent developments, 443-448 drugs
Mu-selective opioid receptor ago- Web resources, 450-452 antidepressants, 517-518
nists, 333, 348 Narcotic antagonists, 335 Neuropeptide Y
Mu-selective opioid receptor an- opioid receptor affinities, 348 and anxiety, 546
tagonists, 333, 348 Nardil, 485 and appetite, 870
somatostatin derived, 437-438 dose for eating disorders, 851 Neurotransmitters. See also spe-
for Parkinson's disease, 729, cific neurotransmitters.
Myasthenia gravis
730 such as Dopamine
cholinergics for, 41
Natural products and sleep, 225,227-228
Mydriacyl, 138 CNS stimulants, 168 Neurotransmitter transporters,
Mydriasine, 117 Navane, 601 498- 499
Mydriatics Necrosis NGD 91-3,580
anticholinergic activity assay, in stroke, 676-677 NGD 94-1,40,41
119-120,153 Nefazodone, 496 Niaprazine, 213,214
anticholinergics, 114-115 affinities for monoamine re- Nicotinamide (vitamin B,)
Myocardial infarction ceptors, 495 analogs tested in pellagra, 690
in stroke patients, 675-676 antidepressant, 485,486,489 and cellular energetics,
inhibition of serotonin, norepi- 687- 689
Nacton, 138 nephrine, and dopamine NAD glycohydrolase inhibitor,
NAD transporters, 500 686
precursors and cellular ener- pharrnacokinetic parameters, PARP inhibitor, 680,686
getics, 687-690 497 Nicotine, 41
substrate for PAW, 677-679 side effects profile, 493 and Alzheimer's disease, 764
synthesis pathway, 689 Negative symptoms, of schizo- analogs and congeners as cho-
NAD glycohydrolase inhibitors, phrenia, 602 linergics, 49-57
686-687 Nembutal, 204 derivatives as cognition en-
Nadolol Nemonapride, 641 hancers, 797-806
P-antagonist, 5 Neodorphins, 357,358 inhibitor of amyloid P-peptide
applications, 16 Neonal. 205 aggregation, 758
Index

possible protective effect in Nopron, 214 Novobiocin


Parkinson's, 717, 718-719 Noradrenaline, See Norepineph- NAD glycohydrolase inhibitor,
Nicotinic acetylcholine receptor rine 686
agonists Noradrenergic-selective re- NPS-1776
for Alzheimer's disease, uptake inhibitors, 486. See anticonvulsant, 312
764-765 also Norepinephrine-selec- NREM sleep, 224-225
Nicotinic acetylcholine recep- tive reuptake inhibitors NS-2710,580 f
tors, 41-43 Nordazepam, 207 Nubain, 335
agonists for Alzheimer's dis- Norepinephrine, 2 Nucleotide-excision repair, 677
ease, 764-765 and anxiety, 543-544 Nucleus tractus solitaris, 873 -
and cognition enhancement, applications, 9 Numorphan, 334
797-811 biosynthesis, storage, and re- NW-1015
Nicotinic acetylcholine recep- anticonvulsant, 312
lease, 22-25
tors, muscle-type, 42
and body weight, 855
Nicotinic acetylcholine recep- Obe-Nix 30-P, 171
general adrenergic agonist, 3

/
tors, neuronal, 42 Obesity, 838, 839-840. See also
Night-eating syndrom, 840 inhibition by depressants, 500 Anti-obesity drugs
Nimetazepam, 207 metabolism, 16-17 CNS stimulants for, 173, 193
physiological significance,
1 Nipecotic acid analog anticon-
21-22
comorbidities associated with,
vulsants 840
ADME, 286-291 role in CNS stimulant action, guidelines for treatment, 842
Niravoline 183-184 Obsessive-compulsive disorder,
analgesic, 389 role in CNS stimulant effects, 527
Nitrazepam, 207 181,183-184 Octamethylpyrophosphoramide
ADME, 282 Norepinephrine-selective re- (OMPA), 91,92
anticonvulsant, 266, 267, 307 uptake inhibitors, 486,494, Ocupress, 5
side effects, 277 496 Ohmfentanyl, 383,384
Nitric oxide synthase, 695 combined with dopamine re- Olanzepine
Nitric oxide synthase inhibitors, uptake inhibitors, 885 dose, 601
695-706 serotonin-selected contrasted, for Parkinson's disease, 725
Nitrites 501 receptor binding and side ef-
antispasmodic, 111 structure-activity relationship, fects, 606
6-Nitrodopamine 510,511-512 Oleamide, 254-255
nitric oxide synthase inhibi- OM991
Norepinephrine transporter,
tors, 705 for Alzheimer's disease, 754
498- 499
6-Nitronorepinephrine OM992
nitric oxide synthase inhibi- inhibition by antidepressants,
for Alzheimer's disease, 754
tors, 705 500 Onchidal
5-Nitrouracil Normison, 207 anticholinesterase, 94
PARP inhibitor, 681 Normodyne, 5 Ondansetron, 573
NMDA receptor antagonists, Nornicotine, 49 cognition enhancer, 813,
689-695 Noroxyphenonium, 123 815-816
analgesics, 449 Norpramin, 485 OPC-4392,650
antidepressants, 516 dose for eating disorders, 850 OPC-14597,650
NMDA receptors Nortriptyline Opioid agonists, 333
and anxiety, 546 affinities for monoamine re- delta-receptor selective,
and schizophrenia, 604 ceptors, 495 395-400
Nocistatin, 357 antidepressant, 485,486,487 kappa-receptor selective,
Noctal, 205 dose for eating disorders, 851 387-395
Noctamid, 207 for eating disorders, 858 opioid receptor affinities, 348
Noctec, 209 inhibition of serotonin, norepi- Opioid analgesics, 331-333
NoDoz, 170 nephrine, and doparnine ADME, 339341
Nonsteroidal anti-inflammatory transporters, 500 central nervous system, 341
drugs pharmacokinetic parameters, currently used drugs, 333,
for Alzheimer's disease, 767 497 334-335
first tier of cancer pain treat- side effects profile, 493 cytochrome P,,, substrates
ment, 332-333 Novaltropine, 117 and inhibitors, 339
Index

Opioid analgesics (Continued) Opioid receptors, 331. See also pediatric indications, 274
endogenous opioid peptides, Delta opioid receptors; side effects, 279
341-354 Kappa opioid receptors; Mu Oxotremorine analog cholin-
future developments, 448-450 opioid receptors ergics, 71-78
history, 358360 characterization, 343-350 Oxotremorine-M
miscellaneous nonpeptide opi- cloning, 341-342,350 cholinergic, 75
ates, 407 computational models, 352 Oxycodone, 332,363 9
radioligand binding assays, dimerization, 354,443-444 dose, 334
344-347 mutagenesis studies, 351-352 OxyContin, 334
recent developments, 443-448 nomenclature, 341-342 Oxymetazoline
receptor types, 341354 nonpeptide affinity labels used a,-agonist, 3
side effects, adverse effects, to study, 400-407
applications, 13
and drug interactions, signal transduction mecha-
333339 structure-activity relationship,
nisms, 342-343
signal transduction mecha- 30-31
splice variants, 352-354
nisms, 342-343 structure and molecular biol- Oxymorphone, 363
structure-activity relation- ogy, 350-354 dose, 334
ships of nonpeptide ligands, subtypes, 331,352-354 0xyph'encyclimine
360-407 Opium, 331,358-359 anticholinergic, 136
in vitro efficacy assays, OptiPranolol, 5 relative anticholinergic activ-
347-349 Orap, 601 ity, 157
in vivo evaluation, 349350 Orexin A, 872 Oxyphenonium
Web resources, 450-452 ORG-12962,572,581,886 anticholinergic, 137
Opioid antagonists, 333 Orlaam, 334 mydriatic and cycloplegic ac-
delta-receptor selective, Orlistat tivity, 153
367-370 absorption and metabolism, relative anticholinergic activ-
kappa-receptor selective, 860 ity, 156
365-367 dose, 844
opioid receptor affinities, 348 structure-activity relation- Pagoclone, 558-559
structure-activity relation- ships of analogs, 880-881 Pain, 331-333. See also Narcotic
ships, 364-370 Orphanin FQ/Nociceptin, 342, analgesics; Opioid analge-
Opioid bowel dysfunction, 337 357,358,444-445 sics
Opioid peptide analogs, 407-409 structure-activity relationship, cholinergics for, 41
from amphibian skin, 446-447 Pamelor
409-410 Web resources dealing with, dose for eating disorders, 851
P-casomorphin and endomor- 451 Pamine, 117
phin analogs, 422-425 Orphenadrine Panadiplon, 564565
deltorphin analogs, 432-437 for Parkinson's disease, 731, Panic disorder, 527
dermorphin analogs, 428-432 732 Papaverine, 361
dynorphin analogs, 418-422 Oxandrin, 854 antispasmodic, 111
enkephalin analogs, 410-418 Oxandrolone Paraoxon, 91,93
other peptides with high affin- dose, 854 Parasyrnpathomimetics, See
ity for opioid receptors, metabolism, 867 Cholinergics
437-440 for wasting, 858,860 Parathion, 91,93
peptidase inhibitors, 440-443 Oxazeparn, 530 Paregoric, 337338
peptide affinity label deriva- dose for anxiety, 529 Parkin
tives, 440 Oxazolam, 551-552 and Parkinson's disease, 716
TIPP and related peptides, Oxazolidinedione anticonvul- Parkinsonian dementia, 780
425-428 sants, 271 Parkinsonism, 712,716
with Tyr-D-aa-Phesequence, ADME, 282-284 in Alzheimer's disease, 745
428-437 Oxcarbazepine and MPTP (designer heroin),
Opioid-receptor-like 1 (ORL1) ADME, 275,286 717-721
receptor, 341-342,358,444 anticonvulsant, 265, 268, 269, Parkinson's disease, 674,
nonpeptide ligands for, 298,306 712-713
447-448 clinical efficacy, 273 cholinergics for, 41
Web resources dealing with, development, 302-303 diagnostic agents for, 734-736
451 dose, 270 etiology, 715-721
Index

pathophysiology, 713-715 PD 117302 dose, 846


role of manganese, 716, 717 analgesic, 389,390 structure-activity relationship,
Parkinson's disease therapeu- PD 128763 185
tics. See also L-Dopa PARP inhibitor, 681 Phenelzine
adenosine antagonists, 733 Pellagra, 687 antidepressant, 485,486,488
anticholinergic agents, nicotinamide analogs tested, dose for eating disorders, 851
731-733 690 for eating disorders, 858 P
catechol-0-methyltransferase PemADD, 170 for Parkinson's disease, 729,
(COMT) inhibitors, 731 Pemoline, 170 730
dopamine Dl receptor ago- side effects, adverse effects, pharmacokinetic parameters, .

nists, 726-728 and drug interactions, 497


174-175 side effects profile, 493
dopamine D2 receptor ago-
Penbutolol
nists, 725-726 Phenergan, 214
P-antagonist, 5
dopamine potentiating agents, 2-Phenethylarnines
applications, 16
729-731 appetite suppressants,
Pentazocine, 333,335,375
future directions, 736 Penthienate 855-856
glutamate antagonists, anticholinergic, 137 structure-activity relation-
733-734 relative anticholinergic activ- ships, 875-881
monoamine oxidase inhibitors, ity, 156 Phenmetrazine
729-731 Pentobarbital, 204 structure-activity relationship,
serotonin agonists, 734 Pentothal, 204 185
Parlodel Pepsin inhibitors Phenobarbital
for Parkinson's disease, 722 antiulcer application, 158 ADME, 282-283
Parnate, 485 Pepsinogens, 111-112 anticonvulsant, 265, 267, 298
for Parkinson's disease, 730 Peptic ulcer, 113-114 clinical efficacy, 273
Paroxetine, 530 Peptidase inhibitors, 440-443 dose, 270
affinities for monoamine re- Peptide affinity label derivatives, side effects, 278
ceptors, 495 440 Phenothiazine antipsychotics
antidepressant, 485,486,488 Peptidomimetics pharmacokinetics, biotrans-
dose for anxiety, 529 with high affinity for opioid formation, and drug interac-
dose for eating disorders, 849 receptors, 438-440 tions, 633-635
for eating disorders, 857 Percocet, 335 Phenoxybenzamine
inhibition of serotonin, norepi- Percodan, 335 a-antagonist, 4
nephrine, and dopamine Pergolide applications, 15
transporters, 500 for Parkinson's disease, 722, Phenoxyethylamine, 33
pharmacokinetic parameters, 725 Phenserine
497 Peripheral adiposity signals, anticholinesterases related to,
side effects profile, 493 872-873 89
PARP-1,679 Peripheral satiety signals, 873 Phensuximide, 267
PARP-2,679 Permatil, 601 dose, 270
PARP-3,679 Permax Phentermine, 171,185,186,
PARP inhibitors, 680-686 for Parkinson's disease, 722, 855-856
PARP (poly(adenosine5'-diphos- 725 absorption and metabolism,
phateribose)polymerase), Pernoston, 205 861
674 Perphenazine dose, 844, 848
and cellular energetics, dose, 601 Phentolamine
679-680 receptor binding and side ef- a-antagonist, 4
and DNA repair, 677-679 fects, 606 applications, 15
Parsidol Petichloral, 208,209 structure-activity relationship,
1 for Parkinson's disease, 731, Petrin, 209 31
732 Phanodorm, 205 N-Phenylacetamidines
j
Pathilon, 139 Phenampromide nitric oxide synthase inhibi-
Pavatrine, 134 analgesic, 385, 387 tors, 698, 700-701
Paxil, 485,529 Phendimetrazine, 171, 187,856 Phenyl-2-aminopyridines
dose for eating disorders, 849 absorption and metabolism, nitric oxide synthase inhibi-
Pazinoclone, 558-559 863 tors, 702-704
Index

Phenylephrine Pirbuterol Presenilins


a,-agonist, 3 P-agonist, 4 and Alzheimer's disease,
applications, 13 applications, 14 745-746
structure-activity relationship, Pirenzepine Pretz-D 0.25% spray, 171
30 anticholinergic, 128-129 Primidone
Phenylethylamines, 3 , 4 , 5 Piribedil ADME, 283
metabolism, 16-18 for Parkinson's disease, 723, anticonvulsant, 265,267-268
structure-activity relationship, 726 298
2830 Placebo effect clinical efficacy, 273
Phenylpiperidine analgesics, 334 depressants, 488-489 dose, 270
structure-activity relation- Placidyl, 209 side effects, 278
ships with carbon substitu- Plegine, 171,846 Priscoline, 4
ent at C,, 377-380 PNU-95666-E ProAmatine, 3
structure-activity relation- for Parkinson's disease, 723, Probanthine
ships with oxygen substitu- 726 anticholinergic, 128,138
ent at C,, 380-381 Poldine Probarbital, 204
Phenylpropanolamine, 843 anticholinergic, 138 Prochloperazine
dose, 848 relative anticholinergic activ- receptor binding and side ef-
Phenytoin ity, 156 fects, 606
ADME, 273 Polymethylene tetramine anti- Prochlorperazine
anticonvulsant, 265-267,298 cholinergics, 131 dose, 601
clinical efficacy, 273 Positive symptoms, of schizo- Procyclidine
dose, 270 phrenia, 602 anticholinergic, 135
side effects, 276 Positron emission tomography for Parkinson's disease, 731,
Phobias, 526-527 (PET) 732
Phosphorus-derived cholin- for Parkinson's disease diag- relative anticholinergic activ-
ergics, 90-93 nosis, 734-736 ity, 157
Physical dependence serotonergic activity in anxi- stereoisomerism, 149
narcotic analgesics, 336 ety, 579 Prodine, 376
Physostigmine Postoperative atony of gutluri- Prodorm, 209
anticholinesterases related to, nary bladder Proenkephalin peptides, 357,
88 -90 cholinergics for, 40 358
Pilocarpine Posttraumatic stress disorder, Prokinetic agents
as cholinergic, 61-62 527
for eating disorders, 852,858
Pimozide Potassium channels
Prolixin, 601
dose, 601 and cognition enhancement,
817-820 Promazine
pharmacokinetics, biotrans-
formation, and drug interac- Potato, solanaceous alkaloids dose, 601
tions, 639-640 from, 120-126 receptor binding and side ef-
receptor binding and side ef- Pramipexole, 650 fects, 606
fects, 606 for Parkinson's disease, 721, Promethazine, 213,214
Pindolol, 4 722,725-726 antiulcer application, 158
applications, 16 Prantal, 136 Pronethalol
Pipenzolate Pravastatin history, 27
anticholinergic, 138 for Alzheimer's disease, 757
relative anticholinergic activ- Prazosin Propantheline
ity, 156 applications, 15-16 anticholinergic, 138
Piperidolate selective a,-antagonist, 4 relative anticholinergic activ-
anticholinergic, 136 structure-activity relationship, ity, 156
relative anticholinergic activ- 31 Propavan, 214
ity, 157 Pregabalin, 580 Propine, 3
Pipethanate anticonvulsant, 312-313 Propiomazine, 213,214
anticholinergic, 136 Prelu-2, 171 Propivane
Piptal, 138 Preludin, 185 relative anticholinergic activ-
Piracetam, 304 Premarin ity, 157
for Alzheimer's disease, 764 dose for eating disorders, 853 Propofel, 214, 215
Propoxyphene, 332 Psychosis, 600-602,604-605. Remifentanil, 383
cytochrome P,,, isozyrne sub- See also Antipsychotic dose, 334
stratelinhibitor, 339 agents Reminyl
dose, 334 Psychostimulants, 168. See also for Alzheimer's disease, 762 .
Propranolol CNS stimulants for cognition enhancement,
applications, 16 Pyridostigmine 781
history, 27 anticholinesterase, 90 REM sleep, 225 P
metabolism, 19-21 Pyrilarnine, 212, 214 nonhypnotic drugs affecting
structure-activity relationship, Pyrrolidinone acetamide anti- OFF switch, 227
3233 convulsants nonhypnotic drugs affecting -
R(-IN-n-Propyl-llhydroxynora- ADME, 291 ON switch, 225-227
porphine
REM sleep rebound, 203
for Parkinson's disease, 723 Quazepam, 207,549-550
Requip
Prostaglandins Quazium, 207
for Parkinson's disease, 722,
antiulcer application, 158 Quetiapine
and gastric secretion, 113 dose, 601 725
Protein kinase C for Parkinson's disease, 725 Resedorm, 204
and a-secretase shift, 761 pharmacokinetics, biotrans- Reserpine
Prothiaden, 485 formation, and drug interac- antiadrenergic, 4
Protriptyline tions, 637 applications, 15
affinities for monoamine re- receptor binding and side ef- Resperidone
ceptors, 495 fects, 606 receptor binding and side ef-
antidepressant, 485,486, 487 Quick Pep, 170 fects, 606
inhibition of serotonin, norepi- Quinazolines, 4 Restoril, 207
nephrine, and dopamine metabolism, 19 Retigabine
transporters, 500 structure-activity relationship, anticonvulsant, 313
pharmacokinetic parameters, 30-31 Retrothiorphan
497 Quinazolinone PARP inhibitors, opioid peptide metabolism in-
side effects profile, 493 682,686 hibitor, 442
Proventil, 4 Quinuclidine-based anticholin- Rev-Eyes, 4
Provigil, 170, 193 ergics, 129-131 Rexigen Forte, 171
Prozac, 484,529,531 Rifampicin
affinities for monoamine re- R-84760 inhibitor of amyloid p-peptide
ceptors, 495 analgesic, 391,392 aggregation, 758
antidepressant, 485,486,488 R-121919,578 Riluzole
discovery, 509-510 RB101,441,442,443 for ALS, 674
dose for anxiety, 529 RB120,441-443 NMDA receptor antagonist,
dose for eating disorders, 849 RB38A, 441,442 695
for eating disorders, 857 Reboxetine, 496 for Parkinson's disease, 733,
inhibition of serotonin, norepi- affinities for monoamine re- 734
nephrine, and dopamine ceptors, 495 Rimonabant, 883-885
transporters, 500 antidepressant, 485,486,488 Ripazepam, 554
pharmacokinetic parameters, inhibition of serotonin, norepi- Risperdal, 601
497 nephrine, and dopamine Risperidone, 646-647,648
side effects profile, 493 transporters, 500 dose, 601
Pseudoaddiction pharmacokinetic parameters, pharmacokinetics, biotrans-
narcotic analgesics, 336 497 formation, and drug interac-
Pseudocholinesterase, 40 Recombinant human growth tions, 639
Pseudococaine, 189-190 hormone Ritalin, See Methylphenidate
Pseudoephedrine for wasting diseases, 854,858 Ritanserin, 57570-571
adrenergic, 2 , 3 Regitine, 4 Ritodrine
applications, 10, 11 Reglan P-agonist, 4
structure-activity relationship, dose for eating disorders, 852 applications, 14
30 Remacemide structure-activity relationship,
Pseudotolerance anticonvulsant, 313, 319 30
narcotic analgesics, 336 Remeron, 485 Rivastigmine
Pseudotropine, 121,149-150 Remestan, 207 for Alzheimer's disease, 762
Index

Rivastigmine (Continued) Sarin, 91,92 Selegiline


for cognition enhancement, Saripidem, 562 for Alzheimer's disease,
781,782 Sarizotan 758-759,768
RJR-2403 for Parkinson's disease, 733, for Parkinson's disease, 729,
for Alzheimer's disease, 764 734 730-731
cognition enhancer, 799-800 Satiety signals, 873 Senile placques, 744
Ro-11-3245, 553-554 SB-202026 Serax, 529 f
Ro-60-0175, 886 for Alzheimer's disease, 763 Serentil, 601
Ro-64-6198 SB-204269 Serevent, 4
opioid analgesic, 447,449 anticonvulsant, 316-318 Seroquel, 601
Robinul, 137 SB-206848,368,369 Serostim, 854
Rofecoxib SB-242084,571 Serotonergic agents, 486
for Alzheimer's disease, 767 SB-277011,643 5-HT,, receptor, 503405
Rohypnol, 207,550 SB-334867-4 887-888 5-HT, receptor, 503
Rolcapone SB-205588B, 368,369 mixed function ligands,
for Parkinson's disease, 730, SCH 57790 505-506
731 for Alzheimer's disease, 763 receptor populations, 502-503
Rolipram, 508 SCH 72788 Serotonergic regulation of food
Ropinirole for Alzheimer's disease, 763 intake, 873-874
for Parkinson's disease, 722, Schizophrenia, 600-602. See Serotonin
725-726 also Antipsychotic agents and anxiety, 541-543,
Roxindole, 650 and dopamine, 602-603 578-579
RP60180 and glutamate, 603-604 and body weight, 855
analgesic, 392 and serotonin, 603 inhibition by depressants, 500
RTI 15,190 Scopolamine role in CNS stimulant action,
RTI 55 mydriatic and cycloplegic ac- 182-183
Parkinson's disease diagnostic tivity, 153 and schizophrenia, 603
radioligand, 735 relative anticholinergic activ- Serotonin agonists
RTI 5989-29,378 ity, 156 for Parkinson's disease, 734
RU-35926 in solanaceous alkaloids, Serotonin 5-HT,, receptor, 502,
for Alzheimer's disease, 763 120-126 503-505
RU-51599 stereoisomerism, 147-149 Serotonin 5-HT,, receptor, 502
analgesic, 389,391 therapeutic use, 117 Serotonin 5-HT,, receptor, 502
Rubreserine Secobarbital, 204 Serotonin 5-HT,, receptor, 502
anticholinesterase, 88 Second, 204 Serotonin 5-HT, receptor, 502
Rufinamide a-Secretase, 752 and anxiety, 542
anticonvulsant, 313-314,319 p-Secretase, 753 Serotonin 5-HT2receptor, 502,
Ruptured berry aneurysm, 676 cu-Secretase shift, 761 503
RWJ-37868,297 Sectral, 5 and anxiety, 542
RWJ-38293,562 Sedative-hypnotics, 202-203 Serotonin 5-HT, receptor, 502
RWJ-51204,580 ADME, 211-223 and anxiety, 542
RWJ-51304,563 classification, 202 Serotonin 5-HT, receptor, 502
I currently used drugs, 203 Serotonin 5-HT, receptor, 502
S-18986-1 evaluation, 228 Serotonin 5-HT, receptor, 502
for Alzheimer's disease, 764 future developments, 255-256 Serotonin 5-HT, receptor, 502
Sabcomeline history, 235-237 Serotonin receptors
for Alzheimer's disease, 763 miscellaneous compounds, and anxiety, 541-543
Salbutamol 214-215 and cognition enhancement,
applications, 14 pharmacology, 228-235 811-817
Salivation, 110 physiology of sleep, 223-228 types of, 502
Salmeterol recent developments, 251-255 Serotonin-selective reuptake
P-agonist, 4 side effects and drug interac- inhibitors, 484,485-486
applications, 14 tions, 203-211 additional indications, 490
structure-activity relationship, structure-activity relation- for anxiety disorders, 531-532
29 ships, 237-251 for eating disorders, 849-850,
Sandoptal, 205 Seizures, 264-265,291-292,298 857-858,859
Sanorex, 845 from antipsychotics, 608 efficacy relative placebo, 489
I
i
I
f
Index
I
I norepinephrine-selective con- SKF 81297 Stereoisomers
I
1
trasted, 501
pharmacokinetics, 496-497
for Parkinson's disease, 727,
728
and anticholinergic activity,
147-150
1 side effects, 493-494 SKI? 82958 Steroid hormones
! for Parkinson's disease, 727, for Alzheimer's disease, 767
j structure-activity relationship,
1 511-512,513-515 728 for neurodegenerative condi-
Serotonin syndrome, 494 Skopalate, 117 tions, 675 r
Serotonin transporter, 488,498 Skopyl, 117 Stilnox, 211
inhibition by antidepressants, SL-65,1498,580 Stimulants, 168. See also CNS
500 Sleep, 202,223-228. See also stimulants
Serotonin transporter (SERT) Sedative-hypnotics Stiripentol
gene, 490 and neurotransmitters, 225, anticonvulsant, 314
Seroxat, 485 227-228 Stroke, 675-676. See also Neu-
Sertindole, 548,647 REM, 225 rodegenerative conditions
Sertraline, 530 states of, 224 and cellular energetics,
affinities for monoamine re- Sleep cycle, 225 679-680
ceptors, 495 Sleep studies, 224 DNA damage caused by, 677
antidepressant, 485,486,488 SM-9018,647 Sublimaze, 334
dose for anxiety, 529 SMS-201,995,437 Substance P, 517
dose for eating disorders, 849 SNC 80,395-399 Substance P-NK1 receptor an-
for eating disorders, 857 Social anxiety disorder, 526-527 tagonists, 517
inhibition of serotonin, norepi- Social phobia, 526-527 Succinimide anticonvulsants,
nephrine, and dopamine Solanaceous alkaloids, 120-124 271
transporters, 500 semisynthetic derivatives, ADME, 282
pharmacokinetic parameters, 124-126 Sufenta, 334
497 Soman, 91,92 Sufentanil, 383
side effects profile, 493 Somatostatin cytochrome P,,, isozyme sub-
Serzone, 485 mu-receptor opioid antago- strate, 339
SGB-017 nists derived from, 437-438 dose, 334
anticonvulsant, 306 Sombem, 209 Sulfamate anticonvulsants
SIB-1553A Sombulex, 204 ADME, 291
cognition enhancer, 805-806 Sonata, 211 Sulfoarecoline, 69
Sibutramine Sulfonamide anticonvulsants
Sonepiprazole, 40
absorption and metabolism, ADME, 286
Soretolide
860-861 Sunepitron, 569,581
anorectic agent, 855-856, 875 anticonvulsant, 315
Suriclone, 558-559
discovery, 874-875 SoRI 9409,369
Surital, 204
dose, 844 Sotalol Surmontil, 485
SIB-1508Y P-antagonist, 5 Sweating, 110
cognition enhancer, 799 applications, 16 sx-3933
Signal transducer and transcrip- Spacolin, 158 binding affinity with GABAA/
tion factor 3 (STAT-3),885 Sparine, 601 Bz, 795
Sila-difenidol anticholinergics, Spasms, 111,116-118 Sycotol, 136
132 Specific phobias, 527 Symmetrel
Simvastatin Speda, 205 for Parkinson's disease,
for Alzheimer's disease, 757 Spiradoline 733-734
Sinequan, 485 analgesic, 389 Sympathetic nerves nerves, 27
Single photon emission com- Spirodioxolane, 60 Sympathomimetic chemicals, 27
puted tomography (SPECT) Stadol, 335 Synalgos-DC, 335
for Parkinson's disease diag- Starbucks, 170 Syntropan, 134
nosis, 734-735 Statins a-Synuclein, 715-716
SKF 10,047,375 for Alzheimer's disease,
ligand to characterize delta 756-758 Tabun, 91,92
receptor, 342 Stay Alert, 170 Tacrine
SKF 38393,182 Stay Awake, 170 for Alzheimer's disease,
for Parkinson's disease, 727 Stelazine, 601 761-762
Index

Tacrine (Continued) 1,2,3,4-Tetrahydro-9-aminoacri- Thyroid hormone, as anti-obe-


for cognition enhancement, dine sity agent, 843
781,782 reversible noncovalent acetyl- dose, 847
reversible noncovalent anti- cholinesterase inhibitors Tiagabine
cholinesterases related to, related to, 86-88 ADME,286
86-88 Tetrahydrobiopterin anticonvulsant, 265,268,269,
Talambrol, 209 nitric oxide synthase binding 295-296,298 T
Talampanel site, 698 clinical efficacy, 273
anticonvulsant, 307 Tetrahydrozoline development, 303
Talbutal, 204 a,-agonist, 3 dose, 270
Talipexole, 650 applications, 13 pediatric indications, 274
Talsaclidine structure-activity relationship, side effects, 279
for Alzheimer's disease, 763 31 Tiaspirone, 647
Talwin, 335 Tetrazepam, 550 Tifluadom
Thebaine, 361,371 analgesic, 387
Tamsulosin, 33
Theobromine Timolol
applications, 16
CNS stimulant, 169 0-antagonist, 5
metabolism, 17-18 PARP inhibitor, 681 applications, 16
selective a,-antagonist, 4 Theophylline Timoptic, 5
structure-activity relationship, CNS stimulant, 169,174 TIPP (Tyr-Tic-Phe-Phe),
28,31 PARP inhibitor, 681 425-428
TAN 67 Thermogenesis, 857 a-Tocopherol
analgesic, 399-400 Thermogenic agents, 843, inhibitor of amyloid 0-peptide
Tandospirone, 531,566 846-847 aggregation, 758
Tankyrase, 679 clinical applications, 857 Tofranil, 485
Tardive dyskinesia Thiamylal, 204 dose for eating disorders, 850
for antipsychotic agents, 607 Thiocitrulline Tolazoline
Tasmar nitric oxide synthase inhibi- a-antagonist, 4
for Parkinson's disease, 730, tor, 698-699 applications, 15
731 Thiopental, 204 structure-activity relationship,
Tau protein Thioridazine 31
and Alzheimer's disease, 748 dose, 601 Tolerance
TC-2559 receptor binding and side ef- narcotic analgesics, 336
for Alzheimer's disease, 764 fects, 606 Topimax, 882,885
Telenzepine Thiorphan Topiramate
anticholinergic, 129
opioid peptide metabolism in- ADME,291
hibitor, 442 anticonvulsant, 265,268,269,
Temazepam, 207
Thiothixene 295,298
Tenex, 3 dose, 601 anti-obesity agent, 882,885
Tenormin, 5 pharmacokinetics, biotrans- clinical efficacy, 273
Tenuate, 171,185 formation, and drug interac- development, 303-304
Tenuate propion, 845 tions, 635 dose, 270
Terazosin receptor binding and side ef- pediatric indications, 274
applications, 15-16 fects, 606 side effects, 279
metabolism, 19 Thiouracil antithyroid agents Toprol-XL, 5
selective a,-antagonist, 4 nitric oxide synthase inhibi- Tornalate, 4
structure-activity relationship, tors, 705 Tral, 139
31 Thioxanthene antipsychotics Tramadol, 408
Terbutaline pharmacokinetics, biotrans- Tranquilosedatives, 600
P-agonist, 4 formation, and drug interac- Tranxene, 207,529
applications, 14 tions, 635 Tranylcypromine
Terguride, 649 Thiphenamil antidepressant, 485,486,488
Testosterone anticholinergic, 138 for Parkinson's disease, 729,
for Alzheimer's disease, 766 Thiry-Vella fistules, 116-117 730
and a-secretase shift, 761 Thorazine, 601 pharmacokinetic parameters,
Tetraethyl pyrophosphate Thymidine 497
(TEPP),92 PARP inhibitor, 681 side effects profile, 493
Trasentine, 134 Trihexethyl UH232,650
influence of cyclic radicals on relative anticholinergic activ- Ultiva, 334
anticholinergic activity, 143 ity, 157 Unisom, 214
Traumatic head injury Trihexyphenidyl
and Alzheimer's disease, for Parkinson's disease, 731, Valethamate
748-749 732 anticholinergic, 138
7
Trazodone, 494-496 Trilafon, 601 relative anticholinergic activ-
affinities for monoamine re- Trimethadione ity, 156
ceptors, 495 ADME, 284 Valium, 529. See also Diazepam
-
antidepressant, 485,486,489 anticonvulsant, 265, 267, 268, discovery, 547
inhibition of serotonin, norepi- 297,298 Valnoctamide, 214,215
nephrine, and dopamine dose, 270 Valpin, 117
transporters, 500 side effects, 278 Valproic acid
pharmacokinetic parameters, Trimipramine ADME, 275,282
affkities for monoamine re- anticonvulsant, 265, 266, 267,
497
ceptors, 495 298
side effects profile, 493
antidepressant, 485,486,487 clinical efficacy, 273
Tremorine, 71 inhibition of serotonin, norepi- side effects, 277
Trest nephrine, and dopamine structure-activity relationship,
anticholinergic, 128, 135 transporters, 500 310-311
Triazine anticonvulsants pharmacokinetic parameters, Valrocemide
ADME, 284-285 497 anticonvulsant, 310-311
Triazolam, 207 side effects profile, 493 Vanlafaxine
Triclofos, 208, 209 Triphenarnil antidepressant, 485,486,488
Triclos, 209 relative anticholinergic activ- Vascular dementia, 780
Tricoloid, 139 ity, 157 Vasoconstrictors
Tricyclamol Triptramine adrenergics, 2
anticholinergic, 139 anticholinergic, 131 Vasodilan, 5
relative anticholinergic activ- TRK-820 Vasoxyl, 3
ity, 157 opioid analgesic, 363, 387,447 Vedaclidine
stereoisomerism, 149 Trocinate, 138 cholinergic, 78
Tricyclic antidepressants, Tropicamide Venlafaxine, 494,531,875
484-485,486 anticholinergic, 138 affinities for monoamine re-
for anxiety disorders, 528 mydriatic and cycloplegic ac- ceptors, 495
tivity, 153 dose for anxiety, 529
for eating disorders, 850-851,
Tropine, 149-150 inhibition of serotonin, norepi-
858,859
in solanaceous alkaloids, nephrine, and dopamine
efficacy relative placebo, 489
120-126 transporters, 500
with opioid analgesics, 333 Tropine-modified atropines, 123 pharmacokinetic parameters,
pharmacokinetics, 496 Tropisetron 497
side effects, 492-493 cognition enhancer, 816 side effects profile, 493
structure-activity relationship, Tryptophan Ventolin, 4
510-512 niacin synthesis from, Vesamicol
Tricyclic antipsychotics 688- 689 cholinergic, 40
discovery of, 618 T-type calcium channels Vesicular monoamine transport-
structure-activity relation- and anticonvulsants, 297 ers, 499
ships, 619-625 TV 1901 Vespoerone, 205
Tricyclic benzodiazepine anti- anticonvulsant, 310 Vesptin, 601
cholinergics, 128-129 VH-AH-37
Tridihexethyl U50,488 anticholinergic, 129
anticholinergic, 139 analgesic, 387-392,406 Vicodin, 335
Trifluoperazine U69,066 Vicoprofen, 335
dose, 601 analgesic, 389 Vigabatrin
receptor binding and side ef- U69,593 ADME, 284
fects, 606 analgesic, 389, 390, 406 anticonvulsant, 265, 268, 295,
Triflupromazine U594494A 298
dose, 601 anticonvulsant, 315-316 clinical efficacy, 273
Vigabatrin (Continued) Welldorm, 209 pharmacokinetics, biotrans-
development, 299-300 WIN 35,065-2 formation, and drug interac-
dose, 270 CNS stimulant, 191 tions, 639
side effects, 278 WIN 44,441,375 receptor binding and side ef-
Vinbarbital, 205 Wine-and-cheese syndrome, 491, fects, 606
Vinylbital, 205 532 Zispin, 485
Vio-Thene, 136 Wyamine, 3 ZK 93423,557 T
Visken, 5 Wygesic, 335 binding affinity with
Vitamin B,, 687 Wytensin, 3 GABAA/Bzreceptor, 788
Vitamin B, family
ZK 93426
for Parkinson's disease, 724
Xanax, 529 cognition enhancer, 794-795
Vitamin E family
dose for eating disorders, 852 Zofran, 815
for Alzheimer's disease, 674,
Xanomeline Zolazepam, 554
768
Vitamin K, for Alzheimer's disease, 763 Zoloft, 485,529
NAD glycohydrolase inhibitor, Xenical, 844 dose for eating disorders, 849
687 Xopenex, 4 Zolpidem, 210,211,561-562
Vitamin K, Xylometazoline ADME, 221-223
NAD glycohydrolase inhibitor, a,-agonist, 3 binding affinity with GABAA/
687 applications, 13 Bz, 795
Vivactil, 485 structure-activity relationship, discovery, 236237
Vivarin, 170 31 Zonisamide
V-PARP, 679 ADME, 286
Y7131,554 anticonvulsant, 265,268,269,
WAL 2014 Yohimbine 297,298,319
for Alzheimer's disease, 763 and neuropeptide Y, 545 clinical efficacy, 273
Wasting disease drugs, 843,854 Yutopar, 4 development, 303
absorption and metabolism, dose, 270
866-867 Zacopride pediatric indications, 274
clinical applications, 858 cognition enhancer, 816 side effects, 279
Wasting diseases, 838,840 Zaleplon, 210,211 Zopiclone, 210, 211, 558-559
guidelines for treatment, ADME, 223 binding afiinity with GABAA/
842-843 Zantryl, 171 Bz, 795
WAY-100135,570 Zebeta, 5 Zopliclone
Wellbutrin, 485. See also Bupro- Ziprasidone, 648 ADME, 221
pion dose, 601 Zotepine, 648- 649
anorectic agent, 883,885 for Parkinson's disease, 725 Zyprexa, 601
Cumulative Index
P
Terms that begin with numbers A-308165 biguanides, 421-23
are indexed as if the number were endothelin receptor antago- as bottleneck in drug discov-
spelled out; e.g., "3D models" is nist, 3:206 ery, 1:592 -
located as if it were spelled A-787733,4214 estimation systems,
"ThreeD models." Aablaquine, 5:934 1:389-390
Abacavir a-glucosidase inhibitors,
50-125 anti-HIV drug, 5:471,5:472 431-33
endothelin receptor antago- selective toxicity, 5:267 insulin and analogs, 45- 8
nist, 3206 Abbott 53385,394 insulinotropic agents, 415-17
Abbreviated New Drug Applica- molecular modeling,
A-23187,4:214 tion, 2:742 1:154-155
A-63162,4:213 Abciximab, 329,3:318 opioid analgesics, 6:339-341
A-64077,4:213 ADME, 3997 prodrugs, 2:501
A-68930 clinical trials, 3:293,3:294 receptor targeting drugs,
for Parkinson's disease, 6:727, formula weight, mechanism of 2:320,2:342-343
6:728 action, and route of admin- sedative-hypnotics, 6:211-233
A-77003 istration, 3:287 thiazolidinediones, 4 2 4
structure-based design, for thrombolytic therapy, transport proteins, 2266
1:437-438 3167 Absorption, distribution, metab-
A-77636 treatment regimen, 3:298 olism, excretion, and toxic-
for Parkinson's disease, 6:727, ABELCET, 5:890,5:892 ity (ADMET), 1:389
6:728 Abercarnil, 6:558 and druglikeness screening,
A-79175,4:214 binding affinity with GABAA/ 1:245
A-79176,4214 Bz, a788 transport proteins, 2266
A-80987 Absidia, Ex883 and virtual screening filter
structure-based design, 1:438, Absolv program, 1:389 cascade, 1:267
1:439 Absorption
ABT-080,4219
A-84543 of radiation energy, 5153
ABT-089
cognition enhancer, Absorption, distribution, and
6:802-803 elimination, 2:633-634 cognition enhancer, a805
A-85380 pharmacokinetic applications ABT-418, 1:808-810
cognition enhancer, 6:802, in development process, cognition enhancer,
6:804 2:645-647 6:799-800
A-86929 pharmacokinetic parameters ABT-431
for Parkinson's disease, 6:727, in drug disposition, for Parkinson's disease, 6:727,
6:728 2:635-641 6:728
A-87380 pharmacokinetic parameters ABT-594
for influenza, 5:376 in therapeutics, 2:641-645 cholinergic, 6:53
A-127722 polymorphism in, 2472 cognition enhancer,
endothelin receptor antago- Absorption, distribution, metab- 6:804-805
nist, 3206 olism, and excretion ABT-627, 1:811-812
A-192558 (ADME),2:31 ABT-675
for influenza, 5:376 adrenergics and adrenergic- for influenza, 5376-377
A-192621 blocking agents, 6:16-21 ABT-761,4214-215
endothelin receptor antago- anticoagulants, antithrombot- ABT-773, It876
nist, 3206 ics, and hemostatics, structure, 2:194
A-216546 3995-298 ABT-963,4240
endothelin receptor antago- anticonvulsants, 6:273-291 Abyssinian tea, 6:168
nist, 3906, 3207 antihyperlipidemic agents, AC-3056,3:373
A-306552, 1:675 3:355-358 AC-4437,2:176
923
Cumulative Index

Acacia transition state analogs, snail ACh-binding protein,


for precipitation inhibition, 1:650-651 2:362-364
2:669 Acenocoumarol, 2:310,3:311 substitution of ester group by -
Academic databases, 1:387388 Acetaminophen, 6:331 other groups, 6:47-49
Acarbose, 1:849,2:205,2:212, first tier of cancer pain treat- variations of acyl group,
431,4:32, 4:33, 4 3 4 3 6 , ment, 6:332-333 6:45-46
436 hepatic toxicity, 2:615-616 variations of ethylene bridge,
Accelerated Approval, in New Acetaminophen (APAP) with 6:46-47
Drug Approval, 2:700 codeine, 6:335 variations of quaternary am-
Accelerated development/review, Acetaminophen (APAP) with monium group, 6:43-45 -
FDA, 2:687,2:696-697 hydrocodone, 6:335 Acetylcholine-atropine antago-
ACCELERATOR RTS, 2:49 Acetaminophen (APAP) with nism, 6:152-153
Accelrys databases, 1:384-385 Acetylcholine receptors,
oxycodone, 6:335
6:41-43. See also Musca-
Accolate, 4225-226 Acetaminophen (APAP) with
rinic acetylcholine recep-
Accord, 1:377, 1:385 propoxyphene, 6:335 tors; Nicotinic acetylcholine
Accord Database Explorer, 1:385 Acetazolamide, 3:64, 3:66,3:70 receptors
ACC-9358 soft analogs, discovery of, 3:69 Acetylcholinesterase, 2:375,
2:562-563 Acetic acid 2:538,6:40
Accutane, 4:320,4373 CML representation, 1:372 catalytic site, 6:84-85
Acebutolol, 3:28,3:32 Acetohexamide, 4 1 2 , 4 1 6 Acetylcholinesterase inhibitors,
fl-antagonist,6:5 Acetorphan 1:718, 6:40
applications, 6:16 opioid peptide metabolism in- for Alzheimer's disease,
cardiovascular effects, 3:39, hibitor, 6:442 6:761-762,6:781
340 Acetrizoate, 4497 carbarnate-derived cholin-
renal clearance, 1:38 angiography application, ergics, 6:88-90
uses and side effects, 3 3 8 4569 for cognition enhancement,
Aceclidine histamine release, 4:558 6:781
cholinergic, 6:65, 6:78-79 neurotoxicity, 4555 CoMFA study, 1:58-59
Acedapsone, 5:830 particulate, 4:576 miscellaneous cholinergics,
ACE inhibitors, 1:718, 1:881, pharmacokinetics, 4561 6:93-97
3198 properties, 4504 for neurodegenerative condi-
with aldactone (spironolac- protein binding, 4556,4557 tions, 6:675
tone), 3:111-112 urography application, 4:571 phosphorus-derived cholin-
as antagonists, 5:251-252 Acetylation ergics, 6:90-93
asymmetric synthesis, 1:807, role in metabolism, 2:456-459 pseudoirreversible, 1:772-774
1:809 Acetyl-L-carnitine reversible noncovalent cholin-
combinatorial library of capto- for Alzheimer's disease, 6:768 ergics related to tacrine,
pril analogs, 2:18,2:20 Acetylcholine, 1:772, 2:391, &86-88
comparative molecular field 6:110. See also Anticholin- reversible quaternary ammo-
analysis, 1:151-153 ergics; Cholinergics; Musca- nium cholinergics, 6:84-86
conformationally restricted rinic acetylcholine recep- substrates from acetylcholine
peptidomimetics, 1:640-641 tors; Nicotinic acetylcholine analogs, 1:697-698
effect on endothelin, 3:207 receptors target of structure-based drug
molecular modeling, 1:131, cation-Tbonding, 1:724-725 design, 1:449-450
1:132-133, 1:145 cholinergics based on, 6:43-49 volume mapping, 1:140
multisubstrate analogs, conformationally restricted X-ray crystallographic studies,
1:746-748 analogs, 1:697-698 1:482
for prevention of ventricular and constrictor muscle fibers, Acetyl CoA carboxylase
remodeling, 3: 180-181 a114 biotin dependent, 4404
prodrug approach, 2:508, dissociation constant, 6:151 Acetylcoenzyme A, 6:40
2:511 gating of anion-selective chan- N-Acetylcysteine
receptor-relevant subspace, nels, 2:360 toxicological profile prediction,
1:204 muscarinic agonist analogs, 1:838, 1:840
soft analogs, 2:565 1:143-144 Acetylsalicylic acid, 1:762-763.
structure-based design, role in nerve transmission, See also Aspirin
1:432-433 6:40 prodrugs, 2:505,2:510
Cumulative Index

N-Acetyltransferase-2 Active transport, 2:257-265 Adenine, 4619


single nucleotide polymor- in kidneys, 3:57-60 Adeno-associated viruses, 5:304
phism~,4630 Activity vectors for cancer gene ther-
Achromycin, 5:740,5:935 binding affinity contrasted, apy, k42
Acid-base ionization properties, 1:131-135 Adenoma-carcinoma, 5:4
2:660-662 Activity-guided fractionation, 1:597 Adenosine, 3:32
Acids Activity similarity, 1:255 P
cardiovascular effects, 3:44
topical antibacterials, 5:551 Actonel multiple inhibitory mecha-
Acitretin, 4320,4373374 selective toxicity, 5:273 nisms, 3:33
Acker's Symmetry rule, 3:386 Actos, 4 2 5 Adenosine antagonists
.

Aclomethasone dipropionate, Acute coronary syndrome for Parkinson's disease,


3:750,3:753 single gene pharmacogenetic 6:733
Acne studies in genes influencing
xanthines, 3:121-122
retinoids used for, 4:372-373 progression, 4638- 639
Adenosine deaminase inhibitors,
Acquire database, 1:386 Acyclic analgesics, a 3 3 4
structure-activity relationship, 1:717
ACTH, See Adrenocorticotropic
hormone (ACTH) 6:385-387 mass-spectrometricscreening
Actinetobacter baumannii Acyclovir, 1:717, 1:719, 1:756 for ligands to, 1:604
penicillin-binding protein, classification in various coun- transition-state analogs,
5:614,5:616 tries, 4:430 1:750-752
Actinocin for hepatitis B virus, 5:331 X-ray crystallographic studies,
antitumor natural product, 5:111 for herpes virus, 5:305-326 1:482
Actinomycin C prodrug, 2:508,2:511, S-Adenosyl-L-homocysteine,
antitumor natural product, 5111 2:515-516 1:733, 1:740
Actinomycin D selective toxicity, 5:254, 5:267 S-Adenosyl-L-homocysteine hy-
antitumor natural product, 5:111 Acylation drolase inhibitors,
PLD repair inhibitor, 5:192 role in metabolism, 2:456-459 5432-434
reaction with nucleosides, Acyl-CoA cholesterol AcylTrans- S-Adenosyl-L-methionine, 1:733
2:616 ferase (ACAT) inhibitors, Adenoviruses, 5:303-304
thermodynamics of binding to 3:370 antiviral agents, $340
DNA, 1:183 Acyl halides dendritic cell transdudion by,
Actinomycins filtering from virtual screens, 5:242
antitumor natural product, 1:246 vectors for cancer gene ther-
5:111-115 Acylides, 5:781-782 apy, 5:41-42
Actinoplanes utahensis, 1:878 Adair equation, 2:299 Adenylyl cyclase, 3:158
Action potential duration test- ADAM (program) ADEPT (antibody-directed en-
ing, 2:627 geometric/combinatorial zyme-prodrug therapy),
Actiq, a334 search, 1:295 5:83,5:87-90
Activated partial thromboplastin ADAMs (membrane proteins), ADEPT suite, 1:225, 1:226,
time, 3:291 1:652 1:237
Activated protein C, 2:301 Adapalene, 4:320,4:373 Adequate Intake, 4368
Activator protein-l,5:25 Adaprolol, 2:540-541 biotin, 4:405
Active Analog Approach, 1:58, ADAPT, 1:53 folic acid, 4:411
1:60, 1:639 Adaptive immunity, 5:224-226 niacin, 4397
flow of information in, 1:146 Adaptive toxicological responses, pantothenic acid, 4402
and molecular modeling, 2:617-618 vitamin A, 4371
k134,1:151 to W radiation, 4464-465 vitamin B,, 4389
and systematic search, Adatanserin, 6:572 vitamin B,, 4392
1:144-145 Adderall, 6:3, 6:170 vitamin B,, 4400
Active moiety, prodrugs, 2:500, Addiction vitamin C, 4418
2:502-503 narcotic analgesics, 6:336 vitamin D, 4379
Active pharmaceutical ingredi- Addison's disease, 3:594, a 7 4 8 vitamin E, 4384
ents, 2:408. See also Drug Adefovir vitamin K, 4387
synthesis anti-HIV drug, 5:471,5:472 Adhesins, 2:262-263
solid-state properties, 2:414 for hepatitis B virus, Adinazolam, 6:552
Active-site directed, irreversible 5332-333,5:334,5:335 Adipex, 6:844
inhibitors, 1:755 for papillomavirus, 5:339 Adipex-P, 6:171
Cumulative Index

Adiphenine Adrenergic-blocking agents, 6:2, a,-Adrenergic receptor antago-


anticholinergic, e l 3 4 6:4 nists, 6:2
influence of cyclic radicals on ADME, 6:16-21 selective, 6:4
anticholinergic activity, applications, 6:14-15 p-Adrenergic receptor antago-
6:143 applications of agoniststantag- nists, See /3-Blockers
local anesthetic activity, 6:154 onists, 6:16 Adrenergic receptors, 6:2
relative anticholinergic activ- applications of 0-antago- effector mechanisms, 6:25 T
ity, 6:156 nists, 6:16 selected tissue response to,
Adipose tissue, 6:873 applications of p-antagonists, 6:23
Adipost, 6:171 6:16 subtype characterization,
ADME studies, See Absorption, applications of nonselective 6:25-26
distribution, metabolism, a-antagonists, 6:15 a-Adrenergic receptors, 6:2
applications of selective a,,-
and excretion (ADME) activation after myocardial
antagonists, 6:33-34
ADMET studies, See Absorption, infarction, 3:158
applications of selective a,-
distribution, metabolism, and depression, 6:506-507
antagonists, 6:15-16
excretion, and toxicity current drugs, 6:3-9 effector mechanisms, 6:25
(ADMET) history, 6:26-28 gene expression profiling
Adornments (in combinatorial physiological significance, study, 4:612
libraries), 2:14-15 6:21-22 selected tissue response to,
Adozelesin recent developments, a 3 3 3 5 6:23
alkylating agent, k54, structure-activity relation- a,,-Adrenergic receptors, 6:2
k61-64 ships, 6:28-33 characterization, 6:26
ADP analogs, 1:763-764 Adrenergic nerves, 6:27 a,,-Adrenergic receptors, 6:2
Adrenaline, 1:885, 1:886, 6:2 Adrenergic receptor agonisttan- characterization, 6:26
applications, 6:9-10 tagonists, 6:5 a,,-Adrenergic receptors, 6:2
general adrenergic agonist, applications, 6:16 a%-Adrenergic receptors, 6:2
6:3 a,-Adrenergic receptor agonists, a,,-Adrenergic receptors, 6:2
history, 6:26-27 6:2,6:3 aZc-Adrenergicreceptors, 6:2
metabolism, 6:16-17 applications of, 6:12-13 a,-Adrenergic receptors, 6:2
role in clotting, 3:304 a,-Adrenergic receptor agonists, effector mechanism, 6:25
role in insulin regulation, 4:2 6:2,6:3 selected tissue response to,
synthesis, 6:23-25 applications, 6:13-14 6:23
Adrenal steroidogenesis, p-Adrenergic receptor agonists, subtype characterization,
3:llZ-113, a615 6:2,6:4 6:25-26
Adrenal steroids applications, 6:14 a,-Adrenergic receptors, 6:2
biosynthesis, 3:612-616 P,-Adrenergic receptor agonists, effector mechanism, 6:25
Adrenergic agonists, 6:2,6:3 6:2 selected tissue response to,
ADME, 6:16-21 applications of selective, 6:23
applications of a,-agonists, 6:34-35 subtype characterization,
&12-13 for eating disorders, 6:886 6:25-26
applications of a,-agonists, a-Adrenergic receptor antago- p-Adrenergic receptors, 6:2
6:13-14 nists effector mechanisms, 6:25
applications of p-agonists, applications of alp-antago- selected tissue response to,
6:14 nists, 6:16 6:23
applications of agonistslantag- applicationsof nonselective, e l 5 PI-Adrenergicreceptors, 6:2
onists, 6:16 a@-Adrenergic receptor antago- characterization, 6:26
applications of general, 6:9-12 nists, 6:5 selected tissue response to,
applications of selective p,- applications of, 6:16 6:23
agonists, 6:34-35 a,,-Adrenergic receptor antago- single nucleotide polymor-
current drugs, 6:3-9 nists phism~,4635-636
history, 6:26-28 applications of selective, p,-Adrenergic receptors, 6:2
physiological significance, 6:3334 activation after myocardial
6:21-22 a,-Adrenergic receptor antago- infarction, 3158
recent developments, 6:33-35 nists characterization, 6:26
structure-activity relation- applications of selective, recombinant DNA studies,
ships, 6:28-33 6:15-16 2:102
Cumulative Index

selected tissue response to, Affinity chromatography-mass Aggregated band 3


6:23 spectrometry, 1:598-599 interaction with sickled cells,
single nucleotide polymor- Affinity grids, 1:292-293 3:458
phism~,4636 Affinity labels, 1:756-764 Aggrenox, 3:287
p,-Adrenergic receptors, 6:2 Affinity NMR, 1:571 AGI-1067,3:373
characterization, 6:26 Affirmative defenses, in patent Agitation
selected tissue response to, infringement cases, 2:748 in large-scale synthesis, P
6:23 African homozygous sickle-cell 2:415-416
p,-Adrenergic receptors, 6:2 disease, 3456 Agonists, 5:250-251
Adrenergic regulation of food African trypanosomiasis (Afri- Agouti Gene-related peptide, -
intake, 6:873-874 can sleeping sickness) 6:870
Adrenocorticoids, 3:598 antiprotozoal agents for, L-Agrobactin, 3:483,3:485,
synthesis, 3612-616
51035-1045 3:490
Adrenocorticotropic hormone
Aftate, 5891 pM values, 3:484
(ACTH),3612-613
Afterdepolarizations, 3159-160 synthesis, 3:522
ulcers from, 6:118
Adrenomedullin, 3:218,3:219, Afterload, 3:9 AHC-52
3:220 2-AG, 1:853 cardioprotective drug, 3:47
therapeutic potential, 3221 AG31 AHC-93
Adrenomedullin receptor, structure-based design, cardioprotective drug, 3 4 7
3:220-221 1:428-429 AIDS,5458-459,5712. See
Adrenoreceptors, See Adrenergic AG85 also Anti-HIV drugs; HIV
receptors structure-based design, 1:428 protease inhibitors; H N
Adriamycin AG331 virus
antitumor natural product, structure-based design, associated fungal infections,
5128 1~428-429 5:884
prodrugs, 2:505 AG337 and malaria, 5:930
Adrucil structure-based design, 1:428 and tuberculosis, 5823,5824
antimetabolite, 5 7 6 AG2034 AIDS database, 1:386
Adulteration of Various Sub- structure-based design, AIMB, 1:255
stances Used in Medicine 1:431-432 AK-2123
and the Arts (Beck), 2:684 AG2037 radiosensitizer, 5179
Adurazyme, 2:218-219 structure-based design, Akineton
Advanced glycation end-prod- 1:431-432 for Parkinson's disease, 6:731,
ucts (AGES),4 4 6:732
AG3340
Advance notice of proposed rule- ALADDIN, 1:259, 1:363
antiangiogenic agent, 5217,
making, 4425 in molecular modeling, 1:111,
Adverse drug events 5218 1:113
defined, 4545-546 AG7088 Alamar Blue, 2:50
reporting, 4473-474 picornavirus antiviral, Alaninates
Adverse drug reactions 5404-405 binding to chymotrypsin, 1:35
defined, 4546 Agalsidase alfa, 2:211,2:212 Alanine racemase inhibitors,
Advicor, 3:343,3:368 Agathisflavone 1:717
Aerobactin, 3:486 influenza antiviral agent, Alanine-scanning mutagenesis,
pM values, 3:484 5389 2:88-89
synthesis, 3524 Age D-Alanyl-D-alanine transpepti-
Aerosol administration and metabolism, 2:474 dase, 5:610
phosphorothioate oligonucleo- Age-associated memory impair- inhibition by p-lactams,
tides, 2:134 ment, a780 5:611-612
AF-DX-116 Agenerase Albendazole
anticholinergic, 6:129 structure-based design, 1:440, antihelmintic, 51090-1091,
Afenta, 6:334 1:441 51091
Afferent, 1:387 Agent, 1:398 Albumin, See Serum albumin
Affinity calculation, 1:118-122 Aggrastat, 3:29,3:287 Albumin-heme, 3421
Affinity capillary electrophore- Aggrecan, 2:238 Albuterol, 6:2
sis-mass spectrometry, Aggregate concept, in molecular P-agonist, 6:4
1:599-600 modeling, 1:90-91 applications, 6:14
Cumulative Index

Albuterol (Continued) Alipamide, 3:82,3:84 targets for drug discovery,


impact of polymorphisms on Aliphatic acid anticonvulsants, 2:313315,2:314
effectiveness, 4636 6:270 theories of, 2:296-301
metabolism, 6:17-18 ADME, 6:275-282 Alloxanthine, 3:141
structure-activity relationship, Alitretinoin, 4320,4374 Allylamine antifungal agents,
6:29 Alkeran 5:890,5:891,5:899-900
Alcaligin, 3:486, 3487 allsylating agent, 5:54 N-Allylmorphine, 1:850
synthesis, 3:527-528 Alkyl amines Allylprodine, 6:376
Alcohol dehydrogenase polarization energy, 1:173 Almond program, 1:202
QSAR studies, 1:5 protonation, 1:179-180 Alnespirone, 6:581
Alcohols Alkylating agents Alogp, 1:390
pharmacophore points, 1:249 Alopecia, 4:433. See also Hair
cyclopropylindoles, 554,
QSAR studies, 1:27-29 growth disorder drugs
5:61-64
topical antibacterials, Alor 51500, a335
mustards, 5:52,5:53-59 Alosetron
5:547-548
nitrosureas, 5:54,5:64-65 cognition enhancer, 6:816
Alcuronium, 1:856, 1:857
platinum complexes, 5:54, removedlrestricted by FDA,
Aldactone, 3:111,3:115,3:117
5:59-61 4642
Aldehydes
filtering from virtual screens, sickle hemoglobin modifiers, Alpha,-acid glycoprotein
1:246 3:461 binding of drugs to, 2:637
residues in pseudopeptide ar- triazenes, 5:54,5:65-67 Alpha-amylase, 1:482
rays, 2:12 Alkyl chain homologation ana- a-Blockers, 3:28
sickle hemoglobin modifiers, logs, 1:699-704 Alphagan, 6:3
3461 Alkyl halides Alpha-L-iduronidase, 2:219,
topical antibacterials, 5:551 filtering from virtual screens, 2:220
Aldenosulfone, 5:830 1:246 N-Alpha-(2-naphthylsulfonylgly-
Aldomet, 6:3 Allantoin, 3:138 cy1)-4-amidinophenylal
Aldose reductase Allantoinase, 3138 [NAPAP] piperidide
in diabetes, 43-4 Allegra structure-based design, 1:442,
Aldose reductase inhibitors selective toxicity, 5:275 1:444
novel lead identification, 1:321 Allegron, 6:485 Alphaprodine, 6:718
target of structure-based drug Allele-specific amplification, Alpidem, 6:561-562
design, 1:447-449 4624 Alprazolam, 6:530
Aldosterone, 1:746 Allinger force field, 1:80 dose for anxiety, 6:529
ACE inhibitor effects on, 3 2 8 Allobarbital, 6:205 dose for eating disorders,
angiotensin I1 effects on, Allococaine, e l 9 1 a852
3197 Allogeneic bone marrow trans- for eating disorders, 6:858
steroidal antagonists, plantaion Alprenolol
3:111-120 for sickle-cell anemia, membrane function disrup-
synthesis, 3:612,3:613-4, 3:465-466 tion, 2:614
3:615 Allomuscarine, 6:57 renal clearance, 1:38
transport mechanism in renal Allopurinol, 3:139,3:141 Alprostadil, 4:299-301,4:442
tubules, 35'7-58, 3:59 Allosteric effectors, 2:296-313 adverse effects, 4443
Aldosterone biosynthesis inhibi- basis as therapeutic agents, development of, 4448
tors 2:312-313 mechanism of action, 4:446
diuretic agents, 3:120-121 of hemoglobin, 3386, pharmacokinetics, 4444
Aldurazyme, 2:219,2:220 3:388 -394 structure-activity relationship,
Alemtuzumab, 5:229,5:231-233 and lock-and-key hypothesis, 4:447
Alendronate 1:5 ALS drugs, a675
selective toxicity, 5:273 Allosteric proteins, 2:295-296 Alteplase, 3:166,3:322
Alert wakefulness, 6:224 allosteric transitions at molec- clot selectivity, 3290
Alfentanil, 2:544,6:383 ular level, 2:305-312 treatment regimen, 3:298
cytochrome P,,, isozyme sub- common features of, Alternative dispute resolution,
strate, 6:339 2:304-305 22750-751
dose, 6:334 hemoglobin as example, Alternative macrophage activa-
Algorithms 1:421-424,2:296, tion-associated CC chemo-
nonpatentability, 2:718 2:301-306 kine (AMAC), 4150
Cumulative Index

Altracurium muscarinic acetylcholine re- AM1 227


lead for drugs, 1:856-858 ceptor agonists and antago- radiopaque material, 4491
Alupent,6:4 nists, 6:762-764 Amides
Alvosulfon, 5:810 nicotinic acetylcholine recep- enzyme-mediated asymmetric .
Alzheimer's disease, 6:674-675, tor agonists and antago- bond formation, 1:804-805
6:744-745 nists, 6:764-765 exchange ratesltemperature
amyloid cascade hypothesis, a-secretase inhibitors, coefficients, in NMR, 1:512 *
6:749-761 6:752-753 pharmacophore points, 1:249
cholinergics for, 6:40 P-secretase inhibitors, Amidines
-
epidemiology, a745 6:753-754 topical antibacterials,
etiology, 6:745-749 a-secretase shift, a761 5:554-555
genetic determinants, statins, 6:756-758 N-Amidino-3-aminopyrazinecar-
6:745-746 AM-1155,5853 boxamides, 3:132
genetic risk factors, 6:746-748 AM1 wave function, 1:15,1:102 N-Amidino-3,5-diamino-6-chlo-
nongenetic risk factors, AM404,1:854 ropyrazine-carboxamide,
6:748-749 Amanozine, 3:123 3:130
role of iron, 3:504-505 Amantadine, R361 Amidotrizoate
single gene pharmacogenetic anti-HIV drug, 5:469 neurotoxicity,4554
studies in genes influencing for Parkinson's disease, Amikacin, 2:183,5:748
progression, 4:638- 639 6:733-734 antimycobacterial application,
susceptibility locus on chro- selective toxicity, 5:266,5267 5:810,5:844
mosome 10,a747 Amaryl, 4:13 efficacy and dosage, 5810
susceptibility locus on chro- Amaryllidaceae (snowdrops, daf- indications, R625
mosome 12,6:747-748 fodils, etc.), 1:892 Amikin, 5748,5810
Alzheimer's disease therapeutics Amastatin, 1:738 Amiloride, 3:124,3130-132,
acetylcholinesterase inhibi- AMBER energy function, 1:264, 3142
tors, 6:761-762,6:781 1:307-308 hydrochlorothiazide-amilo-
AMPA response modulation, performance in structure pre- ride, 378
6:765 diction, 1:315 Amine prodrugs, 2508-509
amyloid P-peptide aggregation seeding experiments, 1:319 Amines
inhibitors, 6:758-760 AMBERIOPLS force field, 1:80, pharmacophore points, 1:249,
amyloid p-peptide catabolism 1:81,1:103 1:250
and removal, 6:760 in molecular modeling, 1:118 Aminidine
Ambien, 6:211,6:561 pharmacophore points, 1:249
amyloid P-peptide disaggrega-
Ambisone, 5890,5893 Amino acid conjugates,
tion accelerators, 6:760
Amcinonide, 3:750,3:752 2:459-461
amyloid P-peptide neurotoxic- AMD2763,4:168 formation, 2459-461
ity modulators, 6:760-761 AMD3100,4168-170 Amino acid fluorides
amyloid precursor protein anti-HIV drug, 5467 use in solid phase organic syn-
gene-knockdown agents, AMD3329,4:168 thesis, 2:15
6:761 Amentoflavone Amino acid mimetics, 1:640
anti-inflammatory agents, influenza antiviral agent, Amino acids
a767 5:389 chemical modification re-
antioxidants, 6:758,6:767-768 American mandrake, drugs de- agents, 1:755
apoptosis inhibitors, rived from, 1:865 chirality, 1:784
6:766-767 American trypanosomiasis (Cha- classical resolution, 1:797
cholinergic transmission at- gas' disease) conglomerate racemates,
tenuation, 6:761-765 antiprotozoal agents for, 1:802-803
compounds affecting fibril for- 5:1045-1047 nitric oxide synthase inhibi-
mation, 6:758 American Type Culture Collec- tors, 6:699-700
estrogens and androgens, tion, 2:723 novel chi-constrained, 452
6:765-766 Ametrone peptide arrays, 2:6-13
y-secretase inhibitors, topoisomerase I1 inhibitor, transport mechanism in renal
6:754-756 5:69 tubules, 3:57-58
immunosuppression, 6:766 AM125 Aminoacyl-tRNA synthetases
immunotherapy, 6:766 radiopaque material, 4:491 binding of alkyl groups to, 1:8
Cumulative Index

3-Aminobenzamide 2-Aminomethyl-3,4,6-trichloro- P-glycoprotein substrate,


NAD glycohydrolase inhibitor, phenol, 3:108-109 4:631
a686 Aminometradine, 3:122-123, soft analogs, 2:563-565
PARP inhibitor, 6:680 3:124 synergy with /3-blockers, 3:46
PLD repair inhibitor, 3-Amino nocardicinic acid deriv- thyroid hormone antagonist,
5:191-192 atives, 5:660-663 3:576
Aminobenzoate sunscreens, 6-Aminopenicillanicacid uses and side effects, 3:40
4460,4461 (6-AF'A), 1:869, 1:870 Amisulpride, 6:641
absorption and disposition, compounds derived from, discovery, &618
4462-463 5:609,5:630-637 Amithiozone, 5832
development of, 4470 isolation and characterization, Amitriptyline, 1:692
structure-activity relationship, 5628-629 affinities for monoamine re-
4467-468 structure-activity relation- ceptors, a 4 9 5
y-Aminobutyric acid amino-
ships, 5:630-637 antidepressant, 6:485,6:486,
transferase (GABA-T)in-
Aminopenicillins, 5:632 6:487
hibitors, See GABA amino-
use recommendations, 5626 CYP2D6 substrate, 4627
transferase (GABA-T)
inhibitors Aminopentamide dose for eating disorders,
y-Aminobutyric acid (GABA), anticholinergic, a135 6:851
See GABA relative anticholinergic activ- for eating disorders, 6:858
9-Aminocamptothecin ity, &I57 inhibition of serotonin, norepi-
antitumor natural product, Aminopeptidases nephrine, and dopamine
5:133 transition state analog inhibi- transporters, 6500
Amino-carbofluorene tors, 1:652 pharmacokinetic parameters,
anticholinergic, e l 3 4 Aminophylline, 3:124 6:497
7-Aminocephalosporanic acid p-Aminopropiophenone side effects profile, 6:493
(7-ACA), 1:871, 1:874, radioprotective agent, 5:165 use for depression ruled obvi-
5:638-639 Aminopterin ous by Court of Appeals,
4-Amino-6-chloro-1,3-ben- antimetabolite, 5:76,5:78 2:732
zenedisulfonamide, 8-Aminoquinolines, 1:888-889 Amlodipine, 3 2 1
370-71,3:73,3:80 Aminorex, 6:843 bioavailability and half-life,
2-Amino-3-chlorobutanoic acid dose, &847 3:20,3:23
nonclassical resolution, 1:803 p-Aminosalicylic acid, cardiovascular effects, 3:20
Aminoglutethimide, 1:717, 5830-831 CYP3A4/5/7 substrate, 4:627
3:643,3:724 efficacy and dosage, 5:810,
vascular-to-cardiac selectivity
applications, 3631, 3:632 5863
ratio, 3:172
chromatographic separation, side effects, 5:831-832
1:792 3-Amino-1,2,4-triazole Arnmi visnaga (toothpick plant),
classical resolution, 1:798, radioprotective agent, 5:162 1:883
1:799 2-Amino-4,6,6-trimethyl-1,3- Ammonium chloride
Aminoglycoside antibiotics, thiazine osmotic diuretic, 3:64
2:207. See also Gentamicin; radioprotective agent, Amobarbital, 6:204
Neomycin; Streptomycin 5:164-165 Amodiaquine, 5:979
biosynthesis, 5:751-753 Aminouracils, 3:122-123 antimalarial, 5:981-982
clinical use and currently used Amiodarone, 1:884, 1:885,3:32, dosage forms, kg35
drugs, 5:747-748 3:41, 3:167 Amopyroquine, 5:979
drug resistance, 5:753-757 ATP-sensitive potassium Amorolfine, kg03
pharmacology and mode of channel inhibition, 3:178 formulations and indications,
action, 5:749-751 cardiovascular effects, 3:40, 5:891
recent developments, 342 Amorphous solids, 2:651,
5:757-758 with implantable cardioverter 2:653-654
selective toxicity, 5:260-261 defibrillator, 3:46 metastable, 2:669
side effects, toxicity, and con- increased use of, 3:45 Amoxapine
traindications, 2:184-185, multiple inhibitory mecha- affinities for monoamine re-
2:615, 5:748-749 nisms, 3 3 3 ceptors, &495
8-Aminolaevulinic acid P-glycoprotein inhibitor, antidepressant, 6:485,6:486,
radiosensitizer, 5:175 4631 6:488
Cumulative Index

inhibition of serotonin, norepi- Amprenavir, 1:648, 1:659 chain branching alteration,


nephrine, and dopamine anti-HIV drug, 5:475-476 1:689
transporters, 6500 selective toxicity, 5:267 fragments of lead molecule,
pharmacokinetic parameters, structure-based design, 1:440, 1:689, 1:707-710
6:497 1:441 interatomic distances varia-
side effects profile, 6:493 Amprotropine tion, 1:689, 1:710-712
Amoxicillin, 5609 anticholinergic, 6:134 limitations of, 1532 P
Amoxycillin, 1:869, 1:870, 5632 local anesthetic activity, e l 5 4 rigid or semirigid analogs,
antimycobaderial application, relative anticholinergic activ- 1:689, 1:694-699
5:858 ity, 6:156 ring-position isomers, 1:689 -

in vitro antibacterial activity, Amsacrine ring size changes, 1:689


5635 with etoposide, 5:71 stereochemistry alteration and
AMP397A topoisomerase I1 inhibitor, design of stereoisomers/geo-
5:68,5:70 metric isomers, 1:689,
anticonvulsant, 6:315-316
Amsidyl 1:704-707
AMP-activated protein kinase
topoisomerase 11inhibitor, 568 substitution of aromatic ring
system a-Amylases, 4 3 3 for saturated, or the con-
role in carbohydrate metabo- X-ray crystallographic studies, verse, 1:689
lism, 4 2 3 1:482 Anandamide, 1:853
AMP analogs, 15'64 Amylin, 3:218 Anandron, 3717
Amphetamine, 6:170, 6:172, Amy1 nitrate, 3:13 Anastrozole, 3:632, 3:643
6:174,6:855 P-Amyloid (+)-Anatoxin-A
applications, 6:10 role in Alzheimer's disease, cholinergic, 6:56,6:93
general adrenergic agonist, 6:744-768 Ancestim, 3:268
6:3 X-ray crystallographic studies, Anchorage-dependent growth,
metabolism, 6:176-177 1:482 5:12-14,521
physiology and pharmacology, Amyloidoses, 6:744 Anchor and grow algorithm,
6:180, e l 8 3 Amyloid P-peptides, 6:744-768 1:294, 1:296
stereotyped behaviors induced Amyloid precursor protein Ancistrocladine
by, 6:615 and Alzheimer's disease, a746 antimalarial, 5994-995
structure-activity relation- gene-knockdown agents, a 7 6 1 Ancobon, 5:890
ships, 6:184-187 Arnylopectin, 4 3 3 AND logical operator, 1:406
Amphibian skin, opioid peptide Amylose, 4:33 Androcur, 3717
analogs from, 6:409-410 Amyotrophic lateral sclerosis, Androderm, 3:697
a674 AndroGel, 3697
Amphocil, 5890,5893
Arnytal, 6:204 Androgen antagonists,
Amphotec, 5:890,5:893
Anabaseine, 6:764 3716-721
Amphotericin B, 5889-893
analogs as cognition enhanc- Androgen binding protein, 3:686
with flucytosine, 5905 ers, 6:808-809 Androgenetic alopecia, 4433,
formulations and indications, cholinergic, 6:54-55 4:435,4:440
5890,5891 Anabasine, 6:49 Androgen insensitivity syn-
for leishmaniasis, 51051 Anabolic steroids drome, 3:695
membrane function disrup- absorption, distribution, and Androgen receptors, 3694-695
tion, 2:614 metabolism, 3:707-715 X-ray crystallographic studies,
selectivity, 5886 toxicities, 3:715-716 1:482
Amphotericins Anafranil, 6:485 Androgen response elements,
selective toxicity, 5268 Anagen phase, of hair growth, 3:694,3:696
Amphoteric surfadants 4425 Androgens, 3:598,3:680- 681.
topical antibacterials, 5:557 Anakinra, 4: 174 See also Anabolic steroids
Ampicillin, 1:869, 1:870, 5:609, Analgesics, 6:331. See also Nar- absorption, distribution, and
5632 cotic analgesics metabolism of endogenous,
antimycobacterial application, Analog design, 1:687-689 3:620,3:685-692
5858 alkyl chain homologation, absorption, distribution, and
pharmacokinetics, 5:624 1:689, 1:699-704 metabolism of synthetic,
prodrugs, 2:504,2:510 bioisosteric replacement and 3:703-705
use recommendations, 5:626 nonisosteric bioanalogs, for Alzheimer's disease,
Ampligen, 2:117 1:689-694 6:765-766
Cumulative Index

Androgens (Continued) Angioplasty, 3:156 4-Anilidopiperidine analgesics,


biosynthesis, 3:616-618, Angiostatin, 5:45 6:334
3:682-685 Angiotensin-converting enzyme structure-activity relation- .
conversion to estrogens, (ACE), 1:650, 1:881,3:195. ships, 6:381-385
3:690-692 See also ACE inhibitors Animal Drug Amendments of
and estrogen biosynthesis, active site molecular model- 1968,2:687
3:642 ing, 1:131, 1:132-133 Animal models and studies P
mechanism of action, single nucleotide polymor- antipsychotic agents,
3:692-697 phism~in insertioddeletion, 6:611-617
occurrence and physiological 4633 anxiety, 6:548-549
roles, 3681-682 target of structure-based drug cognition, 6:780-781
synthetic, 3:697-706 design, 1:432-433 and delay of marketplace en-
temperature-dependent up- Angiotensin I, 1:432-433, 1:746, try of new drugs, 2:705
take, 3686 1:881
diuretics, 3 6 2
toxicities of synthetic, 3705 formation, 3:195,3:196
for gene function determina-
Android, 3:697 and renin-angiotensin-aldoste-
rone system, 3:114 tion, 2:43
Androisoxazol, 3:712,3:715
anabolic activity, 3716 Angiotensin 11, 1:432, 1:746, Good Laboratory Practices,
5a-Androstane-3a,l7a-diol, 1:881 2:612
3696 binding to receptors, iron chelators, 3534-540
Androstanes, 3:597,3:598,3:749 3:196-197 for nitrogen retention, 3:705
Androstenedione, 3:616,3:621, biological actions, 3:197 as part of IND process, 2:691,
3682 biosynthesis and metabolism, 2:692-693
absorption, 3:685 3:195 permeability, 2:659
and estrogen biosynthesis, formation, 3:195,3196 sickle-cell anemia, 3:459
3:642 and neutral endopeptidase throughput limitations, 2:72
metabolism, 3:620 inhibitors, 3135 Animals
Androsterone, 3:681 non-peptide antagonists, patentability, 2:718
cholesterol lowering effect, 1:668-669, 1:670 Anionic polysaccharides
3:682 and renin-angiotensin-aldoste- marketed antithrombotics,
testosterone metabolite, 3687 rone system, 3:114, 3:286
Anectine, 2:539 3197-199 mechanism and sites of action,
Anemia, 3:386,3:503-504. See structure, 3:195-196 3310
also Sickle-cell anemia and vasopressin, 3:200,3:201 Anionic surfactants
Anesthesia and ventricular remodeling,
topical antibacterials,
anticholinergic premeditation, 3:164
5:556-557
6:115 Angiotensin III,3:195,3:196
Angiotensin IV,3195 Anions
Angina pectoris, 3:3,3:8,
3:9-11. See also Antianginal Angiotensinogen, 3:195 counterions suitable for salt
agents Angiotensin, receptor, formation, 2:651-652
and blood clotting, 3290 3:196-197 Anion-selective receptors, 2:360
treatment and prevention, single nucleotide polyrnor- Anisoactinomycins
3:11,3:298-299 phisms, 4633-635 antitumor natural product,
Angiogenesis, 5:216 Angiotensin, receptor, 3:197 5:111
and cancer, 5:20-21 Angiotensin, receptor antago- Anisotropine
compounds inhibiting, nists, 3:198-199 therapeutic use, a117
5:216-220 effect on endothelin, 3:207 Anisoylated plasminogen strep-
conditions related to, 5:220 Anhisan, 6:214 tokinase-activated complex,
plasmid DNA-mediated gene Anhydrides 3165
therapy, 4656 filtering from virtual screens, Annexin V, 2:77
Angiogenic switch, 5 2 0 1:246 Anomalous Patterson maps,
Angiography, 4567. See also 1,5-Anhydrohexitol-basednu- 1:477
Radiopaques cleic acids, 2:152 Anordiol, 3:658
CT application, 4568 Anhydrolides, 5:781-782 Anorexia nervosa, 6:840-841,
radiopaques applications, Anhydron, 3:77 6:874
4:569-570 Anidulafungin, 5:888,5:901, Anorexia nervosa drugs, 6:171,
Angiomax, 3:286, 3:316 5~902-903 6:843,6:849-853
Cumulative Index

Anoxia Class IC, 3:31,3:32,3:37-38, Antibody-dependent cytotoxic-


radioprotective agents utiliz- 3:167 ity, 5:225-226
ing, 5:152,$167-168 classification, 3:31-33, Antibody-directed enzyme-pro-
ANP clearance receptor block- 3:167-168 drug therapy (ADEPT),
ers, 3:134 Class 11: P-adrenergic blocking 2:518,5:83,5:87-90
Anracetam agents, 3:31,3:32, 3:38-40, Antibody-directed immunother-
for Alzheimer's disease, 6:764 3:167 apy, 5226-235 P
Antagonists, 5:250-252 Class 111: repolarization pro- Antibody microarrays, 4600
Antedrug, 2:536 longators, 3:31,3:32, Antibody-toxin conjugates
Anthracyclines 3:40-3,32167 (armed antibodies), 5:83, .

alkylating agents, $52 Class IV: calcium channel $92-94


antitumor natural products, blockers, 3:31,3:32, selective toxicity (paclitaxel),
5:110,5:126-128 3~43-44,3:167-168 5258
future directions, 3:45-46 Anticancer drugs. See also Anti-
P-glycoprotein substrate,
miscellaneous agents, 3:44 tumor drugs; Cancer; Tu-
4631
multiple inhibitory mecha- mor-activated prodrugs
Anthranilate sunscreens nisms, 3:33 antiangiogenic agents,
structure-activity relationship, soft analogs, 2:562 5:215-220
4469 Antiasthma drugs COX-2 selective inhibitors,
Antiadrenergics, See Adrenergic- natural products as leads, k249-250
blocking agents 1~883-886 drug resistance in chemother-
Antianginal agents. See also Va- selective toxicity, $252 apy, 5:281-290
sodilators Antibacterial agents, 5:538-539 electron-affinicdrugs in,
factors affecting myocardial broad-spectrum p-lactams, $180-183
oxygen supply, 3:8 -9 5~705-709 enzyme inhibitors, 1:717,
factors governing myocardial drug resistance, $543, 1:718
oxygen demand, 3:9 5:572573,5586,5:590 lipiodol as carrier for, 4494
future directions, 3:46-47 selective toxicity, $539-543 market for, 5:109
Antiangiogenic agents, 5:38-39, soft analogs, 2:560-562 molecular modeling, 1:151
5:216-220 systemic synthetic, 5:557-596 natural products as leads,
gene therapy approaches, 5:45 topical synthetic, 5:539-557 1~858-868
Antianxiety agents Antibacterial enzyme inhibitors, radioprotective agents with,
adverse effects, 6:532-533 1:717 5172-173
clinical applications, Antibiotic resistance, See Drug retinoids, 4:374
a527437 resistance selective toxicity, 5:257-259
current and future develop- Antibiotics, $738-739. See also Anticancer gene therapy
ments, 6:578-581 Aminoglycoside antibiotics; approaches for, 5:43-46
currently used drugs, Erythromycins; Macrolide plasmid DNA-mediated, 4653
e527-532 antibiotics; specific types of prospects for, 5:39-43
for eating disorders, 6:852, Antibiotics, such as Tetracy- Anticholinergics, 6:110-111
a858 clines anticholinergic activity as side
history, 6:546-548 as antimalarials, 5:982-983 effect of drugs, 6:115
metabolism, 6:533-537 antimycobacterial agents, antispasmodic activity assay,
nonbenzodiazepine ligands, 5~840-853 6:116-118
6:555-566 carbohydrate-based, as antispasmodics, el11
physiology and pharmacology, 2:207-208 antiulcer activity assay,
6:537-546 hybrid, 2:84 6:118-119
structure-activity relation- natural products as leads, as antiulcer agents, 6:111-114
ships, 6:548-578 1~868-878 atropine analogs, 6:126-128
Antiarrhythmic agents radioprotective agents, 5166 benzothiazepines, a129
Class I: membrane-depressant selective toxicity, 5259-263 biocomparative assay,
agents, 3:31,3:32,3:34-38, Antibodies, $224-226 6:116-120
3:167, a168 general structure, 5:227 classification based on sub-
Class IA, 3:31, 3:32, 3:3436, Antibody-based therapeutics, types of muscarinic recep-
3:167 2:88 tors. 6:115-116
Class IB, 3:31, 3:32,3:36-37, Antibody-dependent, cell-medi- developed for specific uses,
a167 ated cytotoxicity, 2:85 6:154-158
Cumulative Index

Anticholinergics (Continued) Anticoagulants, 1:882-883, recent and future develop-


diphenylacetyloxy derivatives, 3:166,3:284. See also Hepa- ments, 6:516-518
6:132-133 rin side effects, 6:490-496
dissociation constants, 6:150 ADME, 3:295-298 structure-activity relation-
dual cholinergic/anticholin- calcium channel blockers, 3:29 ships and metabolism,
ergic compounds, 6:150-151 for cancer treatment, 5:38 6:510-516
himbacine, a133 clinical use, 3:284-299 Antidiuretic hormone
indene derivatives, 6:131-132 next-generation, 3:291 transport mechanism in renal
interaction at muscarinic re- treatment regimens, tubules, 3:57-58
ceptors, 6:151-153 3~298-299 Antiendothelial receptor anti-
kinetic basis for mechanism of Anticonvulsant receptor models, bodies, 3:462
action, 6:152 6:319320
miscellaneous activity assays, Antiestrogens, 3:631
Anticonvulsants, 6:264-265
6:120 currently marketed, 3:632
ADME, 6:273-291
mydriatic and cycloplegic ac- currently used drugs, 6:265 Antifolates, 576-79
tivity assay, 6:119-120 future developments, antimalarial, 5954-960
as mydriatics and cycloplegics, 6:315-320 structure-based design tar
6:114-115 GABA, receptors, 6:295-296 gets, 1:425-432
for Parkinson's disease, GABA, receptors, 6:296 Antifungal agents
6:731-733 glutamate receptors, allylamines, 5890, 5:891,
polymethylene tetramines, 6:296-297 5:899-900
6:131 history, 6:297-304 aureobasidins, 5:906-907
in premedication during anes- ion channels, 6:292 azoles, 5:890, k891,
thesia, 6:115 NMDA receptor antagonists, 5893-899
quinuclidine-based antago- 6:694,6:696-697 benanomycins, 5:908
nists, 6:129-131 with opioid analgesics, 6:333 candins, 5:890,5900-903
receptor-subtype-selective, physiology and pharmacology, epidemiology of resistance,
6:128-133 62291-297 5884-885
relative activities, 6:156 recently developed agents, fungal efflux pump inhibitors,
side effects, 6:154 6:311-315 5:909
sila-difenidols, 6: 132 side effects, adverse effects, miscellaneous compounds,
soft analogs, 2:558-560 and drug interactions, 5~903-910
solanaceous alkaloids, 6:265-273 morpholines, 5:903
6:120-126 structure-activity relation- N-myristoyl transferase inhib-
specificity of antagonism, ships, 6:304311 itors, 5:908-909,5:910
6:152 T-type calcium channels, nikkomycins, 5906
stereoisomerism and activity, 6:297 polyenes, 5:889-893, 5890,
6:147-150 ANTIDE, 2:265 5:891
structure-activity relation- Antidepressants, 6:484. See also polyoxins, 5:906
ships, 6:133-151 Monoamine oxidase inhibi- pradimicins, 5:908
synthetic, 6:126-133 tors; Serotonin-selective selective toxicity, 5254,
therapeutic uses, 6:153-154 reuptake inhibitors; Tricy- 5266-268,5886
tricyclic benzodiazepines, clic antidepressants sordarins, 5907-908
6:128-129 cardiotoxicity, 2:619 thiocarbamates, 5:903
Anticholinergic syndrome, clinical efficacy, 6:486-490 for treatment of superficial
6:115-116 CNS stimulants in terminal cutaneous mycoses, 5:891
Anticholinesterases, 6:40. See illness, 6:173 for treatment of systemic my-
also Acetylcholinesterase currently used drugs and clas- coses, 5:890
inhibitors sification, 6:484-486 trends in, 5:910-911
al-Antichymotrypsin (ACT), for eating disorders, 6:843, Antifungal enzyme inhibitors,
6:767 6:849-851 1:717
Anticlotting agents, See Antico- efficacy relative placebo, a489 Antigen-presenting cells,
agulants; Antiplatelet history, 6:508-510 5:224-225, 5235
agents; Thrombolytic agents for Parkinson's disease, 6:725 and organ transplant rejec-
Anticoagulant protein C pharmacokinetics, 6:496-498 tion, 5487
X-ray crystallographic studies, physiology and pharmacology, Antiglucocorticoids, 3:837-845
1:482 6:498-508 Antihelmintics, 51090-1096
Cumulative Index

Antihistamines side effects, adverse effects, resistance, 5:921, 5:928-930


ADME, 6:223 drug interactions, and con- selective toxicity, 5:254, 5:268
currently used drugs, traindications, 3:352-355 Antimetabolites, 5:75-76
6:212-214 structure-activity relationship, antifolates, 5:76-79
discovery, 6236 3363-367 purine analogs, 5:76, 5:81-82
pharmacologic effects, 6:230 thyroid hormones (potentially) pyrimidine analogs, 5:76,
as, 3:565,3:571,3:575 P
selective toxicity, 5:275-276 5:79-81
side effects and drug interac- Antihypertensives Antimicrobials
tions, 6:211 adrenergics, 6:2 (See also ACE soft analogs, k560-562
Anti-HIV drugs. See also HIV inhibitors; p-Blockers) Antimycin A
.

protease inhibitors; HIV Antiinfectives renal and hepatic toxicity,


reverse transcriptase inhibi- selective toxicity, 5:259-263
2:615
tors Anti-inflammatory agents
Antimycobacterial agents,
for Alzheimer's disease, 6:767
combination therapies, 5:479 5:809-813
Anti-inflammatory steroids,
drug resistance, 5:478-479 antibiotics, 5:840-853
3:747-751. See also Glu-
drugs in clinical use, currently used drugs,
cocorticoids
5:477-478 adverse effects, 3751-756 5:829-840
HIV vaccines, 5465 clinical uses, 3:751 drugs under investigation,
inhibitors of Gp120 binding to 3D-QSAR, 3793-796 5:853-860
T-cell receptors, 5:467-468 effects on corneal penetration, future developments,
inhibitors of HIV gene expres- 3:771 5~866-867
sion, 5:473-474 effects on drug distribution, recent developments and
inhibitors of HIV integrase, 3:771-773 present status of chemo-
5:465,5:473 effects on drug receptor affin- therapy, 5:860-867
inhibitors of HIV-1 protease, ity, 3:780-786 screening and evaluation,
5:465, $475-477 effects on intestinal absorp- 5:826-829
inhibitors of HIV reverse tran- tion, 3:756-759 selective toxicity, 5:266
scription, $465, $469-473 effects on intra-articular ad- Anti-obesity drugs, 6:844-849
inhibitors of HIV ribonucle- ministration, 3:767-768 absorption and metabolism,
ase, 5:473 effects on percutaneous ab- 6:860-866
inhibitors of viral entry, sorption, 3:759-767 clinical applications,
5:465-468 electronic factors affecting,
6:843-860
inhibitors of viral fusion, 3793
$468 -469 mechanism of action,
CNS stimulants for, 6:173,
inhibitors of viral maturation, 6:193
3~776-780
5:475-477 neural networks application, new drugs in development,
inhibitors of viral uncoating, 3:791-792 6:881-886
5:469 QSAR analyses, 3786-792 new targets for drugs,
inhibitors of virion assembly, skeletal change effects on ac- 6:886 -888
5:474-475 tivity, 3:796-837 structure-activity relation-
need for new, 5:478-479 steric factors affecting, ships, 6:875-881
selective toxicity, 5:267 3792-793 thyroid hormones (potentially)
viral adsorption inhibitors, structure-activity relationship, as, 3:565,3:575
5:465-467 3:786-837 Antioxidants, 5:33
virus "knock-out" strategy, water-soluble esters, for Alzheimer's disease, 6:674,
5:478-479 3:768-771 6:675,6:758,6:767-768
Antihyperlipidemic agents, Anti-inflammatory therapeutic for atherosclerosis treatment,
32339-342 antibodies, 5:233-235 3:372-374
ADME, 3:355-358 Antimalarial agents Antiparasitic drugs. See also An-
clinical applications, for Alzheimer's disease, 6:767 timalarial agents
3342-352 currently used drugs, antihelmintics, 5:1090-1096
new treatments for lowering 5:933-985 natural products as leads,
LDL and TG, 3:368-370 experimental agents, 1:886-891
new treatments for raising 5:985-993 selective toxicity, 5:254, 5:268
HDL and lowering TG, natural products, 5:993-999 a2-Antiplasmin inhibitors,
3:368-370 new targets, 5:993 3329-331
Cumulative Index

Antiplatelet agents, 3:285 seizures, a 6 0 8 Antithrombotic agents. See also


with alternative mechanism of sexual side effects and hyper- Anticoagulants; Antiplatelet
actions, 3:326-329 prolactinemia, 6:609-610 agents
calcium channel blockers, 3:29 structure-activity relation- ADME, 3:295-298
clinical uses, 3:284-299 ships, 6:619-632 with alternative mechanism of
mechanisms and sites of ac- tardive dvskinesia.
" 6:607 actions, 3:323-326
tion, 3:308-322 therapeutic indications, bleeding and other adverse *
next-generation, 3:291 6:604-605 effects, 3:291-294
nitrates as, 3:12 weight gain, 6:610 challenges, 3:284
structures of marketed, a289 Antiradiation testing, 5:154 clinical use, 3:284-299
for thrombolytic therapy, Antisense oligonucleotides, future developments,
3:166 2:117-118 3:331332
treatment regimens, amyloid precursor protein marketed, 3:286-287
3:298-299 gene-knockdown agents, a761 mechanisms and sites of ac-
Antiprogestins, 3:632, antisense concept described, tion, 3:308-322
3651-652 2:117-118 nitrates as, 3:12
binding to glucocorticoid re- 5'-capping, 2:125 treatment regimen, 3:298-299
ceptors, 3:841 disruption of necessary DNA Antitumor drugs. See also Anti-
Antiprotozoal agents, structure, 2:124 cancer drugs; Cancer; Tu-
5:1034-1035 double-stranded RNase activa- mor-activated prodrugs
for African trypanosomiasis, tion, 2:128 drug resistance in chemother-
5:1035-1045 HBV virus antiviral agents, apy, 5:281-290
for American trypanosomiasis, 5:337 macrolides, 5:784-785
5:1045-1047 hepatitis C virus antiviral prodrug by use of CYP450 me-
for Leishmaniasis, agents, 5:415-417 diated activation, 2:518
5:1047-1052 influenza antiviral agents, radioprotective agents with,
new drug therapy perspec- 5:384385 5172-173
tives, 5:1052-1076 inhibition of 5'-capping, 2:123 selective toxicity, 5:257-259
Antiprotozoal enzyme inhibi- inhibition of 3'-polyadenyla- toxicity, 2:616
tors, 1:717 tion, 2:125-126 Antitumor natural products,
Antipsychotic agents, 6:600-602 inhibition of splicing, 5:109-111
animal models of efficacy and 2:123-124 drugs attacking DNA, 5:110,
side effects, 6:611-617 mechanisms, 2:120-128 5:111-124
anticholinergic effects, 2-0-(2-Methoxyethyl)chime- drugs inhibiting DNA process-
6:608-609 ras, 2:153-155 ing enzymes, 5:110,
cardiotoxicity, 2:619 for receptor targets, 2:351 5124-136
cardiovascular effects, 6:609 RNase H activation, drugs interfering with tubulin
cognitive impairment, a 6 0 8 2:126-128 polymerization/depolyrner-
dermatologic effects, 6:611 translational arrest, 2:124 ization, 5:110,5:136-143
discovery, 6:617-619 Antisense technology, 2:116-117 Antiulcer agents
drug discovery strategies for gene expression profiling, anticholinergic activity assay,
based on dopaminergic ap- 4613 6:118-119
proaches, 6:640-651 organ transplant rejection ap- nonanticholinergics as,
drug discovery strategies plications, 5:524-525 6:155-158
based on non-dopaminergic with plasmid DNA-mediated Antiviral agents. See also Anti-
approaches, 6:651-655 gene therapy, 4666 HIV drugs
extrapyramidal symptoms, as tool for gene functionaliza- antisense, 2:122,2:124,2:135
6:600,6:605-607 tion and target validation, carbohydrate-based, 2:208
hematologic effects, a610 2:128-129 selective toxicity, 5:254,5:266
hepatic effects, 6:610-611 Antiseptics, 5:539 Antiviral agents, DNA, 5:305
neuroleptic malignant syn- testing, 5:544-545 adenoviruses, 5:340
drome, 6:607-608 Antisickling agents, 1:419-421 hepatitis B virus, 5:326-337
for Parkinson's disease, 6:725 Antispasmodics herpesviruses, 5:305-326
pharmacokinetics, biotrans- anticholinergic activity assay, papillomaviruses, 5:337339
formation, and drug interac- 6:116-118 parvoviruses, 5:341-342
tions, 6:632-640 anticholinergics,6:111 polyomaviruses, 5:339-340
sedation, 6:608 Antithrombin, 2:302-303 poxviruses, 5:340-341
Cumulative Index

Antiviral agents, RNA, Apex-3D, 1:60 Aprobarbital, 6204


5:360-361 Aphrodyne, 4442 Aptamers
arenaviruses, 5:430 Apical sodium-dependent bile as drugs and diagnostics,
broad spectrum, 5:432-435 acid transporter, 2277-285 2:94
flaviviruses, 5427-430 Apicidin AQ4N
hepatitis C virus, 5:361-364, antimalarial, 5:994 radiosensitizer, 5:182
5:415-427 Apnea of prematurity tumor-activated prodrug, r
influenza A and B viruses, CNS stimulants for, 5:83,5:84,5:85
5:364390 6:173-174 AQ-RA 741
measles virus, 5:390-396 Apolipoprotein AT, 3:341 anticholinergic, 6:129 -
orthopoxviruses, 5:435-440 Apolipoprotein B48, 3341 Aquaphor, 3:88
parainfluenza virus, Apolipoprotein B100, 3341
Aquaporin 1
5:390-398 Apolipoprotein E
paramyxovirus fusion pro- X-ray crystallographic studies,
and Alzheimer's disease,
teins, 5:390-396 1:482
4637,4:638-639,
picornaviruses, 5:398-415 6:748-749 Aquatag, 3:76
respiratory syncytial virus, Apolipoprotein E gene, 3:lO-11 Aqueous solubility
5:390-398 Apolipoproteins, 3 3 4 0 3 4 1 and Biopharmaceutics Classi-
rotaviruses, 5:430-431 Apomorphine, 4450 fication System, 2:665-666
rubella virus, 5:431-432 for Parkinson's disease, 6:723, characterization, 2:656-658
Antiviral enzyme inhibitors, 6:726,6:728-729 Class I drugs: high solubility
1:717 stereotyped behaviors induced high permeability,
Antrenyl, 6:137 by, 6:615 2:665-667
Anturane, 3:139 Apoptosis, 2:76-77 Class I1 drugs: low solubility
Anxiety, 6:526 and adaptive immunity, 5:225 high permeability,
animal models, 6:548-549 and Alzheimer's disease, 6:749 2:667-671
Anxiety disorders, 6:526-527. and carcinogenesis, 5:16-19 Class I11 drugs: high solubility
See also Antianxiety agents and drug resistance in cancer low permeability,
physiology and pharmacology, chemotherapy, 5:287-289 2:674-676
6:537-5546 inhibitors for Alzheimer's dis- Class IV drugs: low solubility
Anxiolytic agents, See Antianxi- ease, 6:766-767 low permeability, 2:676
ety agents necrosis contrasted, after and dissolution rate, 2:658
AO-33 myocardial infarction, 3157 hydrate pseudopolymorphs,
anticonvulsant, 6:314 AT, receptor effect on, 3197 2:653
AOP-RANTES ligand in stroke, 6:676-677 polymorphs, 2:652
and CCR1,4137 Apoptotic tumor cells, 5239 salts, 2:651
and CCR3,4150 Appellate courts, patent in- and structure-based design,
and CCR5,4155 fringement cases, 1:408
CCRl antagonist, 4139 2:740-742 weak acids and bases, 2:661
Aorta, 3:3,3:4 Appetite stimulants, 6:843, Aquex, 3 8 2
Aortography, 4:567. See also Ra- a854 Arabidopsis thaliana
diopaques absorption and metabolism, genome sequencing, 1:344
AP-811, 3:134 6:866-867 Arabinose binding protein
Apadoline clinical applications, 6:858 genetic algorithm study of
analgesic, 6:392 Appetite suppressants, 6:843, docking, 1:88-89
Apalcillin, 5633 6~844-846.6~847-848 Arachidonic acid, 1:762, 1:763,
Apamin absorption and metabolism, 2:616
molecular modeling, 1: 124 6:860-866 leukotriene biosynthesis from,
APC-6336 clinical applications, 66443, 4205-207
hepatitis C antiviral, 6:855-856 Arden, 5:934
5:422-433 structure-activity relation- Aramine, 6:3
APC (adenomahus polyposis coli) ships, 6:875-881 Aranidipine, 3 2 1
gene, 5:5-6,5:27,5:2930 Application tier, 1:392, 1:398, bioavailability and half-life, 3 2 3
gene therapy target, 5:44-45 1:406 cardiovasdar effects, 3:20,3:24
hypermethylation, 5:9 Apraclonidine Arbekacin, 2:207,2:212
AP descriptors, 1:55, 1:56 a,-agonist, 6:3 AR-C69931,3:320,3:321
Apex, 1256, 1:387,4:624 applications, 6:13 Ardeparin, 2:210,2:212
Cumulative Index

Arecoline analogs, 1:693-694 Arrayscan HCS System, 2:626, Artificial organs, 5526
as cholinergics, 6:62-71 2:627 Arylalkylamine calcium channel
Arenaviruses Arrhythmias, See Antiarrhyth- blockers, 3:16-20
antiviral agents, 5:430 mic agents; Cardiac ar- Arylesterase, 2:538
Argatroban, 3:29,3:285 rhythmias Aryloxy acetic acid high ceiling
ADME, 3296 Arsumax, 5:935 diuretics, 3:93-94
clinical trials, 3:293 Artabotrys uncinatus, 1:887 Aryloxypropanolamines, 6:5, t
development of, 3314-315 Artane 6:16
formula weight, mechanism of for Parkinson's disease, 6:731, metabolism, 6:19-21
action, and route of admin- 6:732 structure-activity relationship,
istration, 3286 Arteannuin, 5:961 &30-31
structure, 3:288 Arteether, 1:887,5:964 Arylpropionic acids
structure-based design, 1:442, antimalarial, 5:974-975 inversion in metabolism,
1:444 dosage forms, 5:935 2:460
Arginase inhibitors, 1:736-737 Arteflene Arylsulfatase B, 2:219,2:220
Arginine antimalarial, 5:984-985 N-Arylsulfonamides
chemical modification re- Artelinic acid, 5:964,5:974-975 selective COX-2 inhibitors,
agents, 1:755 Artemether, 1:887-888,5:964 4241-242
Arginine vasopressin, See Vaso- antimalarial, 5:973-974 Arylsulfonamidophenethanol-
pressin dosage forms, 5:935 amine analogs, 1:703
Aricept Artemisia annua (sweet worm- p-Arylthio cinnamide antago-
for Alzheimer's disease, 6:762 wood), 1:886, 1:888 nists, 1:566-567
for cognition enhancement, Artemisinin, 1:849, 1:886-888, Aryplase, 2:219,2:220
6:781 5:960-963 Arzoxifene, 3:668
Arimidex, 3632 dosage forms, 5:935 estrogen receptor affinity,
Aripiprazole, 6:650 first generation, 5:970-976 3:659
Arixtra, 3:286,3:310 mechanism of action, ASA with codeine, a 3 3 5
ARL17477 5966-970 ASCII (American Standard Code
nitric oxide synthase inhibi- structure-activity relationship, for Information Exchange),
tor, a706 5:963-966 1:398
Armed antibodies, 5:83, 5:92-94 9-epi-Artemisinin, 5:965 Ascomycin
Aromasin, 3:632,3:728 Artemotil, 5935 binding to FKBP, 1:552,
Aromatase Arterial thrombosis, 3:290 1:553-554
in androgen metabolism, antithrombotic treatment reg- Ascorbic acid, 4:399. See also
3:692 imen, 3298-299 Vitamin C
in estrogen metabolism, 3642 Arteries, 5:216 Asendin, 6:485
Aromatase inhibitors, 1:717, Arteriography, 4567. See also Asendis, 6:485
1:770,3:604,3:642-643 Radiopaques Asepsis, 5539
C-20 steroids as, 3:726-728 CT application, 4568 Ashimycin A, 2:172
currently marketed, 3632 Artesunate, 5:964,5:972-973 Ashimycin B, 2:172
nonsteroidal, 3:668-669 dosage forms, 5:935 Asimadoline
Aromatic aldehydes Arthrobactin, 3:483,3:486 analgesic, 6:394, a 3 9 5
hemoglobin allosteric effec- synthesis, 3:524 Asinex catalog, 1:385
tors, 3:394-396 Artificial intelligence, 1:398 Asparenomycin A, 5:670,5:671
Aromatic-aromatic interactions, in automated high-throughput in vitro activity, 5:692
1286 screening, 2:65 Aspartate transcarbamoylase
Aromatics Artificial neural networks (ATCase)
analogs based on substitution anti-inflammatory steroids functional domains in,
of aromatic for saturated application, 3:791-792 2:307308,2:310
ring; or the converse, for druglikeness screening, Aspartate transcarbamoylase
1~699-704 1:247-248, 1250 (ATCase)inhibitors,
complexation, 2:670 in molecular modeling, 1:126 1:743-744
growth inhibition by, 1:38 in QSAR, 1:53, 1:62, 1:67 Aspartic acid
molecular comparisons, 1:139 for structural genomics study, chemical modification re-
ArrayExpress, 1:345 1:353 agents, 1:755
Cumulative Index

Aspartic peptidase inhibitors Asymmetric synthesis, 1:784, ATP


recombinant DNA studies, 1~804-820 and cellular energetics,
2:98,2:99 enzyme-mediated, 1:804-807 6:679-680
transition state analogs, Asymmetric transformation depletion after myocardial in- -
l:647- 649 crystallization-induced, farction, 3:156,3:159
virtual screening, 1:3 15 1~798-799 and membrane transport, 2:258
Aspergillosis, 5:883 Atarax, a214 ATP analogs, 15'63-764,1:765
Aspergillus, 5:883,5:884 Ataxia telangiectasia, 5:32 H+,KC-ATPaseinhibitors, 1:718
Aspergillus alliaceus, 1:855 Atazanavir Na+,K'-ATPase inhibitors,
-
Aspergillus fumigatus, 5882 anti-HIV drug, 5:476-477 k718
Aspergillus nidlans, 1:878 Atenolol, 1:882,3:28, 3:179 ATP-binding cassette genetic
Aspergillus terreus, 1:879 P-antagonist, 6:2,6:5 superfamily, 2:267
Asperlicin applications, 6:16 and drug resistance, 5:285
ATP-sensitive potassium chan-
fragment analogs, 1:708 cardiovascular effects, 3:39,
nel, 3 7 , 3:162-163
lead for drugs, 1:855-856 3:40
and arrhythmias, 3:163-164
Aspirin, 1:762-763, 1:764, metabolism, 6:21 and preconditioning, 3:157
3:285,6:331 renal clearance, 1:38 ATP-sensitive potassium chan-
ADME, 3:297-298 uses and side effects, 3:38 nel agonists, 3:163-164,
clinical trials, 3:291-292, Atherosclerosis 3:177-178
3:293 and myocardial oxygen supply, ATP-sensitive potassium chan-
discovery, 2:39, 4:230 3:9 nel antagonists, 3:162-164,
effects on COX-1,4244-245 new antihyperlipidemic treat- 3:175-176
effects on thromboxane A,, ments, 3:372-374 Atracurium, 1:857, 1:859
3:326 role of lipids, 3:340-342 Atrasentan (ABT-627),
first tier of cancer pain treat- Atherosclerotic angina, 3:9 1:811-812
ment, 6:332333 Atherosclerotic plaque rupture, Atratran, 6:117
formula weight, mechanism of 3:290 Atrial fibrillation, 3:9, 3:31
action, and route of admin- ATI-2001, 2564 Atrial flutter, 3:9, 3:31
istration, 3:287 Ativan, 6:207,6:529,6:551 Atrial natriuretic factor, 1:650
IL-12 inhibition, 4180 Atom-atom mapping, 1:380, Atrial natriuretic peptide,
loss of trademark status, k398 3:133-138
2:762 Atom-centered point charges, biological action, 3:217
mechanism and sites of action, biosynthesis, metabolism, and
1:lOl-102
3~321-322 structure, 3:214-216
Atomic counts, 1 5 4
prodrug for, 2:505,2:510 and endothelin, a 2 0 5
selective toxicity, 5274 Atom list, 1:398
therapeutic potential, 3:218
structure, 3:289 Atom-pair interaction potentials, Atrial natriuretic peptide (ANP)
for thrombolytic therapy, 1:120 clearance receptor blockers,
3166 Atom stereochemistry, 1:365, 3:134
treatment regimen, 3:298 1:398 Atrial natriuretic peptide recep-
warning label, 4:427 Atom-type E-State index, 1:26 tor, 3:218
Assay Explorer, 1:387 Atorvastatin, 1:744, 1:880, recombinant DNA studies, 2:103
Association thermodynamics 3:343,3:345,3:609 Atrial tachycardia, 3:9
drug-target binding, ADME, 3:356 Atrioventricular (AV) node, 3:3,
1:170-171,1:177-179 for angina treatment, 3:11 3:4
Astemizole discovery, 3:362-363 and disorders of signal genera-
CYP3A4/5/7 substrate, 4627 enzyme activity, 3:364 tion, 3:29
removedkestricted by FDA, P-glycoprotein inhibitor, and reentry excitation,
4642 4631 3:30-31,3:161
Asthma side effects, 3:354 Atrium, 3:3,3:4
and leukotrienes, 4210 single nucleotide polymor- Atrolactate, 1:762
Asulacrine phism~influencing response Atropine, 6:110-111. See also
topoisomerase I1 inhibitor, to, 4:644 Anticholinergics
5:68-69,5:71 Atovaquone anesthesia application, 6:115
Asymmetric centers, 1:784, antimalarial, 5976-978 and constrictor muscle fibers,
1:785 dosage forms, 5935 6:114
Cumulative Index

Atropine (Continued) Automaticity, of myocardial 6-Azauridine, 2253


and gastrointestinal spasms, cells, 3:5 flavivirus antiviral, 5:427-428
6:111 Automation 2-Azetidinone, 3:366
lead for drugs, 1:851 in high-throughput screening, Azide
molecular factors in absorp- 2:40, 2:63-66 radioprotective agent, 5:162
tion, fate, and excretion, Autonomic ganglia Azidocillin, 5:609
6:122-124 nicotinic acetylcholine recep- Azimilide, 3:41 ?
mydriatic and cycloplegic ac- tors, 2:385,2:388 cardiovascular effects, 3:43
tivity, a 1 5 3 Autoplex potassium channel subtype
relative anticholinergic activ- hemostatic preparation, 3292 selective, 3:45
ity, 6:156 Autosomal-dominant nocturnal uses and side effects, 3:40
in solanaceous alkaloids, frontal lobe epilepsy, Aziridine, 3665
6:120-126 2:392-393 Azithromycin, 1:848, 1:849,
stereoisomerism, 6:147-149
Available Chemicals Directory 1:875-876,2:191,6:763
therapeutic use, 6:117
(ACD), 1:385, 1:386 antimalarial, 5:935,5:983
tropine-modified, 6:123
virtual screening application, antimycobacterial application,
Atropine-acetylcholine antago-
nism, 6:152-153 1:254 5:857-858
Atropine analog anticholin- Avandia, 4 2 5 selective toxicity, 52261
ergics, 6:126-128 Avasimibe, 3370 structure, 2:189
Atropinesterase, 6:124 Aventyl, 6:485 Azlocillin, 5:633
Atrovent, 6:117, e l 5 8 dose for eating disorders, indications, 5:625
Attention-deficit hyperactivity a851 pharmacokinetics, 5:624
disorder (ADHD), 6:855. See Avermectins, 1:891, 12392 Azolastone
also Methylphenidate Avidin, 4405 alkylating agent, 5:54
(Ritalin) Avilamycin, 2214 h o l e antifungal agents, 5890,
CNS stimulant for, 6:172-173, Avloclor, 5:934 5:891,5:893-899
6:193 AV nodal reentry, 3:9 Azolimine, 3:132-133
Augmented-Acute Normovol- AV node, See Atrioventricular Azopt, 3:67
emic Homodilution A-ANH, (Am node Azosemide, 388, 3104
3:427 Avobenzone M T , See Zidovudine
Augmentin, 1:869,5:695 mechanism of action, 4:466 Aztreonam, 1:873-874,5:609,
Aura-Mol, 1:388 structure-activity relationship, 5:666
Aureobasidins, 5:906-907 4469-470 activity, 5:667
Aureomycin, 5:740 sunscreen, 4460 indications, 5:625
AUSPYX, 1:387 AV reciprocating tachycardia, /3-lactamase classification
Australia 3:9 based on activity, 5:620
patentable subject matter, AWD-131-138 pharmacokinetics, 5:624
2:720 anticonvulsant, 6:311 side effects and interactions,
trade secret protection, f i n , 529-30 5:625
2:768-769 Axisonitrile use recommendations, 5:626
AutoDock antimalarial, 5:993
affinity grids, 1293 Axokine, 6:882,6:883-885 B-283,5:838
explicit water molecules, AX-RA 513 B-663, 5:838
1:303 anticholinergic, a 1 2 9 B-90063
flexible ligands, 1:263 M-242,3:370,3:371 endothelin-converting enzyme
Lamarckian genetic algo- 5-Azacytidine, 3:464 inhibitor, 3:208
rithm, 1:299 Azadicarbonamide Babel, 1:372
Monte Carlo simulated an- anti-HIV drug, 5:469,5:470 Baby-boomer consumers, 4:423
nealing, 1:297 Azapeptides Bacampicillin, 2:510,5:609,
protein flexibility, 1:301 picornavirus antiviral, 5:632
Autoignition temperature, 2:413 5:408-409 Baccatin 11, 1:863
Autoimmune diseases Azathioprine, 1:717,5:489, Backtracking, 1:382, 1:399
plasmid DNA-mediated gene 5:490 in virtual screening, 1:67
therapy, 4656 clinical use for organ trans- Bacterial adhesins, 2:262-263
Autolysins, 5:610-613 plants, 5:513-516 Bacterial infections, 5738
Automap, 1:398 side effects, 5:516 Bacterial invasins, 2:262-263
Cumulative Index

Bacterial luminescence Barium sulfate chemokinelcytokine receptors,


inhibition by ROH, 1:27 radiopaque material, 4133
Bacterial natural products, 4487-489 exosome secretion, 5241
1:848, 1:893,2:39 Barium titanate Bcl-2 protein, 522, 524, 5:26 -
Bacterial radiosensitizers, 5:197 radiopaque material, 4488, and apoptosis, 5 1 9
Bacterial resistance, See Drug 4493 and COX-2,534
resistance 'C
Barnard Chemical Information, and drug resistance, 5:287,
Bacterial ribosome, 5738-739 1:388 5:288-289
Bacterial toxins, 2:263 Barnidipine, 3 2 1 Bcl-x, protein, 5 1 9
Bacteriorhodopsin bioavailability and half-life, target of spin-label NMR
.

electron cryomicroscopy, 3:23 screening, 1:573-574


1:612 cardiovascular effects, 3:24 BCNU
homology with GPCRs, 1:123,
B-arrestin systems, 2:75 alkylating agent, 5:54,
1:150
Basal cell carcinoma, 4465 5:64-65
Bactrim, 5934
Bad protein, 5 2 4 Basal ganglia Bcr-abl tyrosine kinase, 5 2 2
Bafilomycin A1 nicotinic acetylcholine recep- BCUT descriptors
flavivirus antiviral, 5429 tors, 2:389 defined, 1:399
Bak protein, 5:19 and Parkinson's disease, estimation systems, 1:388
Baldness, 4433. See also Hair 6:713, a 7 1 4 for molecular similarityldiver-
growth disorder drugs Basal lamina, 5:216 sity methods, 1:193-194,
Bambuterol Basen, 4 3 2 1:203-204
prodrug, 2:504-505 Basiliximab, 5:490,5:510-513 with pharmacophore finger-
BANA compounds Basophilic granulocytes, 3:252, prints, 1:223-224
antiviral application, 3253 for target class-focused ap-
5372-374 Basophils proaches, 1:228-229,
Banthine chemokinelcytokine receptors, 1:232-233
anticholinergic, 6:128, e l 3 7 4133 BCX-1812
Baogongteng-A Batimastat, 5:217, 5:218 for influenza, 5:364,
cholinergic, 6:79 for Alzheimer's disease, 6:752 5374-376
BAPTA-AM, 3:160,3:170-171 Bax protein, 5 1 9 structure-based design, 1:452
Barbital, 6:204 Bay 12-9566 BDE index, 1:11
Barbitalum, 6:204 antiangiogenic agent, 5217 BE-18257A
Barbiturate antianxiety agents, BAY 139952,3368 endothelin receptor antago-
6:527 Baycaron, 3:82 nist, 3206
Barbiturate anticonvulsants, Baycol, 3:343 BE-18257B
6:271 Bayer ~7195,4222-223 endothelin receptor antago-
ADME, 6:282 Bay g2821,3:108 nist, 3206
structure-activity relationship, Bay K8644,3:178 Bebulin
6:306-307 calcium channel agonist, hemostatic preparation, 3292
Barbiturate sedative-hypnotics, 3160,3:161,3:175 Beclomethasone dipropionate,
6:203 Bay X1005,4217-219 3750, 3753
ADME, 6:211-217 Bay Y1015,4:218 Beilstein Database, 1:362, 1:385
currently used drugs, Bay Y5959 Beilstein Online, 1:385
6:204-205 calcium channel agonist, Belladonna alkaloids, 6:120 -126
discovery, 6:235 3:175 Bemitradine, 387-89
pharmacologic effects, 6:229 BBNH Benactyzine
receptor interactions, 6:237 anti-HN drug, 5:473 relative anticholinergic activ-
side effects and drug interac- BBR 2778 ity, 6:156
tions, 6:203-206 topoisomerase I1 inhibitor, Benadryl, a 2 1 4
structure-activity relation- 568,571 for Parkinson's disease, 6:731,
ships, 6:237 BBR 3464 a732
structure-function relation- alkylating agent, 554,5:61 selective toxicity, 5275
ships, 6:246-247 B-cell receptors, 5224 Benanomycins, 5:908
Barium meals, 4488 B-cells, 3:253,3:254 Bench-scale synthesis experi-
Barium metatitanate and adaptive immunity, ments, 2:408,2:411-414
radiopaque material, 4493 5~224-225 Bendroflume thiazide, 3:76
Cumulative Index

Benzodiazepine anticholinergics, structure-activity relationship,


hemostatic preparation, 3:292 6:128-129 6:186
Benemid, a139 Benzodiazepine anticonvulsants, Benzthiazide, 3:76
Benflumetol, 5:978 6:271 Benztropine mesylate
Benicillin, 5:632 ADME, 6:282 for Parkinson's disease, 6:731,
Benidipine, 3:21 structure-activity relationship, 6:732
bioavailabilityand half-life, 323 6:307-310 Benzylpenicillin, 1:868, 1:870. .t
cardiovascular effects, 3:24 Benzodiazepine libraries, 2:4, See also Penicillin G
Benign prostatic hypertrophy 2:15-18 chemical delivery system,
Benzodiazepine receptors 2:583
expression probabilities, 1:343
fluorescence polarization stud- p-lactamase classification
Benserazide
based on activity, 5619
for Parkinson's disease, 6:724, ies, 2:48
structure, 5:628
6:730 GABAA/benzodiazepinerecep-
in vitro antibacterial activity,
Bentazepam, 6:554 tor complex, 6:538-541 5:667
Bentyl, a134 Benzodiazepine sedative-hypnot- (R)-2-Benzylsuccinic acid, 1:746
Benzacetamide ics, 6:206 Bepridil, 3:17,3:18,3:32
analgesic, 6:387-388 ADME, 6:217-220 cardiovascular effects, 3:16,
Benzamide clinical pharmacology, 3:44
PARP inhibitor, 6:680 6:230-234 multiple inhibitory mecha-
Benzamide antipsychotics currently used drugs, 6:207 nisms, 3:33
structure-activity relation- discovery, 6:235-236 uses and side effects, 3:43
ships, 6:627-631 pharmacologic effects, Beraprost, 3:328,3:329
Benzamidines 6:229-230 Beriberi, 4387488,4389
inhibitors of trypsin, 1:120 receptor interactions, 6:237 Besipirdine
residues in pseudopeptide ar- side effects and drug interac- cholinergic, 6:79
rays, 2:12 tions, 6:206-208 Bestatin, 1:652, 1:654, 1:728
Benzanthrone derivatives structure-activity relation- Best mode, patents, 2:723-724
RSV antiviral agents, 5395 ships, 6:237-242 provisional applications,
Benzbromarone, 3:139, structure-function relation- 2:726,2:727
3:141-142 ships, 6:247-251 p,-Agonists
Benzedrine, 6:172 Benzoisothiazole antipsychotics soft drugs, 2:554-555
Benzene pharmacokinetics, biotrans- P,-Antagonists, See p-Blockers
electron density, 1:135 formation, and drug interac- P-Blockers, 1:881-882,6:2. See
intermolecular interactions, tions, a639 also alp-Adrenergic receptor
1:174 Benzolamide, 3:69,3:70 antagonists
Benzhexol Benzomorphans, 1:850 as antiarrhythmic agents,
relative anticholinergic activ- analgesics structure-activity 3:179-180
ity, a157 relationships, 6:373-376 applications, 6:16
stereoisomerism, 6:149 Benzophenone sunscreens as class I1 antiarrhythmic
Benzimidazole antihelmintics, structure-activity relationship, agents, 3:31,3:32,3:38-40,
51090-1093 4469 3:167
Benziodarone, 1:884 Benzopyran currently used drugs, 6:5
Benzisoxazole antipsychotics enzyme-mediated oxidation, discovery, 2:40
pharmacokinetics, biotrans- 1:806 effect on coronary care unit
formation, and drug interac- Benzothiadiazine diuretics, mortality after introduction,
tions, 6:639 3:76-77 3:156
Benznidazole Benzothiazepine anticholin- enantiomers, 1:786
for American trypanosomiasis ergics, 6:129 gene expression profiling
(Chagas' disease), Benzothiazepine calcium chan- study, 4612
5:1046-1047 nel blockers, 316-20 with implantable cardioverter
Benzodiazepine antianxiety Benzoxazole PARP inhibitors, defibrillator, 3:46
agents, 6:528-531 6:681-682 membrane function disrup-
discovery, 6:546-548 Benzphetamine, 6:171 tion, 2:614
metabolism, 6:533-536 absorption and metabolism, nonrenal clearance, 1:39
structure-activity relation- 6:861-863 prodrugs, 2:520
ships, 6:548-578 dose, a845 renal clearance, 1:38
!
r Cumulative Index

soft drugs, 2:540-544 Bi-directional conduction block, homogeneous and nonhomo-


synergy with amiodarone, 3:29 geneous, 2:45,2:46-49
3:46 Bid protein, 6:19 miniaturization. 2:66-67
Betagan, 6:5 Bifenthrin, 1:41, 1:42 peptide hormones, 4 5 2
Betaine Biguanides, 4:21-24 for profiling of high-through-
long-chained esters, 2:561-562 topical antibacterials, put screening hits, 2:59-62
Betamethasone, 3:604,3:750, 5:554-555 Bioavailability, 1:716,2:636, 7
3:752,3:764-766,3:770, BIIL 284,4228,4229 2:638-639
3:772,3:788,3:797,3:803, Bik protein, 5:19 assessing effect of meals in
3:813-816,3:824, Bile acid response element, Phase I trials, 2:646
3:830-833 2:278 characterization for IND pro-
Betamipron, 5:693 cess, 2:645
Bile acids, 2:277-285, a594
Betapace, 6:5 and coadministration with
Bile acid sequestrants/choles-
P-Site APP cleaving enzyme 1 food, 2:672
terol absorption inhibitors
(BACEl), 6:753 lipid formulations, 2:671
P-Site APP cleaving enzyme 2 ADME, 3357
and permeability, 2:659
(BACE2), a753 for angina treatment, 311 prodrugs, 2:522-523
Betaxolol clinical applications, in vivo toxicity testing, 2:619
P-antagonist, 6 5 3:347-349 BioCatalysis database, 1:384
applications, 6:16 marketed agents, 3:343 Biochemical force fields,
Betaxon, 6:5 new treatments for lowering 1:175-176
Betoptic, 6:5 LDL and TG, 3:368-370 Biochemical shock
Bexarotene, 4320,4374 side effects, adverse effects, radioprotective agents, 6:169
Bezafibrate, 1:422,3:343,3:347 drug interactions, and con- Bioequivalence studies, 2:647
allosteric effectors of hemoglo- traindications, 3:355 Biogastrone, 6:158
bin, 3:388,3:389-394 structure-activity relationship, Bioinformatics, 1:333337,2:38,
for angina treatment, 3:11 3~364-365,3:365-366 2:42
enzyme activity, 3:365 Bile acid transporter inhibitors, databases, tools, and applica-
metabolism, 3:357 2:285 tions, 1:345-349
Bezalip, 3:343 Bile salts defined, 1:399
Biapenem, 5:693 permeation enhancer, 2:676 DNA microanays, 4605-606
in vitro activity, 5:692 Binary data, 1:373, 1:399 and functional genomics,
Bibenzimidazoles Binary QSAR, 1:4 1:338-340
radioprotective agents, 5:172 Binders, 2:678 future developments, 1:354
BIBN4096BS Binding affinity, 1:286 and gene expression profiling,
calcitonin gene-related peptide activity contrasted, 1:131-135 4614
antagonist, 3:222 calculation, 1:118-122 and sequences, 1:364
BIBP 3226, 1:670, 1:673 Binding constant, 1:286 standardization, 1:337
neuropeptide Y antagonist, Binding-gating problem, in nico- and structural genomics,
3212 tinic acetylcholine receptors 1:352-354
BIBR 953 (muscle-type), 2:368-370 for target discovery, 1:335,
structure-based design, 1:443, Binding property classes, 1:192 1:338-345
1:448 Binding site models, 1:130 Bioinformatics knowledge
BIBR 1048 Binge eating disorder, model. 1:349-352
structure-based design, 1:442, 6:840-841,6:842 Bioisosteric replacement ana-
1:443 Binge eating drugs, 6:849-853 logs, 1:689-694
BIBU52, 1:213 new drugs in development, Biological data, 1:399
Bicalutamide, 3:717,3:720 8:881-886 Biological evaluation
Bicarbonate Bioactivity databases, 1:386 in structure-based design,
neutralization in kidneys, 3:58 Bioadhesives, 2:676 1:419
Bicuculline Bioaffinity screening Biological properties
nicotinic receptor antagonist, by electrospray FTICR MS, key properties of interest,
2:389 1:601-603 2:654
Bicyclam Bioassays. See also Cellular as- Biological rhythms
anti-HIV drug, 5:467 says and metabolism, 2:474
Bicyclic polyaza diuretics, construction, 2:45-46 Biopharmaceutics Classification
3:128-130 design, 2:44-45 System, 2:665-666
Cumulative Index

Bioreductives (hypoxia-activated Bismuth subnitrate Bleomycinic acid, 5116-117,


prodrugs), 5:83-87 radiopaque, 4489 5118
radiosensitizers, 5:181-182 18,19-Bisnortestosterone,3:707 BLOB (Binary Large Object)
BioScreen NPISC, 1:385 Bisoprolol, 3:28 data type, 1:399
BIOSTER database, 1902, P-antagonist, 6:5 Blockbuster drugs, 4422,4:423
1:384 applications, 6:16 Blood-brain barrier, 2:577
T
Biosterism, 1:689-690 Bisphosphonates Blood cell development,
and obviousness of patent selective toxicity, 5273-274 3252-255
claims, 2:732 Bistriazoloacridone Blood clotting, 3:284-291,
Biotechnology revolution, 2:705 anti-HIV drug, 5474 3299-308
Biotin, 4:402-405 Bis-triiodo-1,3-benezenedicar- Blood coagulation, 3:284,
deficiency, 4405 boxamide radiopaques, 3:299308
FRET studies of binding to 4497 Blood oxygenation, 3:8-9
streptavidin, 2:48-49 Bis-triiodobenzoate radiopaques, Blood substitutes, 3:388
genetic algorithm study of 4497 clinical trials, 3:398-421
docking to streptavidin, Bisubstrate analog enzyme in- history of, 3:396398
1:89 hibitors, 1:741-742 structure-based design, 1:424
hypervitaminosis biotin, 4405 Bisucaberin, 3:483,3:486 Blood thinners, 3 2 9
interaction with streptavidin, synthesis, 3:527-528 Blood transfusion, 3396
1:181-183 Bithionol erythropoietin use leads to
in leucine catabolism, 4406 antihelmintic, 5:1091, decline in, 3:272
vitamin status assays, 4:367 51095-1096 Blood vessels
Biotransformations database, Bitolterol angiogenesis, 5216
1:384 P-agonist, 6:4 angiogenesis inhibiting com-
Biperiden applications, 6:14 pounds, 5216-220
for Parkinson's disease, 65'31, structure-activity relationship, Bloom's syndrome, 5 3 2
6:732 6:28 Bluensomycin, 2:172
Biphenyls Bitset, 1:399 B-lymphoblasts, 3253
privileged structures, 1:252 Bivalirudin, 3:29, 3:285, B-lymphocytes, See B-cells
Biphenyl tetrazole, 1 2 3 1 3316317 BM 06.022, 2:85
BIRB-796 ADME, 3:296 BM 573,3327
structure-based design, clinical trials, 3293 BMS-40383,5680
1:458-459 formula weight, mechanism of
BMS-40591,5:680
Birth control agents, See Con- action, and route of admin-
BMS-45047,5:681
traceptives istration, 3286
Bis[3,5-dibromo salicyllfumarate structure, 3:288 BMS-45742,5680
sickle hemoglobin modifier, BL-1743 BMS-180549
3461 influenza antiviral agent, radiopaque material, 4491
Bis-ethylhexyloxyphenol me- 5:388 BMS-181139,5:680
thoxyphenol triazine BLAST (Basic Local Alignment BMS-181184,5:908,5:909
(BEMT),4472 Search Tool), 1:347,2:42 BMS-182874
N-JV'-Bis(2-hydroxybenzy1)eth- Blastomeres, 2:626 endothelin receptor antago-
ylenediamine-N-JV'-diacetic Blastomyces dermatitidis, 5:883 nist, 3206
acid (HBED) Blastomycosis, 5:883 BMS-182880,5:681
animal studies of iron chela- Bleeding disorders, 3:291 BMS-193884, 1:674, 1:676
tion, 3:515-520 BLEEP potential, 1:312 BMS-194449,6:33
formation constants with iron performance in structure pre- BMS-196085,6:33
and other metals, 3506 diction, l:314 BMS-200475
pM values, 3:484 Blenoxane for hepatitis B virus,
preclinical toxicity trials, antitumor natural product, 5:331-332
3520-522 5:115-120 BMS-201038, 3368
use with animal models, Bleomycin BMS-247550, 1:864, 1:865
3:537-540 antitumor natural product, BMS-275291
Bisindolylmaleimides 5:110,5:115-120 antiangiogenic agent, 55217
influenza antiviral agents, with tirapazamine, 5 8 5 BMS-298585,3:370,3:371
5388-389 with vinblastine, 5:140 BMY-15037-1,387
Cumulative Index

BMY-26270 Bones Bradykinin


influenza antiviral agent, thyroid hormones effect on, biological actions, 3:225-226
5:387 3:572-573 biosynthesis, metabolism, and
BMY-27709 Bontril, 6:846 structure, 3:224-225
influenza antiviral agent, Bontril PDM, a 1 7 1 Bradykinin antagonists, 3:226
e377-378 Bontril Slow Release, a 1 7 1 Bradykinin receptors, 3:225 z
BMY-27946, k681 Bordetella pertussis toxin Brain creatine kinase
BMY-40732,5:681 effect on chemokines, 4:134 plasmid DNA-mediated gene
BMY-40886,5:681 Born-Oppenheimer approxima- therapy study, 4:655
-
BMY-183021 tion, 1:79 Brain natriuretic peptide, 3:214,
influenza antiviral agent, Born-Oppenheimer surface, a215
5:387 1:85 biological action, 3:217-218
BMY-183355 Boronate residues biosynthesis, metabolism, and
structure, 3:216
influenza antiviral agent, in pseudopeptide arrays, 2:12,
Brain targeted redox analogs,
5:387 2:13
2591
BN80933 Boron neutron capture therapy, Brain-targeting chemical deliv-
nitric oxide synthase inhibi- 5:173-174 ery systems, 2:576-591
tor, 6:706 Bosentan Brallo barbital, a 2 0 5
BO-653,3:373 endothelin receptor antago- Branched DNA, 2:623-624
Board of Patent Appeals and nist, 3:206, a 2 0 7 Brand loyalty, and trademarks,
Interferences, 2:714,2:735, Bothropsjararaca (pit viper), 2:757
2:736 1:881 BRCA-1 gene, 5:8, 5:10, 5:27
Body mass index, 6:839,6:842 Bovine liver DHFR, QSAR inhi- BRCA-2 gene, 5:27
Body weight, 6:867-869 bition studies, 1:34 Breast cancer
adrenergic and serotonergic Bovine pancreatic trypsin inhibi- cell characterization by gene
regulation of food intake, tor expression profiling, 4:608
6:873-874 long range electrostatic ef- tissue attenuation of x-rays,
genetic factors, 6:874 fects, 1:177 4486
and neuroendocrine regula- Bowman's capsule, 3:57 Breast cancer resistance protein,
tion of energy homeostasis BP-897 5:285, 5286
by hypothalamus, experimental smoking cessa- Brefeldin, 2:259
6:869-872 tion agent, 4459 rotavirus antiviral, 5:430
nucleus tractus solitaris and BQ-123 Bremsstrahlung, 4484
Brequinar, 5:489
peripheral satiety signals, endothelin receptor antago-
clinical use for organ trans-
6:873 nist, 3:206
plants, 5:516-518
peripheraVcentral adiposity BQ-153 with leflunomide, $523
signals, 6:872-873 endothelin receptor antago- side effects, 5:518
Body weight disorders, nist, 3:206 Bretazenil, 6:563-564
6:838-839 BQ-485 Brethine, 6:4
Bijhm scoring function, 1:264 endothelin receptor antago- Bretylium, 3:32,3:41, 3:167
Bolasterone, 3:709 nist, S:206 cardiovascular effects, 3 4 2
Boltzmann law, 1:93, 1:310-311 BQ-610 multiple inhibitory mecha-
Boltzmann probability, 1:94 endothelin receptor antago- nisms, 3:33
Boltzmann weighted average, nist, 3:206 uses and side effects, 3:40
1:97, 1:98 BQ-788 Brevibloc, 2:576,6:5
Bombesin, 3:229 endothelin receptor antago- Brevital, a 2 0 4
BOMT, 3:719 nist, 3:206 BRIDGE, 1:113
Bonadorm, 6:209 BR2 Brimonidine
Bond stereochemistry, 1:365, radiopaque material, 4574 a,-agonist, 6:3
1:399-400 BR21 applications, 6:13-14
Bone marrow transplantation radiopaque material, 4574 structure-activity relationship,
and organ transplant rejec- Bradycardia, 3:9,3:31 6:31
tion, 5:524 Bradykin, 1:746, 1:881 Brinaldix, 3:82
for sickle-cell anemia, targeted library design, 1:69, Brinzolamide, 3:67
3:465-466 1:70 Bristuron, 3:76
Cumulative Index

Brivudin Brush polymers inhibition of serotonin, norepi-


for herpes virus, 5:308 resins for combinatorial li- nephrine, and dopamine
BRL-32872,3:45-46 brary synthesis, 2:29 transporters, 6:500
BRL-36650,5636-637 Bryostatin-1, 1:868, 1:869 mechanism of action, 4455
BRL-41897,5651-652 BTA-188 pharmacokinetics, 4453-454,
BRL-42715,5:698-699 picornavirus antiviral, 5402 6:497
arnoxycillin MIC, 5695 BTM-1086 for sexual disorders, 4:450 9
0-lactamase inhibitory activ- anticholinergic, 6:129 side effects profile, 6:493
ity, 5695 BU48,6:371 structure-activity relationship,
BRL-44154,5634 Budapest Treaty, 2:723 4456-457
in vitro antibacterial activity, Budesonide, 3:750, 3:753,3:775, B/U ratio, of contrast agents,
5635 4538
3:824,3:827
BRL-52974 Bureau of Narcotics and Dan-
Bufuralol
analgesic, 6:394 gerous Drugs, 2:686-687
BRL-57342,5643 renal clearance, 1:38
Burinex, 3:88
BRL-52537A soft analogs, 2:543-544,
Burst-forming units, 3:253,
analgesic, 6:391, 6:392 22569-570
3256
BRL-52656A Bugula neritina, 1:868 Bush classification, of p-lactam-
analgesic, 6:391, a392 Building block hypothesis, 1:88 ases, 5621
BRN (Beilstein Registry Num- Bulaquine, 5:953-954 Business rules, 1:378, 1:400,
ber), 1:378, 1:400 dosage forms, 5934 1:403
Broad spectrum antiviral agents, Bulimia nervosa, 6:840-842 BuSpar, 6:529
5432-435 Bulimia nervosa drugs, 6:843, Buspirone, 6:530, a566
Brobactam, 5700 6~849-853 for anxiety disorders, 6:531
Brofaromine Bumetanide, 3:88,3:95-103, dose for anxiety, a 5 2 9
for Parkinson's disease, 6:729, 3:142 metabolism, 6:536-537
6:730 Bunamiodyl Butabarbital, 6:205
Bromazepam, 6:207,6:530 biotransformation, 4565 Butalbital, a 2 0 5
dose for anxiety, 6:529 cholecystography application, Butallylonal, 6:205
Bromfenac 4:570 Butenahe, 5:899-900
removed/restricted by FDA, Bundle branches, 3:4 formulations and indications,
4642 Bundle of His, 3:3,3:4 5891
Bromoaspirin, 1:763 Butethal, 6:205
a-Bungarotoxin
Bromobutide, 1:42 Buthiazide, 3 7 6
ligand for nicotinic receptors,
Bromocriptine Butirosin, 2:183
for Parkinson's disease, 6:722, 2:358,2:386,2:388, 2:389,
Butisol, a 2 0 5
a725 2:390,2:391,2:394
Butoconazole
Bromodeoxyuridine K-Bungarotoxin
formulations and indications,
radiosensitizer, 5194-195 ligand for nicotinic receptors, 5:891
5-Bromo-2'-deoxyuridine 2:394 Butorphanol, 6:335,6:372
PARP inhibitor, 6:681 Bupivacaine 3-Butylamino-4-chloro-5-sulfa-
5-Bromouracil selective toxicity, 5:273 moylbenzoic acid, 3 9 5
PARP inhibitor, 6:681 Bupivacaine hydrochloride, N-Butyl deoxynojirimycin,
Bromperidol 1:805, 1:806 2:218,2:220,2:240
HIV protease inhibitor, 1:111, classical resolution, 1:795, Butyrate
1:112 1:796 for sickle-cell anemia, 3:465
Brompheniramine Buprenex, 6:335 Butyrophenone antipsychotics
over-the-counter status, 4426 Buprenorphine, 1:850-851, pharmacokinetics, biotrans-
Bronchodilators, 6:172 6:335, a 3 7 1 formation, and drug interac-
adrenergics, 6:2 Bupropion, 4451, 4:452, 6:494, tions, 6:637-639
currently used drugs, 6:171 6:885 structure-activity relation-
Bronchography, 4567. See also adverse effects, 4453 ships, 6:625-627
Radiopaques affinities for monoamine re- Butyrylcholinesterase, 6:40,
Bronkosol, 6:4 ceptors, 6:495 6:87
Brotizolam, 6:207, 6:554 antidepressant, 6:485, 6:486, B19 virus, 5:304
Brusatol a489 B-W 322,5:490
antimalarial, 5998 development of, 4457-458 BW-A4C, 4:213
Cumulative Index

BW-B7OC, 4213-214 Cahn-Ingold-Prelog stereochem- N-channel anticonvulsants,


BW-12C istry, 1:365, 1:400 6:318319
antisickling agent, 1:419-420 Calabash curare, 1:856 soft analogs, 2:566
BW-723C86, a572 Calcineurin A. 2:100 termination of ventricular fi-
BW-755C, 4:212 X-ray crystallographic studies, brillation, 3:160
BW-373U86,6:395-399 1:483 Calcium channels, 3:7-8 f
BW-1476U89,1:742-743 Calcipotriene, 4:378 Calcium channels, T-type
BW-1555U88 Calcitonin, 3218-219 and anticonvulsants, 6297
anorectic agent, 6:883, 6:885 and vitamin D, 4376,4:377 Calcium pantothenate, 4401,
BX471.4142-143 Calcitonin gene-related peptide, 4:402
3218-220 Calcium tungstate
(2-1311 and substance P, 3:223
radiopaque material, 4493
topoisomerase I1 inhibitor, therapeutic potential, 3:221
Calibration program
6: 72 Calcitonin gene-related peptide
family for large-scale synthesis, 2:419
12C79 Calmette-Guerin, 6:819
biological actions, 3:221
allosteric effector of hemoglo- Calomel, 3:65
biosynthesis, metabolism, and
bin, 3:388,3:394,3:395 structure, 3218-220 Calusterone, 3:698,3:700
C22 in spinal cord motoneurons, Cambridge Crystallographic Da-
influenza antiviral agent, 3:214 tabase, 1:110
5379 therapeutic potenial and an- Cambridge Structural Database,
Cabergoline tagonists, 3:221 1:354, 1:387
for Parkinson's disease, 6:722, Calcitonin gene-related peptide X-ray crystallography applica-
6:725 receptors, 3:220-221 tion, 1:479
Cachexia secondary to other dis- Calcitriol, 4377 CAMP
eases, 6:838,6:840, 6:874 and calcium reabsorption in after myocardial infarction,
guidelines for treatment, kidneys, 3:59 3:158
6:842-843 Calcium and G protein coupling to ad-
Cachexia therapeutics, 6:854 and arrhythmias, 3:159-162 renergic receptors, 6 9 5
absorption and metabolism, and cancer prevention, 6:33 molecular property visualiza-
6:866-867 effects on neuronal nicotinic tion, 1:137
clinical applications, 6:858 receptors, 2:386-387 role in clotting, 3306
structure-activity relation- reabsorption in kidneys, 3:59 TSH effect on, 3:568, 3:572
ships, 6:877-880 regulation by vitamin D fam- CAMP assays, 2:74-75,2:79
Caco-2 cell systems ily, 4 3 7 6 3 7 7 Campath, 5:229,5:233
permeability studies, 2:659, role in heartbeat, 3:4-5 CAMP-dependent protein ki-
2:660,2:666 role of cytosolic after myocar- nase, 3:158
Cactinomycin-3, 5:111 dial infarction, 3:157-159 D-Camphor
CACTVS, 1:254 Calcium channel agonists, connection table, 1:367
Cadherins 3~175-176 tabular molecular file formats,
and carcinogenesis, 5:8,6:10 Calcium channel antagonists, 1:370371
hypermethylation, 5:9 3:168 CAMPphosphodiesterase I1 in-
targets of antiangiogenic Calcium channel blockers, 3:6, hibitors
agents, 5:220 3:15-16. See also ACE in- molecular modeling, 1:130
Caffedrine, 6: 170 hibitors; @ Blockers Camptotheca acuminata, 1:860,
Caffeine, 6:169-172, 6:174 anticlotting agents, 3:29 5:130
complexation, 2:670 arylalkylamines and benzo- Camptothecins
diuretic action, 3:121 thiazepines, 3:16-20 antitumor natural products,
dose as anti-obesity agent, cardiac glycosides, 3:28 5:110,5:130-134
6:846 as class IV antiarrhythmic drugs derived from,
lipolytic agent, 6:857,6:859 agents, 3:31,3:32,3:43-44, 1:860-861
PARP inhibitor, 6:681 3167-168 Canada
physiology and pharmacology, 1-4 dihydropyridine deriva- patentable subject matter,
6:184 tives, 320-28 2:720
radiosensitizer, 5193 effect on endothelin, 3207 patent public disclosure, 2:772
side effects, adverse effects, glycoprotein IIbDIIa receptor Canaline
and drug interactions, 6:176 antagonists, 3 2 9 antimalarial, 5:987, 6:988
Cumulative Index

Cancer. See also Anticancer Cannabinoids brief description, a609


drugs; Antitumor drugs; discovery, 2:39 p-lactamase inhibitors,
Carcinogenesis; Oncogenes lead for drugs, 1:852-854 5:699-700
activation enzymes in cancer soft analogs, 2:566 orally active, 5:709-710
gene therapy or gene-di- Cannabis sativa, 1:852 pharmacokinetics, 5:623-624
reded enzyme prodrug Canonical numbering, 1:378, polycyclic, 5:683-688
therapy, 2:517-518 1:400 synthesis, 5:671-675 T
carbohydrate-based agents in C-ANP,,,, 3:134 use recommendations, 5:626
research, 2:225-227 Cantil, e l 3 7 Carbecillin, 5:609
carbohydrate-based therapeu- Capillary electrophoresis Carbenicillin, 5:632 -
tics in development, for enantiomer separation, indications, 5:625
2:216-218 1:787 P-lactamase classification
cell characterization by gene Capreomycin based on activity, 5:619,
expression profiling, antimycobacterial application, 5:620,5:621
4606-608 5:811,5:844-846 pharmacokinetics, 5:624
and COX-2 selective inhibi- efficacy and dosage, 5:811, prodrugs, 2:510
tors, 4249-250 5:863 Carbenin, 1:849
drug resistance in chemother- side effects, 2845-846 Carbenoxolone
apy, 5:281-290 Caproctamine antiulcer application, 6:158
electron-afinic drugs in che- anticholinesterase, 6:95 Carbidopa
motherapy, 5:180-183 Capsaicin, 1:854 for Parkinson's disease, 6:724,
epigenetic changes, 5:7-10 Capstat, 5 8 1 1 a730
genes related to, 5:21-32 Captopril, 1:646, 1:650, Carbochloral, 6:208, a209
and genetic instability, 1:746-747, 1:881,2:565, Carbofluorene
519-20 3:198 relative anticholinergic activ-
and genetic variability, 5:5-7 asymmetric synthesis, 1:807, ity, a156
heritable syndromes, 5:32 1:809 Carbohydrate-based drugs,
impact of, 5:2 combinatorial library of ana- 2:203-205. See also Heparin
interventions, 5:32-46 logs, 2:18,2:20 agents in research, 2:219-227
molecular basis of phenotypes, impact of ACE polymorphisms analysis, 2:232
5:lO-21 on effectiveness, 4634 carbohydrate chemistry,
prevention strategies, 5:32-33 and snake venom peptides, 2:6 2:227-236
radioprotective agents in ther- structure-based design, enzymatic chemistry,
apy, 5:172-173 1:432-433, 1:434 2~229-230
selective toxicity in chemo- Capture extenders, 2:623 glycobiology, 2:236-242
therapy, 5:257-259 Carbacephalosporins, 5:654 glycoconjugates, 2:237-239
tumorigenesis, 5:2-3,5:5-7 Carbacephems glycoproteins, 2:231
Cancidas, 5:890,5:900-901 brief description, 5:609 and health and disease, 2:242
Candida, 5:882,5:883 Carbamate anticonvulsants immunogens, 2:239-240
diagnostic and microbiological ADME, 6:284-285 lectins, 2:240-242
issues, 5:885 Carbamate-derived cholinergics, to market last decade,
intrinsic resistance to antifun- 6:88-90 2:205-211
gals, 5:885 Carbamates multivalency, 2:233-235
Candida albicans, 5:882, 5:883 pharmacophore points, 1:249 natural product isolation,
biosynthesis and function of synthesis, 3:525 2:232-233
ergosterol, 5:886-888 Carbamazepine solid phase chemistry, 2:230-231
iron uptake by, 3:494-495 ADME, 6:275 solution phase chemistry,
Candida glabrata, 5:882 anticonvulsant, 6:265,6:266, 2:227-229
Candida krusei, 5:882 6:267,6:298,6:306,6:319 therapeutics in development,
Candidaparapsilosis, 5:882 clinical efficacy, 6:273 2:211-219
Candida tropicalis, 5:882 dose, 6:270 Carbohydrate chemistry,
Candidiasis, 5:882,5:883 side effects, 6:276 2:227-236
Candin antifungal agents, 5:890, Carbapenams, 5:609 Carbohydrate libraries, 2:231-232
5:900-903 Carbapenems, 5:668-671 Carbohydrate metabolism. See
Candoxatril, 1:815, 1:818,3:136 anti-gram-positive, 5:703-705 also Glucose
Candoxatrilat, 3: 136 biological properties, androgen effect on, 3:682
Cangrelor, 3:320, 3:321 5:688-694 enzymes involved in, 433-37
Cumulative Index

i
I
role of insulin, 4 2 genetic algorithm study of ac- Cardrase, 3:70
I thyroid hormone effect on, tive site, 1:89 Cardura, 6:4

/ 3:571
Carbo index, l:202
Carbonate
molecular modeling, 1:116
Carbrital, 6:209
Carbromal, 6:208,6:209
Caretakers, 5 2 6
Carfecillin, 2:510, 5:609
Carfentanil, 6:382
binding to hemoglobin, 3:386 Carbutamide, 4 1 8 Carinamide, 3:139
2-Carbon chain elongation, Carcinogenesis, 5:3-5 Carisoprodol 'Z
2~460-461 and apoptosis, 5:16-19 CYP2C19 substrate, 4:627
I Carbon dioxide and diet, 5:7 Carmustine
i binding to hemoglobin, and DNA repair, 5:4,5:5 alkylating agent, 5:54, -
i 3:386-387 epigenetic changes, 5:7-10 564-65
Carbonic acid and ionizing radiation, 5 4 , L-Carnitine esters, 2562
533 a-Carotene, 4:369
production in kidneys, 3:58,
and transforming growth fac- p-Carotene, 4320-321,
3:68
tor p, 530-32 4368-370
Carbonic anhydrase, 3 6 8
UV radiation effects, asymmetrical cleavage,
action in kidneys, 3:58,3:59, 4465-466 4322-323
3:61 Cardiac arrhythmias, 2:76,3:3. symmetrical cleavage,
Carbonic anhydrase inhibitors, See also Antiarrhythmic 4321-322
1:718 agents; Long QT syndrome y-Carotene, 4369
diuretic agents, 3:66-70 and calcium, 3:159-162 Carotenes, 4 3 6 8 3 7 1
4-fluorobenzenesulfonamide disorders in electrical signal Carotenoids, 4:320321
binding to, 1:538 generation and conduction, Carpetimycin A, 5:670,5:671
molecular modeling, 1:120 329 CAR receptor, 2:79
selective toxicity, 5264 heart block, 329-30 Carrier-mediated transport,
virtual screening for, 1:316 malignant, 3:157-164 2:254,2:257-258,2:658
Carbonic anhydrase I1 inhibi- and myocardial oxygen de- Carrier moiety, prodrugs, 2:500,
tors, 1:718 mand, 3:9 2:503,2:525
novel lead identification by re-entrant, 3:30-31,3161 CART, 1:67
virtual screening, 1:320 role of extracellular potas- Carte0101
X-ray crystallographic studies, sium, 3:163-164 P-antagonist, 6:5
1~483-484 thyromimetics for, 3676 applications, 6:16
Carbon monoxide treatment perspective, Cartrol, 6:5
binding to hemoglobin, 3:386 333-34 Carumonam, 5:666
Carbon oxidation and reduction types of, 3:31 in vitro activity, 5:667
in metabolism, 2:441-445 Cardiac Arrhythmia Suppres- Carvedilol
Carboplatin sion Trial, 3:45 alp-antagonist, 6:5
alkylating agent, 5:54,5:59 Cardiac contractility, 3:9 applications, 6:16
with RSR13,5:190 Cardiac glycoside calcium chan- structure-activity relationship,
selective toxicity, 5257-258 nel blockers, 3 2 8 6:32
Carboprost, 4305 Cardiac physiology, 3:2-6 Carzelesin
p-Carboxybenzenesulfonamide, electrophysiology, 3:3-4 alkylating agent, 554,
3:70,3:71 excitation and contraction 561-64
Carboxylesterase, 2:538 coupling, 3:4-6 Cascade clustering
Carboxylic acids and ion channels, 3:6-8 with molecular similaritytdi-
pharmacophore points, 1249 Cardioangiography versity methods, 1:205
privileged structures, 1252 CT application, 4:568 CASE, 2:621
Carboxylic 3-deazaadenosine Cardiotoxicity screening, CASETox, 1246
activity against orthopoxvi- 2:627-628 CAS Numbers, 1:378, 1:400
ruses, 5439,5:440 assays in high-throughput Casodex, 3:717,3:720
Carboxypeptidase A screening, 2:62 P-Casomorphin analogs,
effect on urotensin-II,3:212 and long QT syndrome, 2:76 6:422-425
similarity of active site to Cardiotropin-1, 3269 CAS ONLINE, 1:361
ACE, 1:433, 1:746-747 Cardiovascular disease, 3:2 similarity searching, 1:383
Carboxypeptidase inhibitors Cardiovascular drugs Caspase-3
conformational changes on natural products as leads, and apoptosis, 5 1 8
binding, 1261 1:878-883 and cellular energetics, 6:680
Cumulative Index

Caspase-6 Catechol-0-methyltransferase CCK-A receptors, 6:544


and apoptosis, 5:18 (COMT)inhibitors CCK-B receptor antagonists,
Caspase-7 for Parkinson's disease, 6:573-575
and apoptosis, 5:18 6:731 CCK-B receptors, a544
Caspase-8 CATH, 1:353 CCK-4 receptors, &544
and apoptosis, 5:17-18 X-ray crystallography applica- CCK-8s receptors, 6:544
Caspase-9 tion, 1:494 CCNU P
and apoptosis, 5:18, 5:19 Catharanthus (vinca) alkaloids, alkylating agent, 5:54,
Caspase-1 inhibitors 1:858-860,5:139 5:64-65
target of structure-based drug Cathepsin B CC1 receptor, 4133,4138-139
design, 1:443 transition state analog inhibi- antibodies, 4139
tors, 1:654 peptide antagonists, 4139
transition state analogs, 1:655
Cathepsin D small molecule antagonists,
Caspase-3 inhibitors
combinatorial docking studies, 4:139-143
transition state analogs, 1:655 CC2 receptor, 4133,4143-144
1:318
Caspase-7 inhibitors non-peptide inhibitors, 1:227 antibodies, 4144
transition state analogs, 1:655 Cathepsin K peptide antagonists,
Caspases, 5:17-19 transition state analog inhibi- 4144-145
CASP experiment (Critical As- tors, 1:654-655, 1:656 small molecule antagonists,
sessment of techniques for (-)-Cathinone,(3169 4145-148
protein Structure Predic- structure-activity relationship: CC3 receptor, 4133,4:148-149
tion), 1:123, 1:353 6:185 antibodies, 4149
Caspofungin, 1:848, 1:878, Cationic dyes peptide antagonists,
5:888,5:900-901 radiosensitizers, 5:175 4149-150
formulations and indications, Cationic surfactants small molecule antagonists,
5:890 topical antibacterials, 4150-152
CASREACT, 1:385 5:555-556 CC4 receptor, 4133,4152-153
CAS Registry, 1:363, 1:385 Cation-P interactions, 1:286, CC5 receptor, 4133,4153-154
Catagen phase, of hair growth, 1:313 antibodies, 4:154-155
4425 enzyme inhibitors, 1:724-725 peptide antagonists, 4155
Catalase nicotinic acetycholine recep- small molecule antagonists,
hydrogen peroxide manage- tors, 2:364,2:375 4:155-159
Cations CC6 receptor, 4133,4159-160
ment, 3502
counterions suitable for salt CC7 receptor, 4133,4160-161
Catalyst (program), 1:259
formation, 2:651-652 CC8 receptor, 4133,4161
3D shape-based searching,
Cation-selective receptors, 2:360 CC9 receptor, 4133
1:199, 1:201 CATS descriptors, 1:192 CClO receptor, 4133
for novel lead identification, CAVEAT, 1:111, 1:113 CC receptors, 4:132,4:133,
1:321 Caverjet, 4442 4136-138
Catalyst/Hip/Hop, 1:60 CAVITY, 1:106-107, 1:108 CD36
CatalystIHypo, 1:60 CB 1954 interaction with sickled cells,
Catapress, 6:3 tumor-activated prodrug, 3:458
Catecholamide iron chelators, 5:83, 5:91-92 CD437,4350
3:483,3:485 CB 3717 CDK-4 gene, 5:27
synthesis, 3522-524 with permetrexed, 5 7 7 CDNA
Catecholamines, 2:391 CBS reduction, 1:814 in plasmid DNA-mediated
auto-oxidation, and Parkin- CC-83 gene therapy, 4652
son's, 6:716 antimalarial, 5:957 CDNA clone libraries, 1:341-342
and coronary occlusion, 3:156 CC-1065 CDNA microarray chips,
and cytosolic free calcium, alkylating agent, 5:61 1:344-345,4604
3158 for arming antibodies, 5:94 cancer studies using, 535-37
and malignant arrhythmias, CCD 1042 CD8-positive cytotoxic T-lym-
3:157 anticonvulsant, 6:314-315 phocytes, 5:224-225
TSH modulation, 3:568, 3572 CCF2 reporter gene assay, CD4-positive T-helper cells,
Catechol methyltransferase 2:50-51 5:224
X-ray crystallographic studies, CCK, receptor agonists CDRI 80/53,5:953-954
1:484 for eating disorders, 6:886 CDRI 87/209,5:942
Cumulative Index

Cefaclor, 1:872,5:609,5:639, indications, 5:625 Cell suicide, See Apoptosis


$640 pharmacokinetics, 6:624 Cell surface receptors, 4130
activity, 5644 use recommendations, 5:627 structure, 2259
oral absorption, 5:623 Ceftizoxime, 1:872, 1:873 Cellular adhesion proteins,
synthesis, 5:646-649 pharmacokinetics, 5:624 2:105-106
Cefadroxil, 1:872 Ceftriaxone, 1:872, 1:873 Cellular assays
oral absorption, 5:623 activity, 5640, 5641, 5:644 in high-throughput screening, r
Cefamandole, 5:609,5:639-640 biliary excretion, 5623 2:49-52
activity, 5:644 indications, 5625 in rapid, high-content phar-
pharmacokinetics, 5624 pharmacokinetics, 5:624 macology, 2:72-79 -
Cefazolin, 5639 use recommendations, 5627 Cellular communication,
activity, 5644 Cefuroxime, 1:872, 1:873,5:609, 22320-322
pharmacokinetics, 5624 5639-640 Cellular energetics, 6:679-689
Cefepime activity, $644 and NAD precursors,
activity, 5:641-642,5:643, pharmacokinetics, $624 6:687-690
5644 use recommendations, 5627 Cellular injury, 2:612-617
pharmacokinetics, 5:624 Cefuroxime axetil, 5:639, $640 Cellular proliferation assays,
use recommendations, 5627 Celebrex, 2:86-87,4:204,4:233, 2:2:76-77,2:50
Cefetamet pivoxil, 1:849 4234-235 Cellular retinol binding protein,
Cefixime clinical efficacy and safety, 4323,4:324
activity, 5:640, 5643,5:644 4248-249 Cellular toxicology assays,
Cefmetazole, 5:651 selective toxicity, 5274 2~76-77
synthesis, $650 Celecoxib, 4234-235, 4939 Centchroman, 3:662,3:663
Cefonicid assays, selectivities, and po- Center for Biologics Evaluation
pharmacokinetics, 5624 tencies, 4245 and Research, 2:688
Cefoperazone clinical efficacy and safety, Center for Devices and Radiolog-
activity, 5640, $641 4248-249 ical Health, 2:688
biliary excretion, 5:623 CYP2C9 substrate, 4:627 Center for Drug Evaluation and
indications, 5:625 selective toxicity, 5274 Research, 2:688
pharmacokinetics, $624 in vivo models, 4246 Center for Food Safety and Ap-
use recommendations, 5:627 Celestone Phosphate, 3770 plied Nutrition, 2:688
Cefotaxime Celestone Soluspan, 3771 Center for Veterinary Medicine,
activity, 5:640,5:641,5:644 Celexa, 6:485, a529 2:688
p-lactamase classification Celgosivir, 2:215, 2:220 Centocor, 3 2 9
based on activity, 5620 Cell-based partitioning methods, Central hypothyroidism, 3:574
pharmacokinetics, 5:624 1203 Central Library, 1:378, 1:387
Cefotetan, 5651 Cell-cell communication, Central nervous system, 6264
activity, $640, $641 4130-131 and body weight disorders,
use recommendations, $627 CellCept, 5519,5:520 6:838
Cefotiam, 2:510 structure-based design, nicotinic acetylcholine recep-
Cefoxitin, 5609, 5:651 1:446-447 tors, 2:389-392
activity, 5:640 Cell characterization opioid effects, 6:341
use recommendations, 5627 by gene expression profiling, Central nervous system cancer
. Cefozopran, 1:849 4606-608 cell characterization by gene
Cefpimizole, 1:849 Cell cycle expression profiling, 4:607,
Cefpirome changes in carcinogenesis, 4:608
activity, 5641-642,5:643, 5~14-16 Central nervous system (CNS)
$644 Cell-death assays, 2:76-78 drugs, See CNS drugs
Cefprozil Cell-free screening, 2:72 Centrifugation
selective toxicity, 5269 Cell lines in large-scale synthesis, 2:416
Cefratrizine patentability, 2:718 Centrine, 6:135
oral absorption, 5623 CELLMATE, 2:49 Centroids (in combinatorial li-
Cefsulodin, 1:849 Cell membrane-associated toxic- braries), 2:3,2:14-15
activity, 5:640, 5642 ity, 2:613-615 privileged molecules, 2:16
Ceftazidime, 1:872, 1:873 Cell proliferation, 5 4 Cephabacins, 5638
activity, 5:640,5:642,5:644, Cell-specific targeting of phage synthesis, 5649-650
5:667 display, 2:95-96 Cephacetrile, 1:871, 1:874
Cumulative Index

Cephalexin, 1:871-872,5639 Ceramide, 2:230,2:616 CGS 27023


activity, 5644 Cerebellum structure-based design, 1:444,
building blocks, 2:275 nicotinic acetylcholine recep- 1:446
oral absorption, 5:623 tors, 2:385,2:389 CGS 169494 3120-121
synthesis, 5646-649 Cerebral infarction, 6:676 CGS 27023A
Cephaloglycine, 1:871-872 Cerebral occlusion, 3289 antiangiogenic agent, 5217
oral absorption, 5623 Cerebral vasodilators, 3:12 CGS 25019c, 4228,4:229 P
Cephalolexin, 5609 Cerebrovascular disease, 3340 Chagas' disease (American
Cephaloridine, 1:871, 1:872 Cerivastatin, 1:880, 3:343, trypanosomiasis)
p-lactamase classification based 3:345,3:353 antiprotozoal agents for,
on activity, 5620,5621 ADME, 3:356 5:1035,5:1045-1047
Cephalosporin C, 1:870-871, for Alzheimer's disease, Chain branching alteration ana-
1:874, 5609
6:756-757 logs, 1:699-704
derivatives, 5:638-639
for angina treatment, 3:11 Chalicheamicin-type DNA cleav-
discovery, 5:637
total synthesis, 5:645-649 enzyme activity, 3:364 ing agents, 5 9 2
Cephalosporin combinatorial removedlrestricted by FDA, Change control programs, 2:420
libraries, 2:21, 2:23 4642 Channel blocker antagonists
Cephalosporins, 1:717, single nucleotide polymor- of nicotinic receptors (muscle-
1~870-871,5:637-639 phism~influencing response type), 2:382,2:383
anti-gram-positive, 5:703 to, 4644 Chapman databases, 1:387
antimycobacterial application, Certificate of Correction, for pat- Charge-charge interactions, 1:82
5858 ents, 2:738 Charge-coupled devices (CCDs)
carbacephalosporins, 5:654 Cerubidine for electron cryomicroscopy,
C7-a-formamido derivatives, antitumor natural product, 1:623
5:651-652 5:126-128 for miniaturized screening
C7-a-methoxylatedderiva- Cetirizine, 1:783 assays, 2:67
tives, 5650-651 chromatographic separation, for X-ray crystallography,
oxacephalosporins, 565.2-654 1:790-791 1:474
pharmacokinetics, 5623 Cetylpyridinium analogs, Charge-dipole interactions, 1:82
preventing bacterial degrada- 2:560-561 Charge parameterization,
tion, 1:718 CGMP 1:lOl-102
selective toxicity, 5:253-254, after myocardial infarction, Charge state determination
5260 3:158-159 NMR spectroscopy for, 1:526
side effects and interactions, and endothelin, 3203 Charge transfer energy, 1:173
5624-625 molecular property visualiza- CHARMM, 1:298, 1:299,
structure-activity relationship, tion, 1:137 12307-308
5639-645 role in clotting, 3:306 in molecular modeling, 1:118,
use recommendations, 5627 CGP 28238,4242 1:126
Cephalosporium acremonium, CGP 33101 CheD, 1:387
1:870,5:609,6:637 anticonvulsant, 6:313-314 ChemBase, 1:362
Cephalothin, 1:871, 1:874, CGP 37697,5660 CHEMCATS, 1:385
5609,5639 CGP 385604 3:197-198 CHEMDBS3D, 1:260,1:363
activity, 5644 CGP 51905A ChemDraw, 1:362
indications, 5625 antimalarial, 5:987, 5988 ChemEnlighten, 1:387
pharmacokinetics, 5:624 CGP 716834 6:887 ChemExplorer, 1:384
Cephamandole, 1:872, 1:873 neuropeptide Y antagonist, ChemFinder for Word, 1:384,
Cephamycins, 5:609,5:634, 3212 1:388
5638 CGS 4270,3:131 ChemFolder, 1:388
synthesis, 5649 CGS 8216,6:560 Chemical Abstracts (CAS) regis-
Cephapririn, 1:871, 1:874 CGS 9896,6:560 try file, 1:50
Cephazolin, 5:609 CGS 19755, a 6 5 3 Chemical Abstracts Service da-
Cephems CGS 23425,3:582-584 tabases, 1:254,1:361,1:385
brief description, 5609 CGS 24128,3:137-138 Chemical business rules, 1:378,
Cephradine, 1:872 CGS 24592,3:137-138 1:403
oral absorption, 5623 CGS 25462,3:137-138 Chemical delivery system
pharmacokinetics, 5624 CGS 26214,3583-584, 3587 prodrugs contrasted, 2:537
i

i
I
Cumulative Index

Chemical delivery systems, Chemical representation, CXC receptors, 4132,4:133,


2:536 1:363-373 4136-138
brain targeted redox analogs, Chemical shift, in NMR, 1:511, ligand structure, 4135
2:591 1:512 model of, 4132
brain targeting, 2:576-591 changes on binding, mutation and chimera studies,
examples, 2:580-587 1:536-537 4:137
molecular packaging, perturbations as aid in NMR sequence alignment of CC and .T
2~587-591 screening, 1:562-568 CXC, 4136
receptor-based transient an- Chemical-shift mapping, in signaling, 4135
chor-type, 2:595-596 NMR, 1:543-545 viral chemokines, 4:170-172 -
site-specific enzyme-activated, Chemical similarity, 1:382 XCR1,4133
2:591-595 Chemical space, 1:244, 1:383, Chemokines, 4130-131
site-targeting index and tar- 1:400 for atherosclerosis treatment,
geting-enhancement factors, exploring with molecular simi- 3:372-374
2:580 larityldiversity methods, inducible us. constitutive,
soft drugs contrasted, 2:537 1:188, 12191 4134
Chemical development, reduction by virtual screening, production in T-cell activation
2:408-409 1244-245 by dendritic cells, 5235
nevirapine synthesis example, Chemical Structure Association, Chemotherapy, 5:538
2~422-424 1:360 ChemPort program, k385
Chemical information comput- Chemical structures ChemR1,4161
ing systems, 1:357-363 file conversion, 1:372-373 ChemR13,4153
chemical property estimation searching, 1:379-384 Chemscape, 1:387
systems, 1:388-390 Chemical suppliers searching, ChemScore
chemical representation, 1:384 consensus scoring, 1:266
1:363-373 Chemical warfare agents, empirical scoring, 1:310
databases, 1:384-388 &90-93 ChemSpace, 1:199
data warehouses and data CHEM-INFO, 1:360 ChemText, 1:362
marts, k390-393, ChemInform, 1:386 ChemWindow, 1:388
1:402-403 Cheminformatics, 1:359, 1:400 Chem-X, 1:60, 1:111
future developments, and bioinformatics, 4:614 ChemX/ChemDiverse
1:393-397 Cheminformatics Glossary, 3D pharmacophores,
glossary of terms used, 1:360 1:195-196, 1:206
1:397-412 Chemistry-driven drug discov- optimization approach, 1:217
registering chemical informa- ery, 2:82-83 and property-based design,
tion, 1:377-379 Chemokine modulators, 1234
searching chemical structures/ 4130-131 Chenodeoxycholate, 2277
reactions, 1:379-384 Chemokine receptors, 4130-131 Cherry picking, combinatorial
storing chemical information, binding site model, 4137 libraries, 1:216-217, 1237
1:373-377 biology, 4131-134 Chesire, 1:378, 1:387
Chemical information manage- CCR1,4133,4138-143 Chicken liver DHFR, QSAR in-
ment databases, 1:384 CCR2,4133,4143-148 hibition studies, 1:31-32
Chemical information manage- CCR3,4133,4148-152 L-Chicoric acid
ment systems, 1:384 CCR4,4133,4:152-153 anti-HIV drug, 5:473,5:474
Chemical libraries, See Libraries CCR5,4133,4153-159 Chilies, capsaicin in, 1:854
Chemical production, 2:409-410 CCR6, 4133,4159-160 Chime, 1:369, 1:371, 1:387
Chemical Products Index, CCR7,4133,4160-161 Chimeric antibodies, 6226
1:391-392 CCR8,4:133, 4161 Chiral auxiliary, 1:810-813
Chemical properties CCR9,4133 Chiral catalysts, 1:814-820
key properties of interest, CCR10,4133 Chiral centers, 1:783-785
2:654 CC receptors, 4132,4133, Chiral derivatizing agents, k788
Chemical property estimation 4:136-138 Chiral flags, 1:365, 1:366
systems, 1:388-390 CXCR1,4:161-165 Chirality, 1:781-787, 1:820-821
Chemical reactions, 1:366. See CXCR2,4161-165 asymmetric synthesis,
also Drug synthesis CXCR3,4165-166 1:804-820
searching, 1:379-384 CX,CRl, 4:133 chromatographic separations,
steroids, 3:604-606 CXCJU, 4166-170 1:787-793
Cumulative Index

Chirality (Continued) 6-Chloro-l,3-benzenedisulfon- Cholangiography, 4567. See


classical resolution, 1:793-799 amide, 3 7 2 also Radiopaques
enzyme-mediated asymmetric Chlorobenzilate, 2:555-556 radiopaques applications, -
synthesis, 1:804-807 Chlorocardicin, 5:661 4569-570
large-scale synthesis require- 2-Chloro-2'-deoxyadenosine Cholate, 2:277
ments related to, 2:411 antimetabolite, 5:76 Cholchicine
and metabolism, 2:478-479 Chloroform/water partitioning toxicological profile predidioq,
nonclassical resolution, system, 2:656 1:841, 1:842
1:799-804 Chloromerodrin, 3:66,3:67 Cholecalciferol, 4374,4375. See
and selective toxicity, Chloromethyl ketones also Vitamin D,
5268-273 protease inhibitors, 1:761-762 keto and oxime analogs, 4:381
Chiral pool, 1:807-810 2-Chloronicotine, 651 Cholecystography, 4:567. See
Chiral reagent, 1:813-814 p-Chlorophenylalanine also Radiopaques
Chiral stationary phase, classical resolution by crystal- pharmacokinetics of ra-
1:787-788, 1:790-791 lization, 1:798-799, 1:800 diopaques, 4559-562
Chitosan, 2252 Chloroquine, 1:889, 1:890 radiopaques applications,
Chloexolone, 3:83 antimalarial, 6:938-943 4570
Chloproguanil dosage forms, 5:934 Cholecystokinin, 12355
antimalarial, 5:954-956 resistance to, 5:921, and anxiety, 6544
Chloprothixene 5~928-930 and gastric secretion, 6:112
radioprotective agent, 5:165 4-Chloro-3-sulfamoyl-N-substi- and satiety signals, 6:873
Chloralbetain, 6208 tuted benzenesulfonamides X-ray crystallographic studies,
Chloral hydrate, 6209 diuretics, 3:74 1:484
ADME, 6:220-221 Chlorotestosterone, 5:699, Cholestanes, 3:597, 3598
for anxiety, 6:527 3:700,3:703,3:705 Cholesterol, 2:616,3:340,3:358,
Chloralodol, 6:208,6:209 Chlorothalidone, 3:81,3:82 3:594,3:598
Chloralol, 6209 Chlorothiazide, 3:70,3:71-72, in adrenal steroidogenesis,
Chlorambucil 3:73-78,381 3:112-113,3:615
alkylating agent, 5:53,5:54 metabolism, 3:80 and Alzheimer's disease,
Chloramphenicol, 1:870, metolazone compared, 3:86 6:748-749
5:789-792 selective toxicity, 5264 bile acid synthesis, 2:277-278
blood disease caused by, 2:686 Chlorotrianisene, 3:661 biosynthesis, 3:606-609
hydrophobic interactions, applications, 3:631, a632 conversion to pregnenolone,
2:195,2:196 oxidative metabolism, 3:636 3:613
molecular modeling, 1:150 Chlorpheniramine conversion to testosterone,
prodrug, 2:504 over-the-counter status, 4426 3:604
Chloramphenicol acetyltrans- selective toxicity, 5275 and coronary artery disease,
ferase, 4 2 7 Chlorproguanil 3:lO
Chlorazanil, 3:123,3:124, a125 with dapsone, 5:959 effect of thyroid hormone,
Chlorazepate, 6:207,6:530 dosage forms, 5:934 3572
dose for anxiety, 6529 Chlorpromazine, 1:692 in lipid formulations, 2:671,
Chlordiazepoxide, 6:530, 6:549 arenavirus antiviral, 5:430 2:677
discovery, &548 discovery, 6:617 in liposomes, 2:673
dose for anxiety, 6:529 dose, a 6 0 1 lowering with thyromimetics,
Chlorhexadol, 6:208,6:209 pharmacokinetics, biotrans- 3:575
Chloride-formate exchanger formation, and drug interac- reverse transport, 3:341,3:575
in kidneys, 3:58-59 tions, 6:633-635 role in androgen biosynthesis,
Chlorinated solvents radioprotective agent, 6:165 3683-684
priority pollutants, 2:413 receptor binding and side ef- role in atherosclerosis, 3:342
Chlorine topical antibacterials, fects, 6:606 role in estrogen biosynthesis,
5:545-547 Chlorpropamide, 4:11,412,416 3~642-645
Chlorisondamine selective toxicity, 5264 role in glucocorticoid biosyn-
nicotinic receptor antagonist, Chlortetracycline, 1:870, 2:185, thesis, 3:773-774
2:397 2:186,6:740,5:742 Cholesterol absorption inhibi-
Chlormidazole, S:893-897 Chlor-Trimetron tors, See Bile acid seques-
4-Chloro-l,3-benzenediol selective toxicity, 5275 trants/cholesterol absorp-
allergenicity prediction, 1:834 Chocolate, 6:169 tion inhibitors
Cumulative Index

Cholesterol-reducingagents, reversible quaternary ammo- Ciclopirox, 5:906


2:284-285 nium anticholinesterases, formulations and indications,
Cholesteryl esters, 3340-341 6:84-86 5891
Cholesteryl ester transfer pro- structure-activity relation- CICLOPS, 1:223
tein (CETP) inhibitors, ships, 6:80-84 Ciclosporine, 5490,5:491
3:371 Cholinesterase, 2:538,6:40 Cidofovir
9
Cholestyramine, 3:343, 3348 Chondroitin, 2:221 activity against orthopoxvi-
effect on hydrothiazide ab- Chorismate mutase ruses, 5:439
sorption, 3:80 allostery, 2:306 for adenoviruses, 5:340
metabolism, 3357 Chorismate mutase inhibitors for herpes virus, 5:308,5317 -
Choline transition state analogs, for papillomavirus, 5338339
long-chained esters, 2:561-562 1:753-754 for polyomaviruses, 5:339
nicotinic receptor agonist, Chromafin cells for poxviruses, 5341
2:393 nicotinic acetylcholine recep- selective toxicity, 5:267
representative esters, 6:44 tors, 2:385,2:388 for smallpox, 5:437-440
transport process for, 6:40 Chromatin remodeling, 5 8 Cigarettes. See also Nicotine
Choline acetyltransferase, 6:40 Chromatographic separation and coronary artery disease,
Cholinergic receptors, 6:41-43. of chiral molecules, 1:787-793 310
See also Muscarinic acetyl- with combinatorid libraries, FDA calls drug delivery de-
choline receptors; Nicotinic 2:23,2:26 vices, 2:688
acetylcholine receptors Chromene, 3664 Ciglitazone, 4:28
Cholinergics, 6:4O - 41 Chromenoquinoline, 3:653-654, Cilastin
acetylcholine and analogs, 3668 coadministration with imi-
6:43-49 Chromobacterium violacturn, penem, 5:623,5:693
acetylcholine-release modula- 15373 Cilazapril
tors, 6:97-98 Chromomycosis, 5883 asymmetric synthesis, 1:807,
arecoline, its analogs and con- Chromosomes 1:809
geners, 6:62-71 acquisition of extra, and carci- Ciliary ganglion neurons
carbarnate-derived anticho- nogenesis, 519 nicotinic acetylcholine recep-
linesterases, 6:88-90 in genetic algorithms, 1:87 tors, 2:385
dissociation constants, 6:150 Chromosome X inactivation Ciliary neutrophic factor, 3:269
dual cholinergic/anticholin- and carcinogenesis, 5 8 and axokine, 6:883
ergic compounds, Chrysophanie acid Cilnidipine, 3:21
picornavirus antiviral, 5414 bioavailability and half-life,
6:150-151
Chrysosplenol C 323
miscellaneous, structurally
picornavirus antiviral, 5413 cardiovascular effects, 3:24
unique muscarinic agonists, Chylomicrons, 2:616, 3:341, Cilofungin, 1:877, 5901
6:78-80 3:358 Cimetidine, 2:100
miscellaneous anticholinester- reconstituted fragments for antiulcer application, 6:155,
ases, 6:93-97 plasmid DNA-mediated a158
muscarine, muscarone, and gene therapy, 4667 classification in various coun-
related compounds, Chymotrypsin inhibitors tries, 4430
6:57-61 affinity labels, 1:761, 1:762 discovery, 2:40
nicotine, its analogs and con- molecular modeling, 1:118 selective toxicity, 5275
geners, 6:49-57 QSAR studies, 1:5, 1:3536 Cinchona bark, quinine from,
not closely related structurally CI-977 1:888, 5:933
to acetylcholine, 6:49-80 analgesic, 6:391 Cinchonidine, kg33
oxotremorine, its analogs and CI-988,6:544,6:575 Cinchonine, 5:933
congeners, 6:71-78 CI-1004,4:246-247 Cinchonism, 5:937
phosphorus-derived anticho- CI-1008 Cinchophen
linesterases, 6:90-93 anticonvulsant, 6:312-313 pretreatment effect on ra-
pilocarpine, its analogs and CI-1011,3370 diopaques, 4:563
congeners, 6:61-62 CI-1015,6:575 Cinnarnate sunscreens
reversible noncovalent anti- CI-1031,3324-325 structure-activity relationship,
cholinesterases related to Cialis 4469
tacrine, 6:86-88 selective toxicity, 5:277 Cinolazepam, 6:207
Cumulative Index

Cinoxate CL-253824 Class V drugs: metabolically or


structure-activity relationship, for herpes virus, 5:314 chemically unstable com-
4469 CL-309623 pounds, 2:667,2:676-678 e

sunscreen, 4460 RSV antiviral agent, Clathrates, 2:663


CIP (Cahn-Ingold-Prelog)ste- 5:390-393 Clavulinic acid, 1:718, 1:869,
reochemistry, 1:365, 1:400 CL-316243,6:884, a 8 8 6 1:870,5:609
Cipramil, 6:485 CL-387626 amoxycillin MIC, 5:695 7
Ciprofibrate, 3:343, a347 RSV antiviral agent, antimycobaderial application,
enzyme activity, 3:365 5:390-393 5:858
metabolism, 3:357 Cladosporium, 5:883 discovery, 5694-697
Ciprofloxacin, 5:853-855 Cladribine indications, 5:625
antimalarial, 5935,5:983 p-lactamase inhibitory activ-
antimetabolite, 5:76, 5:81-82
Ciprol, 3343 ity, 5:695
Claims, patents, 2:724
Cisapride use recommendations, 5626
Clarithromycin, 1:849, 1:874,
cardiotoxicity, 2:76 Clazolimine, 3:124, 3:132-133
CYP3A41517 substrate, 4627 1:875-876,5:763
Cleaning and transforming data,
removed/restricted by FDA, antimycobacterial application, 1:400
4642 5:856-857 Cleaning validation, 2:419
Cisplatin CYP3A41517 substrate, 4627 Clearance, 2:635-638
alkylating agent, 554, 5 5 9 P-glycoprotein inhibitor, characterization for IND pro-
with gemcitabine, 5:80,5:81 4:631 cess, 2:645
gene expression profiling selective toxicity, 5 2 6 1 Cleland's reagent
study of drug response, structure, 2:189 radioprotective agent,
4:609 Claritin 5156-157
with ionizing radiation, 5196 selective toxicity, 5:275 Clenbuterol
with nolatrexed, 5:79 Class IA antiarrhythmic agents, chromatographic separation,
with permetrexed, 5:78 3:31,3:32,3:34-36, 3:167 1:787, 1:788
P-glycoprotein substrate, Class I antiarrhythmic agents, Clentiazem, 3:17
4631 3:31,3:32, 3:3438, 3:167, bioavailability and half-life,
selective toxicity, 5:257-258 3:168 3:18
structure-activity relationship, Class IB antiarrhythmic agents, cardiovascular effects, 3:17
560-61 3:31,3:32, 3:36-37, 3:167 Cleocin, 5:935
with tirapazamine, 5:86 Classical resolution, of chiral Cleomycins
with vinblastine, 5:140 molecules, 1:793-799 antitumor natural products,
with vindesine, 1:860 Class IC antiarrhythmic agents, 5:115,5:117
Cisplatin rescue, 5172 3:31,3:32,3:37-38, 3:167 Clevidipine, 2:567-568
Cisltrans stereochemistry, 1:399 Class I drugs: high solubility Clevudine
Citalopram, 6:531 high permeability, for hepatitis B virus, 5327,
affinities for monoamine re- 2:665-667 5:329-330
ceptors, 6:495 Class I1 antiarrhythmic agents, Client-server architecture,
antidepressant, 6:485,6:486, 3:31, 3:32, 3:38-40, 3:167. 1~400-401
6:488,6:508 See also p blockers Climara, 3:632
CYP2C19 substrate, 4627 Class I1 drugs: low solubility Clindamycin, 2:196,5:788-789
dose for anxiety, 6:529 high permeability, antimalarial, 5:935, 5984
inhibition of serotonin, norepi- 22667-671 Clinical reaction modifiers,
nephrine, and dopamine Class I11 antiarrhythmic agents, 5:152. See also Radioprotec-
transporters, 6:500 3:31,3:32,3:40-43, 3:167 tive agents; Radiosensitizers
pharmacokinetic parameters, Class I11 drugs: high solubility Clinical trials
6:497 low permeability, consideration in synthesis de-
side effects profile, 6:493 2:674-676 velopment, 2:408
C-Kit factor, See Stem cell factor Class IV antiarrhythmic agents, and delay of marketplace en-
CKR-L1,4161 3:31, 3:32, 3:43-44, try of new drugs, 2:705
CKR-L3,4159 3:167-168. See also Calcium gene expression profiling of
CL-61917 channel blockers drug response subsets,
influenza antiviral agent, Class IV drugs: low solubility 4610
5:378 low permeability, 2:667, Good Laboratory Practices,
CL-191121,5709 2:676 2:612
Cumulative Index

and pharmacogenomics, pharmacokinetic parameters, Cloxazolam, 6:551-552


4641-644 a497 Clozapine
pharmacokinetics applica- side effects profile, a 4 9 3 discovery, 6:618
tions, 2:645-647 Clonazepam, 6529 doesn't cause extrapyramidal
phosphorothioate oligonucleo- ADME, 6:282 symptoms, 6:600-601
tides, 2:138-139 anticonvulsant, 6:266, 6:267, dose, 6:601
protocol information as part of 6:307 for Parkinson's disease, 6:725 r
IND process, 2:691 dose, 6:270 pharmacokinetics, biotrans-
safety, 2:697-698 dose for anxiety, 6:529 formation, and drug interac-
toxicity testing, 2:611 side effects, 6:276 tions, 6:636-637 -
Clipping, 1:378, 1:401 Clonidine, 2:505 receptor binding and side ef-
Clique search techniques, 1:262 a,-agonist, 6:3 fects, 6:606
Clobazam, 6:551 applications, 6:14 Clozaril, 6:601
ADME, 6:282 metabolism, 6:18 Clustering methods, 1:379,
anticonvulsant, 6:266, 6:267, structure-activity relationship, 1:401
6:307 6:31 for combinatorial library de-
side effects, 6:277 yohimbine reverses ejacula- sign, 1:220
CLOB (Character Large Object) tion inhibition, 4446 with DNA microarrays, 4:606
data type, 1:401 Cloning, 1:127 in molecular modeling,
Clobetasol propionate, 3:750, cDNA clone libraries, 1:90-91
3:752,3:824, 3:833 1:341-342 with molecular similarityldi-
Clociguanil, 5960 for facilitating high-through- versity methods, 1:205
Clocortolone pivalate, 3:750, put screening, 2:74 CMDA
3:752 of human receptors, tumor-activated prodrug,
Clofazimine, 5:837-839 2:104-106 5:87-88
efficacy and dosage, 5810 and potential human patent- CMI 477
side effects, 5:839 ability, 2:719 experimental smoking cessa-
Clofibrate, 3:343,3:346-347 Clopamide, 3:81,3:82, 384, tion agent, 4:459
allosteric effector of hemoglo- 397,3105 CML (Chemical Markup Lan-
bin, 3:388 Clopidogrel, 3:29,3:285, 3320 guage), 1:371-372, 1:401,
enzyme activity, 3:365 ADME, 3:297 1:405, 1:412
metabolism, 3:357 clinical trials, 3293 C-myc protein, 5:25-26
sickle hemoglobin modifier, formula weight, mechanism of and APC gene, 5:30
3:461 action, and route of admin- cDNA microarray studies,
side effects, 3:354 istration, 3:287 537
Clofibric acid, 3:346 structure, 3289 CNI-H0294
antisickling agent, 1:421, for thrombolytic therapy, antimalarial, 5:987
1:422 3:166 CNS drugs
CLOGP, 1:18, 1:389 treatment regimen, 3298 carbohydrate-based agents in
Clog P, 1:17-18,1:36 Clorazepate, 6:551 research, 2:219-221
Clomethiazole, 6:210, a 2 1 1 ADME, 6:282 carbohydrate-based drugs to
ADME, 6:221 anticonvulsant, 6:266,6:307 market last decade,
Clomid, 3:632 dose, 6:270 2:206-207
Clomiphene, 3661-662, 3663 side effects, 6:277 carbohydrate-based therapeu-
applications, 3:631,3:632 Clorexolone, 3:85 tics in development, 2:213
in contraceptives, 3:654-655 Clotiazepam, 6:554 complementarity, 1:134
oxidative metabolism, 3636 Clotrimazole, 1:717, 5:893-897, natural products as leads,
selective toxicity, 5268 5:959 1:849-856
Clomipramine formulations and indications, pharmacophore point filters,
affinities for monoamine re- 5:891 1:250
ceptors, a 4 9 5 selective toxicity, 5:268 polar surface area, 1:245
antidepressant, 6:485,6:486, sickle hemoglobin hydration radioprotective agents, 5:165
6:487 agent, 3:461 CNS program, 1:478
CYP2C19 substrate, 4627 Clotrimazole (vaginal), 4:430 CNS stimulants, 6:168-172
inhibition of serotonin, norepi- Cloxacillin, 5 6 3 1 ADME, 6:176-179
nephrine, and dopamine in vitro antibacterial activity, clinical use of agents,
transporters, 6:500 5:635 6:172-179
Cumulative Index

CNS stimulants (Continued) Cocaine and amphetamine-re- Collagen, 35290


history, 6:172 lated transcript (CART), in clotting, 3:303
physiology and pharmacology, 6:870 glucocorticoid effects on, 3751
6:179-184 Coca leaves, 6:172 Collagenases, 5:13
recent and future develop- Coccidioides immitis, 5:883 NMR binding studies, 1:555, -
ments, 6:192-194 Coccidioidomycosis, 5:883 1:556
receptor types and actions, Cochlea target of structure-based drug
6:180-184 nicotinic acetylcholine recep- design, 1:443
side effects, adverse effects, tors, 2:385,2:387,2:389 Collagen I, 52216
and drug interactions, Cocoa, 6:169 Collagen 111,5216 .

6:174-176 Codeine, 1:849,1:850,6:332, Collagen IV, 5:12,6:216


structure-activity relation- 6:633 Collagen VII,6916
ships, 6:184-187 activation to morphine, 2:500 Collectins, 2241
CNS stimulation, 6:172 CYP2D6 substrate, 4:627 Colloidal plasma volume expan-
Coagulation factor 2 cytochrome P,,, isozyme sub- ders, 3:429-433
X-ray crystallographic studies, stratelinhibitor, 6:339 Colon cancer
1:484-485 dose, a334 cell characterization by gene
Coagulation factor 7 Codons, 4619 expression profiling, 4607,
X-ray crystallographic studies, Coenzyme A, 4:401 4608
1:485 conjugation with in metabo- Colony-forming units, 3252,
Coagulation factor 7a lism, 2:459-461 3253
X-ray crystallographic studies, Coformycin, 1:750-752 Colony-stimulating factor-1,
1:485-486 Cogentin 3272-273
Coagulation factor 9 for Parkinson's disease, 6:731, Colony-stimulating factors,
X-ray crystallographic studies, 6:732 3252
1:486 Cognex CombiBUILD, 1227
Coagulation fador 10 for Alzheimer's disease, 6:762 CombiChem Package, 1:386
X-ray crystallographic studies, for cognition enhancement, CombiDOCK, 15217,1:227
1:484 6:781 combinatorial docking, 1:318
Coagulation factor inhibitors, structure-based design, 1:449 CombiLibMaker, 1:378,1:387
3323-326 Cognition, 6:780-781 Combinatorial chemistry, 1:283,
Coartem, 5:935 measurement, 6:781 1:358,1:591-592,2:38
Cobalamin, 4:405,4:408, Cognition enhancers, 6:780-781 defined, 1:401
4411-415.See also Vitamin clinically approved agents, history, 2:4-5
BIZ a781 and molecular modeling, 1:155
COBRA, 1255 exploratory approaches, and multiple parallel synthe-
Cocaethylene, a177 6:781-782 sis, 2:l-32
Cocaine, 6:169,a170 GABAA/Bzreceptor complex, and natural product screen-
and kappa opioid receptor, 6:782-797 ing, 1:848
6:356 nicotinic acetylcholine recep- oligonucleotide therapeutics,
liver toxicity, 2:79 tor, 6:797-811 2:120
metabolism, 6:177 potassium M-channel, Combinatorial chemistry data-
Parkinson's disease diagnostic 6:817-820 bases, 1:387
radioligand, 6:735 serotonin receptor, 6:811-817 Combinatorial docking,
physiology and pharmacology, therapeutic approaches, a781 1:317318
6:179-180,6:182,6:183 Colchicine Combinatorial libraries, 1:214.
prevention of ventricular fi- radioprotedive agent, 5165 See also Solid phase organic
brillation caused by, 3169, Cold medicines synthesis
3:171 OTC Drug Review, 4426 comparisons, 1:221-223
side effects, adverse effects, Cold sores, 5:298 design for molecular similarity
and drug interactions, Colesevelam, 3348 methods, 1:190,1:214-228
6:175-176 metabolism, 3:357 encoding and identification
structure-activity relation- Colestid with mass spectrometry,
ships, 6:188-192 for angina treatment, 3:11 1:596-597
R-Cocaine Colestipol, 3:343,3348 input for high-throughput
dopamine transporter inhibi- metabolism, 3357 screening, 2:57
tor. 1:268 Colforsin daropate, 1:849 integration, 1:224-225
Cumulative Index

LC-MS purification, 1:592-594 Comparative molecular surface Computer programs


in multiple parallel synthesis, analysis (CoMSA) copyrighting, 2:770
2:2-4 glucocorticoids, 3:791-792 Computing technologies,
optimization, 1:217-221 Comparative quantitative struc- 1:334-335, 1:337. See also .
peptides with high affinity ture-activity relationship Chemical information com-
for opioid receptors, database development, 1:39 puting systems
6:438-440 database mining for models, COMSiA, 1:53, 1:60 T
peptidomimetics, 1:657 1239-41 Comtan
screening for ligands to two COMPARE program, 4609 for Parkinson's disease, 6:730,
receptors simultaneously, Compazine, 6:601 6:731 .

1:601-602 Cornpendial Operations Branch, Com Tox, 2:620


solid and solution phase li- 2:701 Conantokin-G, 6:693
Competitive blocker antagonists Concerned member states, 4:429
braries of small, druggable
of nicotinic receptors (muscle- Concerta, 6:170
molecules, 2:14-30
type), 2:382,2:383 CONCORD, 1:363, 1:366, 1:387,
structure-based design,
Competitive inhibitors, 1:401
1:225-228 1~728-729 3D coordinate generation,
structure/purity confirmation Complementarity, 1:134 1:267
with mass spectrometry, Complementarity-determining 3D descriptors, 1:55, 1:110
1:594-596 region (CDR)grafting, 2:88 virtual screening application,
with virtual screening, 1:317 Complementarity determining 1:254
Combined modality therapy, regions, 5227 Concordance, 1:390, 1:401
5:173 Complexation, 2:670-671 Conformational analysis
S,S-Combretadioxolane, 1:816, Composition of matter claims, in molecular modeling, 1:87,
1:819 2:718,2:719 1:93-94
Combretastatin and prior art, 2:732 NMR spectroscopy for,
tumor-activated prodrug, 5 8 7 Compound decks 1:525-526
Combretastatin A-4, 1:816, construction, 2:54-59 and systematic search,
1:819 screening, 2:58-59 1:89-93
Combretastatin A4, 5:219, 5:220 Compound management Conformational clustering,
CoMFA, See Comparative molec- in high-throughput screening, 1:92-93
ular field analysis 2:38,2:56-58 Conformational flexibility, 1:288
Commercial Investigational New Compound stores, for high- Conformationally restricted ana-
Drugs, 2:689 throughput screening, logs, 1:694-699
Commercial production, 2~56-59 Conformationally restricted pep-
2:417-420 Comprehensive Drug Abuse Pre- tides, 1:636-643
nevirapine synthesis example, vention and Control Act of Conformational mimicry,
2:427-429 1970,2:687 1:140-142
Common recycling compart- Comprehensive Medicinal Conformational mimicry index,
ment, 2:258 Chemistry database, 1:379, 1:142
Compactin, 1:744, 1:879 1:386 Congestive heart failure, 3:156
Comparative binding energy Comprising, in patent claims,274.3 and ventricular remodeling,
analysis (COMBINE), 1:53 Compton scattering, 4485 3:164
and docking methods, Computational Chemistry List, Conglomerate racemates,
1:304-305 1:360 1:799-800, 12801,
Comparative molecular field Computational protein-ligand 1:802-803
analysis (CoMFA), 1:53-54 docking techniques, Conjugase, 4:406
assessment of predictability, 1:262-264 Conjugated hemoglobins,
1:151-153 Computer-aided drug design 3:417-420
3D, 1:58-60 (CADD), 2:38,2:572-576 Conjugation reactions
and docking methods, 1:304 in high-throughput screening, in metabolism, 2:450-475
field mapping, 1:107 2:55-56 Conjugative transposons, 5:614,
glucocorticoids, 3:793-796 Computer-assisted tomography 5:616
molecular field descriptors, NXT) Connection tables, 1:365-368,
1:56-57 radiopaques applications, 1:371, 1:401
and molecular modeling, 4495,4567568 file conversion, 1:372-373
1938, 1:147 x-ray energies used, 4484 ISIS database, 1:376
Cumulative Index

Connectivity, See Molecular con- Coprecipitation cortisol-cortisone conversion,


nectivity for production of amorphous 3:773
a-Conotoxins solids, 2:653 CYP3A4/5/7 substrate, 4:627 .
nicotinic receptor antagonist, Copyrights, 2:705,2:770 effect of structural changes on
2:374,2:386,2:390, CoQSAR, See Comparative activity, 3796-837
2:395396 quantitative structure-activ- half-life, 3776
~Conotoxins ity relationship Hansch-type analysis, T
lead for drugs, 1:851-852 Cord-factor, 5:817 3:788-790
NMR spectroscopy, 1:518-523 Cordycepin metabolism, 3:769
ConQuest search program, 1:387 PLD repair inhibitor, 5:192 over-the-counter status, 4426 .
Conscore constraint score, 1:218 Coreg, 6:5 prodrugs, 2:505
Consensus scoring, 1:265-266, Corgard, 6:5 role in insulin regulation, 4:2
1:291, 1:319-320 CORINA, 1:366, 1:402,3:792
synthesis, 3:612,3:615
3D coordinate generation,
and molecular modeling, Cortisone, 3:595,3748,3:749,
1:267
1:117-118 3:758
3D descriptors, 1:55
Consistent force fields, 1:102 virtual screening application, cortisol-cortisone conversion,
Consisting, in patent claims, 1:254 3:773
2:743 Coronary artery disease, 3:3,3:8 effect of structural changes on
Consisting essentially, in patent causes, 3:lO-11 activity, 3:796-837
claims, 2:743 and lipids, 3:340-342 metabolism, 3:769
Constitutive chemokines, 4:134 treatment regimens, synthesis, 3599-602
Constrained minimization, 3:298-299 synthesis by microbial trans-
1:143-144 Coronary occlusion, 3156-157, formation, 3:602-604
Contact matrix, 1:125-127 3289 Cosalane
Contignasterol, 1:886 Coronary vasodilators, 3 1 2 anti-HIV drug, 5:466
Continuation-in-part (CIP) Corsevin M, 3:326 Cosine coefficient, 1:68
patent application, 2:707, Cortexolone, 3:750 Cosmeceuticals, 4:423,4473
2:716 Cortical microvascular amyloid, Cosmegen
for adding new matter to ap- 6:744 antitumor natural product,
plication, 2:721 Cortical nephrons, 3 5 7 5:111-115
Contraceptives, 3:630, Corticoids, See Glucocorticoids COSMIC force field, 1:80
3650-651 Corticosteroid-binding a-globu- Costimulatry signals, 5:487
lin, 3:686,3:703, 3771, agents capable of inhibiting,
currently marketed, 3:632
3:793-796 5525-526
ovulation modulation,
Corticosteroids, 3:594,3:748 Cotinine
3:654-655
metabolism, 3:619,3:620 experimental smoking cessa-
Contraction coupling, in heart, peptide esters, 2:508 tion agent, 4:459
3~4-6 premedication for contrast Cotransmission, 3:194
CONTRAST, 1:361 agents, 4545 Cotrifazid, 5:959
Contrast agents, See Ra- soft drugs, 2:547-560 Cotrim, 5934
diopaques synthesis, 2:602 Cotrimoxasole
Controlled-atmosphere systems, Corticosterone, 3:748,3:750, systemic antibacterial, 5596
2:662 3:759,3:783, 3788 Coulomb's law, 1:80, 1:82, 1:285
Controlled metabolism, 2:539 binding, 3771 and dielectric problem, 1:83
Controlled-release dosage form synthesis, 3612-613,3:615 Coumadin, 3:286
class I drugs, 2:666-667 Corticotropin-releasingfactor, Coumarin, 1:882
Conus magus, conotoxins from, 3612-613 PARP inhibitor, 6:681
1:851,2:395 and anxiety, 6:544-545 residues in pseudopeptide ar-
Convertases Corticotropin-releasingfactor rays, 2:12
homology modeling, 1:123 antagonists Counterions
CONVERTER, 1:366, 1:402 antidepressants, 6:517-518 and ion paring, 2:675-676
Cooperativity Cortisol, 2:547-548,2:571, suitable for salt formation,
allosteric proteins, 2:296-300, 3:113,3:598,3:748-749, 2:651-652
2:304-305 3~752,3758-759,3772, Counting schemes
Copper complexes 3:782,3:793,3:803 in druglikeness screening,
radioprotective agents, 5163 binding, 3:771 1:245-246
Cumulative Index

Coupling constants, in NMR, CP-70,429, 5660 Cryptococcus neoformans, 5883,


1:511, 1:512 CP-96,345, 1:670, 1:672 5:884
changes on binding, tachykinin antagonist, 3224 diagnostic and microbiological
1:536-537 CP-154,526,6:577 issues, 5:885
for conformational analysis, CP-164,526 Cryptolepine
1:525 antidepressant, 6:518 antimalarial, 5998-999
COUSIN, 1:361, 1:373, 1:387 CP-212,454,6:574-575 Cryptotheca cripta, 1:867 .+
and combinatorial library in- CP-310,713, 6:575 Crystallization
tegration, 1:224 CP-320,626 for asymmetric transforma-
Covalent bonds, 1:6, 1:170 allosteric effectors, 2:314, tion of enantiomers, -

Covalently binding enzyme in- 2:315 1:798-799


hibitors, 1:720, 1:754-756 CP-346,086, 3368 for enhancing chromato-
inactivation of, 1:756-760 CP-526,555 graphic separation of enan-
COX-1,4205,4230-232 tiomers, 1:792-793
experimental smoking cessa-
formulation considerations,
and cancer, 5:34 tion agent, 4459
2:651
role in clotting, 3305 CP-529,414,3:371
hydrate pseudopolymorphs,
role in prostaglandin synthe- CpG island methylated pheno- 2653
sis, 4:232-233 type (CIMP), 5:289 in large-scale synthesis, 2:414
COX-2,4205,4231-232 CPT-11 in nonclassical resolution,
and cancer, 5:33-35 antitumor natural product, 1:799-804
role in prostaglandin synthe- 5:131 precipitation inhibition,
sis, 4232-233 C-QSAR database, 1:39 2:668-669
COX-1 inhibitors, 1:718, 2:86 Crambin solvate pseudopolymorphs,
selective toxicity, 5952, molecular modeling, 1:124 2:653
5274-275 Cremophor Crystalloid plasma volume ex-
X-ray crystallographic studies, P-gp pump inhibition, 2:678 panders, 3:429-433
1:486 Crescendo angina, 3 1 0 CS-505,3:370
COX-2 inhibitors, 1:718, 2:86, Crestor, 3:343, 3368 CS-747,3:320,3:321
4204-205. See also Leuko- Critical micelle concentration, CS-834,5:709-710
trienes 2:672 CS-891
agents inhibiting both 5-LO Crixivan experimental hair growth
and COX-2,4246-248 structure-based design, drug, 4441
for Alzheimer's disease, 6:767 1:438-439 CScore, 1:117
aspirin's effect, 3297-298 Crohn's disease, 3780 CT50547,3:320-321
assays, selectivities, and po- Cromakalim CTLA4-Ig, 5525-526
tencies, 4245-246 and extracellular potassium, C-type lectins, 2940-241
clinical efficacy and safety of 3163 C-type natriuretic peptide,
selective, 4248-250 CROSS-BOW, 1:361 3914, 3215
irreversible, 4244-245 Crossfire Beilstein, 1:385 biological action, 3218
mass-spectrometric binding Cross-licensing agreements, biosynthesis, metabolism, and
assay screening, 1:604 2:705 structure, 3216-217
seeding experiments, 1:319 Cross-linked enzyme crystals, Curare
selective, 4204, 4234-246 1:804 lead for drugs, 1:856-858
selective nonsteroidal anti- Crosslinked hemoglobins, 3:397, Curariform drugs, e l 1 0
inflammatory drugs, 3:405,3:406-408 CURL (compartment of uncou-
2286-87,4242-244 Crosslinking agents, pling receptor and ligand),
selective toxicity, 5:274-275 1:424-425 2258
in vivo models, 4246 Cross validation, 1:57,1:64 Curral, 6205
X-ray crystallographic studies, Crotyl barbital, 6205 Cushing's syndrome, 3748,
1:486 Cruex, 5891 3:751
COX-2-selective nonsteroidal Cryoprobes Cutter mill, 2674
anti-inflammatory drugs, in NMR screening, 1:577 CVT-124,3:122
2:86-87 in NMR spectroscopy, 1:515 CX509
CP-31,398 Cryptates, 2:48 for Alzheimer's disease, a764
dlosteric effector, 2:314, Cryptococcal meningitis, 5:884 CX516
2:315 Cryptococcosis, 5883 for Alzheimer's disease, 6:764
Cumulative Index

CX614 Cyclin-dependent kinase cdc28p Cycloplegics


for Alzheimer's disease, 6:764 gene expression profiling of anticholinergic activity assay,
CXCl receptor, 4133,4161-162 drug response, 4611-612 6:119-120, &I53
antibodies, 4:162 Cyclin dependent kinases anticholinergics, 6:114-115
peptide antagonists, in carcinogenesis, 5:14-16 Cycloprodigiosin
4162-163 and organ transplant rejec- antimalarial, 5:994
small molecule antagonists, tion, 5:487 Cyclopropylindoles F
4163-165 Cyclins alkylating agents, 5:54,
CXC2 receptor, 4133,4161-162 in carcinogenesis, 5:14-16 5:61-64
antibodies, 4:162 and organ transplant rejec- Cyclopropylindolines
peptide antagonists, tion, 5:487 alkylating agents, 5:52
4162-163 Cyclobarbital, 6:205 Cyclorphan, 6:372
Cyclodextrins Cycloserine
small molecule antagonists,
chemical delivery system, antimycobacterial application,
4163-165
2:586-587 5:811,5:846
CXC3 receptor, 4133,4165-166 for complexation, 2:670-671 efficacy and dosage, 5:811,
antibodies, 4:166 Cyclo(G1y.J 5:863
small molecule antagonists, genetic algorithm exploration of side effects, 5:846
4166 conformational space, 1:88 D-Cycloserine, 1:717, 1:719
CX&1 receptor, 4133 Cycloguanil, 5:955, 5:956 Cyclosporine, 1:848
CXC4 receptor, 4133, Cyclogyl, e l 3 4 clinical use for organ trans-
4166-167 Cycloheptadecane plants, 5:489-494
antibodies, 4:167 potential smoothing study, 1:86 CYP3A41517 substrate, 4627
peptide antagonists, Cyclohexanelwater partitioning cytokine IL-1 downregulation,
416'7-168 system, 2:656 4173
small molecule antagonists, Cyclooxygenase 112 inhibitors, cytokine IL-2 downregulation,
4:168-170 See COX-1 inhibitors; 41'75
CXC5 receptor, 4133 COX-2 inhibitors discovery, 2:39
CXC6 receptor, 4133 Cyclooxygenases, 4229. See also with leflunomide, 5523
CXC receptors, 4132,4133, COX-1; COX-2; COX-1 in- molecular modeling, 1:106
4:136-138 hibitors; COX-2 inhibitors NMR spectroscopic binding
CY-208-243 prostaglandin discovery and studies, 1:539
for Parkinson's disease, a727 NSAIDS, 4229-230 P-glycoprotein inhibitor,
Cyclopal, 6:205 4631
Cyanate
Cyclopentenylallylbarbituric P-glycoprotein substrate,
sickle-cell anemia therapy,
acid, 6:205 4631
3:460-461 Cyclopenthiazide, 3:76,3:81 and P-gp pump, 2:658
Cyanide Cyclopentolate pharmacokinetics, 5:491-492
radioprotective agent, 5:162 anticholinergic, 6:134 pharmacology, 5:492-494
Cyanocobalamin, 3:399,4413 mydriatic and cycloplegic ac- rifampin's effect on bioavail-
Cyanornethemoglobin, 3:401 tivity, 6:153 ability, 2:639
Cyclacillin, 5632 relative anticholinergic activ- side effects, 5:494
Cyclazocine, a375 ity, 6:156 structure-activity relationship,
Cyclic AMP response element 8-(Cyclopenty1)-1,3-dipropylxan- 5:494
protein, a508 thine, 3:122 Cyclosporine A
Cyclic lactams Cyclophilin, 1:552 administration with docetaxel,
conformationally restricted Cyclophosphamide, 2:517 2:678
peptidomimetics, 1:640 - 642 alkylating agent, 5:53,5:54, for Alzheimer's disease, 6:766
Cyclic polynitrogen diuretics, 5:55-56 binding to FKBP, 1:552-553,
32121-125 with AQ4N, 5:85 2:99-100
Cyclic protease inhibitors, 1:636 with dactinomycin, 5111 cytokine IL-5 downregulation,
Cyclin-dependent kinase 2 with daunorubicin, &I26 4177
antisense inhibitors, 2:136 with MEA as radioprotective multidrug resistant protein
gene expression profiling of agent, 5:172 inhibition, 5:290
drug response, 4:611,4612 as prodrug, 5:83 self-microemulsifying drug
H717 inhibitor pharmaco- with tirapazamine, 5:85 delivery system, 2:673
phore, 1:253 tumor-activated prodrug, 5:91 Cyclothiazide, 3:77
Cumulative Index

Cycloxygenase-derived eico- polymorphisms in CYP2C19, Cytosine arabinoside, 1:717,


sanoids, 4233 4626,4629 1:867-868
Cylert, 6:170 polymorphisms in CYP2D6, antimetabolite, 5:75, 5:76,
Cylexin, 2:216,2:220 4626-628 5~79-82
Cyproterone acetate, 3:717, role in adaptive responge tox- Cytosine deaminase tumor-acti-
3:718,3721 icity, 2:617-618 vated prodrugs, 5:90-91
Cys-scanning mutagenesis, role in steroid biosynthesis, for cancer therapy, 6:44 T
2:271 3:610,3:614,3619- Cytotoxic drugs, 5:52, k82,
y-Cystathionase inhibitors, and toxicity, 2:612,2:614 5:109. See also Antitumor
1:719-720 Cytochrome P450 3A drugs; Tumor-activated pro- .

Cysteamine and drug metabolism in intes- drugs


radioprotective agent, 5:152, tine, 2:676,2:677 and P-gp pumps, 2:658
5:155-160 effect on cyclosporine bioavail- Cytotoxicity, 2:77
Cysteine ability, 2:639 plasmid DNA-mediated gene
chemical modification re- polymorphisms in, 4626, therapy, 4653,4669-670
agents, 1:755 4629-630 Cytotoxicity assays
radioprotective agent, 5:152, and vitamin D, 4:378 in high-throughput screening,
5:155 Cytochrome P450 reductase 2:49,2:62
Cysteine peptidase inhibitors X-ray crystallographic studies, Cytotoxic T-lymphocytes,
transition state analogs, 1:486 5:224-225
1:652-655 Cytokine modulators, Cytovene
Cysteine protease inhibitors 4130-131,4172-173 tumor-activated prodrug, 5:83
affinity labels, 1:762 IFNy, 4:183-184 cytoxan
Cystic fibrosis transmembrane IL-1,4173-174 alkylating agent, 5:54
conductance regulator IL-2,4174-175
plasmid DNA-mediated gene IL-4,4175-176 D 2163, 1:804, 1:806
therapy study, 4:664 IL-5,4:176-178 D 2916
Cytadren, 3:632 IL-6,4178-180 anticonvulsant, 6:315
Cytallene IL-12,4180-181 DA-1131,5:708
for hepatitis B virus, 5330 IL-13,4181-182 DACA
Cytarabine TNFa, 4182-183 dual topoisomerase 1/11 inhibi-
P-glycoprotein substrate, Cytokines, 4130. See also spe- tor, 5:68,5:73
4631 cific cytokines such a s DACA N-oxide, 5:85
Cytisine Erythropoietin Dacarbazine
neuronal nicotinic receptor for atherosclerosis treatment, alkylating agent, 554,
agonist, 2:386,2:393-394 3372-374 5:65-66
Cytochrome c in cancer, 5 4 3 Daclizumab, 5:490,5:510-513
and apoptosis, 5:17 and glucocorticoids, 3:779 with mycophenolate mofetil,
Cytochrome P450 production in T-cell activation 5:520
activity assays in high- by dendritic cells, 5235 Dactil, a136
throughput screening, 2:61 radioprotective agents, 5:171 Dactinomycin
in adrenal steroidogenesis, radiosensitizers, 5:194 antitumor natural product,
3:112-113 role in blood cell development, 5:110,5:111-115
antitumor prodrug by use of 3952-255 P-glycoprotein substrate,
CYP450 mediated activa- therapeutic implications, 4631
tion, 2:518 3272-273 Daemon, 1:392, 1:402
and drug metabolism, 2:79, tumor secreted, 5:226 Daffodils, drugs derived from,
2:437-439 and VCAM-1,3459 1:892
homology modeling, 1:123 Cytokine syndrome, 4175 Daidzein, 3:652
and leukotriene biosynthesis, Cytomegalovirus, 5298 Dalfopristin, 12376-877
4205, 4207 Cytomegalovirus antiviral drugs Dalgan, 6:335
narcotic analgesic interac- selective toxicity, 5:267 Dalmadorm, 6:207
tions, 6:338-339 Cytomel, 3:576 Dalteparin, 2:210,2:212
polymorphisms in CYP3A41 Cytoplasmic proteins, 5 2 6 formula weight, mechanism of
517, 4:626, 4629-630 cytosar action, and route of admin-
polymorphisms in CYP2C9, antimetabolite, 5:76 istration, 3:286
4626,4628-629 Cytosine, 4619 Spiro-DAMP, 1:696
Cumulative Index

4-DAMP proprietary and academic, Debrisoquine, 4627-628


semirigid analogs, 1:695-696 1:387-388 hypotension from, 4619
Danaparoid, 2:210,2:212,3:29 receptor targeting compounds, Decamethonium, 1:58
clinical trials, 3294 2:343 fragment analogs, 1:708-710
formula weight, mechanism of sequence and 3D structure, lead for drugs, 1:856-858
action, and route of admin- 1:387 nicotinic receptor antagonist,
istration, 3:286 storing chemical information 2:397 T
mechanism and site of action, in, 1:373377 Deceptive fitness functions, 1:88
3:309 for X-ray crystallography, Decision support systems, 1:403
treatment regimen, 3:298 1:478-479 Decision tree approach,
Danazol, 3697,3713,3715 Database tier, 1:393,1:403,1:407 1:247-248
Danocrine, 3:697 Data cartridges, 1:395, 1:402 Declaratory judgment plaintiffs,
Dapiprazole Data compression, 1:402 patent infringement cases,
a-antagonist, 6:4 Data dictionary table, 1:375
2:740-742
applications, 6:15 Data marts, 1:391393, 1:402
Declomycin, 5:740
Dapsone, 5:936,5:957 Data mining, 1:402, 1:410,
antimycobacterial application, 1:411, 1~412 Decongestants
5:829-830 future prospects, 1:394-395 adrenergics, 6:2
with chlorproguanil, 5:959 with QSAR, 1:66-67 currently used drugs, a 1 7 1
dosage forms, 5:934 Data warehouses, 1:390-393, Decontamination, 5539
efficacy and dosage, 5:810 12402-403 Deconvolution, 1:401
with proguanil, 5959 Dative bonds, 1:170, 1:365 Deduplication, 1:378, 1:403
with pyrimethamine, 5:959 DATScan Deep vein thrombosis,
Daptomycin, 1:848 Parkinson's disease diagnostic 3:289-290
Daquin, 3:124 radioligand, 65'35 Defendants, in patent cases,
Daranide, 3:70 Datura, a120 2:741-742
Daraprim, kg34 Daunomycin p Defensins
Darbid, e l 3 5 antitumor natural product, CCR6 binding, 4159
Darbufelone, 4246-247 5:126-128,5:130 Deferiprone, 3508,3:515
Daricon, a136 thermodynamics of binding to formation constants with iron
Darmonoct, a207 DNA, 1:183 and other metals, 3:506
Darstine, 6:139 Daunorubicin iron chelator, 3:512-514
Damsentan antitumor natural product, pM values, 3:484
endothelin receptor antago- 5:110,5:124,5:126-128 promotion of Fenton reaction,
nist, 3206 P-glycoprotein substrate, 3:503
Darvocet-N, a335 4:631 Defibrillators, 3:156
Darvon, 6:335 Daycart, 1:386 implantable cardioverter defi-
selective toxicity, 5:269-270 DayCGI, 1:386 brillator, 3:46
Darvon-N, 6:334 Daylight Chemical Information Dehydroalantolactone
DARWIN, 1:299 Systems databases allergenicity prediction, 1:836
explicit water molecules, 1:303 descriptors, 1:192 7-Dehydrocholecalciferol, 4374,
Databases in virtual screening, 1:254 4375
for bioinformatics, 1:345-349 DBBF-Hb, 3:397 7-Dehydrocholesterol,
cDNA microarray chips, 1:345 DBO-83 4374-375
chemical information manage- cholinergic, 6:54-55 Dehydroepiandrosterone
ment, 1:384 10-Deacetylbaccatin 11, 1:803 (DHEA), 3:113,3:616,
commercial systems for drug- Death domain, 5:17 3:681,3:682
sized molecules, 1:384-387 Death effector domain, 5:17 mechanism of action,
comparative QSAR, 1:39-41 Death-inducing signaling com- 3693-694
comparing expressed sequence plex, 5:17 Id-Dehydromuscarine,6:58
tags with, 1:342 Death receptors, 5:17 Delatestryl, 3:697
history of, 1:360-363 3-Deazaneplanocin A Delavirdine
knowledge discovery in, activity against orthopoxvi- anti-HIV drug, 5:472
1:393-395 ruses, 5:439,5:440 selective toxicity, 5:267
natural products, 1:387, 1:597 for Ebola virus, 5:433 Delayed afterdepolarizations,
for pharmacophore screening, DEBES combinatorial library, 3159-160
1:254-255 2:93 Delestrogen, 3632
Cumulative Index

Deligoparin, 2:216,2:220 Dengue virus, 5427 Dement Selection database,


Delorazepam, 6:207 De novo design, 1:113 1:386
Delta opioid receptors, 6:331, Density Derwent World Drug Index
a341355 polymorphs, 2:652 (WDI), 1:379, 1:386, 1:387
and addiction, 6:336-337 Deoxoartemisinin, 5964 Derwent World Patents Index
ligands used to characterize, Deoxyartemisinin, 5963 (WPI), 1:386
469-75,6:342,6:343-347, (R)-Deoxycoformycin, 1:750-752 10-Desacetylbaccatin 111, 1:863 it
6:451 (S)-Deoxycoformycin, 1:751 Desazadesferrithiocin
signal transduction, 2'-Deoxycoformycin metabolism, 3:550-551
6:342-343 antimetabolite, 5 7 6 Desazadesferrithiocin (DAFT), -
structure and molecular biol- Deoxycorticosterone, 3:113, 3530,3532
ogy, 6:350-354
3:750, 3759 Desciclovir
Deltaprim, 5934
and chlorazanil, 3123 for herpes virus, 5:318
Delta-selective opioid receptor
Deoxycortisone Descriptive marks, 2:758-759
agonists, 6:348, e354-355,
6:395-400 microbial transformation, Descriptor pharmacophores,
Delta-selective opioid receptor 2:602-603 1:60-63
antagonists, 6:348, 21-Deoxydexamethasone, 3:750 Desenex, 5891
6:367-370 3"-Deoxydihydrostreptomycin, Desensitization
Deltorphin analogs 2:176 nicotinic acetylcholine recep-
constrained, 6:435-437 3-Deoxyglucosone (3DG), 2:219 tors, 2:371
linear, 6:432-435 Deoxyhemoglobin, 3:387 Desethermuscarine, 6:61
Delvinal, 6:205 in sickle-cell anemia, Desferal, 3:507,3:515
Demeclocycline, 2:186 3:447-450 Desferri-ferrichrome, 3486,
Dementia, 6:744,6:745,6:780. Deoxynojirimycin, 4:36 3:487
See also Alzheimer's dis- 15-Deoxyspergualin, 5489, Desferrioxamine B (DFO),
ease; Alzheimer's disease 5490 3:483, 3:486,3:496
therapeutics; Cognition en- antimalarial, 5:987 analogs, 3:530,3:531
hancers clinical use for organ trans- antimalarial, 5:991
Demerol, a334 plants, 5:504-506 development of, 3514-515
Demethylchlortetracycline, with leflunomide, 5:523 and Fenton reaction, 3:503
5740 side effects, 5506 formation constants with iron
5'-0-DemethyldioncophyllineA 6-Deoxytetracycline, 2:185, and other metals, 3506
antimalarial, 5:994-995 2:186 iron chelator, 3:507-511
N-Demethylstreptomycin, 2:172 Dependence for iron overload disorders,
6-Demethyltetracycline, 2:186 narcotic analgesics, 6:336 3504-505
Demexiptiline, 1:692-693 Depepsin, &I58 synthesis, 3:524-527
Demser, 6:4 Depolarization, of myocardial use with animal models,
Demulen, 3:632 cells, 3 3 , 3 5 , 3159-160 3:534-540
Denaturing gradient gel electro- Depo-Provera Lunelle, 3632 Desferrioxamine E, 3:483, 3486
phoresis, 4622 Depositions, in patent infringe- synthesis, 3524425,
Denaturing high performance ment cases, 2:749 3528-529
liquid chromatography (dH- Depo-Testosterone, 3:697 Desferrioxamine G, 3483,
PLC), 4:622 Depot neuroleptics, 2:503 3:486,3:530
DENDRAL, 1:393 Depression, 6:484. See also Anti- Desferrithiocin, 3:488
Dendritic cell-derived chemokine depressants design, synthesis, and testing,
(DCCK),4150 CNS stimulants in terminal 3~540-545
Dendritic cell immunotherapy, illness, a 1 7 3 iron-clearance evaluations,
5:235-243 Deracyn, 6:552 3:545-549
Dendritic cells Deramciclane, 6:581 metabolism of desazadesferri-
and adaptive immunity, 5224 DEREK, 1:246,2:621 thiocins, 3:550-551
physiology, 5235-236 Dermatophytoses, 5883 synthesis, 3:530-532
T-cell activation by, 5235-236 Dermorphin analogs toxicity, 3:549-550
transduction by viral vectors, constrained, 6:430-432 Desiclovir, 2:511
5:241-243 linear, 6:428-430 Desicocytes, 4548
tumor cell fusion, 5:240-241 Derwent Information databases, Design in Receptor (DiR)ap-
Dengue fever, 5:1035 1:386 proach, 1:236
Cumulative Index

Design patents, 2:708, Dexamphetamine, 6:843, a 8 5 5 Diacylglycerol, 2:616,3:158


2~770-771 dose as anti-obesity agent, elevation in hyperglycemia,
Desipramine a847 44
affinities for monoamine re- Dexedrine, 6:3, a170 Diadenosine-tetraphosphate
ceptors, 6:495 dose as anti-obesity agent, PARP inhibitor, 6:681
antidepressant, 6:485,6:486, 6:847 Diagnostics
a487 Dexfenfluramine patentability, 2:718 7
clinical trial using genotyping, dose, a848 Dial, 6:205
4643 removedlrestricted by FDA, N-N-Diallylmelanine (DAM)
CYP2D6 substrate, 4627 4642,6:843, a856 hair growth candidate drug,
dose for eating disorders, Dexrazoxane 4438
6:850 radioprotective agent, %I72 2,6-Diamicopurine, 2147
for eating disorders, 6:858 Dextrans Diamicron, 4:13
Diamino, 5Y, 6-Z-quinazolines
inhibition of serotonin, norepi- for conjugated hemoglobins,
QSAR studies of DHFR inhibi-
nephrine, and dopamine 3:417
tion, 1:34-35
transporters, a500 for plasma volume expanders, 2,4-Diamino-6,7-dimethylpteri-
pharmacokinetic parameters, 3:429, 3:430, 3:431, 3:432, dine, 3:125, a126
6:497 a433 4,7-Diamino-N-(2-mopholin-
side effects profile, 6:493 radioprotective agent, 5166 oethy1)-2-phenyl-6-pteri-
Desirudin, 3:29,3:285,3:316, Dextroamphetamine, 6:170 dinecarboxamide, 3:125-126
a317 Dextromethorphan, 6:372 4,7-Diamino-2-phenyl-6-pteri-
clinical trials, 3:294 CYP2D6 substrate, 4627 dinecarboxamide, 3:125,
structure, a288 selective toxicity, 5:255 3:126
Desmethylephedrine Dextropropoxyphene Diaminopyrimidines
metabolism, 6:17 cytochrome P,,, isozyme sub- selective toxicity, 6:263-264
Desmethylmisonidazole stratelinhibitor, 6:339 1,3-Diamino-5-thiomethyltria-
radiosensitizer, 5178 selective toxicity, 6:269-270 zine combinatorial library,
Desmopressin, 3:200 Dextrorphan, a372 2:23
sickle hemoglobin hydration Dextrostat, 6:170 1,2-Diaminoyclohexane-N-,N'-
agent, 3461 Dezocine, 6:335 tetraacetic acid
Desogen, 3:632 analgesic, a308 radiopaque chelating agent,
Desogestrel, a632 DFO, See Desferrioxamine B 4489
biotransformation, a 6 4 1 DFP, 4240 Diamond v. Chakrabarty, 2:718
in contraceptives, 3:654 DFU, 4:239-240 Diampromine
interactions with steroid re- DHC Plus, a 3 3 5 analgesic, 6:385
ceptors, 3:633 DHFR, See Dihydrofolate reduc- Diapamide, 3:83, 3:84
Desonide, 3:750,3:753, a803 tase Diarylbutylamine antipsychotics
Desoximetasone, 3:750,3:752 DHT, See 5a-Dihydrotestoster- pharmacokinetics, biotrans-
2-Desoxyabarbiturate anticon- one formation, and drug interac-
vulsants, 6:271 Diabeta, 4 1 3 tions, 6:639-640
ADME, 6:282-284 Diabetes mellitus. See also Insu- Diarylethylene estrogen antago-
Desoxyn, 6:170 lin and hypoglycemic agents nists, 3:660-661
Desyrel, 6:485 carbohydrate-based agents in Diarylureas
Dexamethasone, 2:513-514, research, 2:219 topical antibacterials,
3:750,3:753,3:758, 3:768, carbohydrate-based drugs to 5:554-555
3:771-772,3:779,3:783, market last decade, Diastereomers, 1:784
3:786,3:788,3:797, 2:205-206 chromatographic separation,
3802-803,3:821,3:824, and coronary artery disease, 1:788
3:826, a839 3:lO Diatrizoate, 4494,4497, 4536,
half life, 3:776 Diabetes mellitus, type 1, 4:2-4 4537
P-glycoprotein inducer, 4631 Diabetes mellitus, type 2,42-4 adverse reactions, 4544
P-glycoprotein substrate, obesity increases risk, a839 analysis, 4539
4631 Diabetic nephropathy, 4:3 angiography application,
side effects, 3:756 Diabetic retinopathy, 4 3 4569
Dexamisole Diabinese, 4:12 biotransformation, 4565,
selective toxicity, k273 Diacetylformoguanamine, 3:123 4566
Cumulative Index

cardiovascular effects, 4:550, Dibenzoylmethane sunscreens Diels-Alder adduct analgesics


4:551 structure-activity relationship, structure-activity relation-
cations used with, 4541, 4469-470 ships, 6:370-372
4542 Dibenz(l,4)thiazepineantipsy- Dienestrol, 1:706-707, 3:632
excretion, 4563,4565 chotics estrogen receptor affinity,
histamine release, 4558-559 pharmacokinetics, biotrans- 3659
hyperosmolality, 4:542,4:543 formation, and drug interac- Diet T
liposome encapsulated, 4573, tions, 6:637 for cancer prevention, 5 3 3
4575 Dibenzylime, 6:4 and carcinogenesis, 5:7
myelography application, DIBRT Dietary Reference Intakes, -
4571 thyroid antagonist, 3:585-586 4361,4363-368
nephrotoxicity, 4552 Dibuline, 6:139 pantothenic acid, 4400
neurotoxicity, 4553,4554, vitamin A family, 4371372
Dibutoline, 6:139
vitamin B,, (cobalamin),
4:555 mydriatic and cycloplegic ac-
4415
osmolality, 4538,4539 tivity, e l 5 3
vitamin B, family, 4:400
particulate, 4576 relative anticholinergic activ- vitamin B, (riboflavin),4392
pharmacokinetics, 4:561, ity, a157 vitamin B, (thiamine),
4562 Dice coefficient, 1:68 4:389-392
pharmacology, 4540 Dichloralphenazone, 6:208, vitamin D family, 4379
properties, 4504 6:209 vitamin E family, 4 3 8 4 3 8 5
protein binding, 4556,4557 Dichlorisone, 3:750 vitamin K family, 4:387
red blood cell effects, 4549 Dichlorodiphenyltrichloroethane Dietary supplements, 4424
spiral CT application, 4569 (DDT), 2:555 and future of over-the-counter
urography application, 4:571 l7a-Dichloroester soft steroids, drugs, 4:473
Diazenes 2:549-550 increased popularity of, 4:422,
radiosensitizers, 5:192-193 Dichlorophenamide, 3:69,3:70, 4:423
Diazepam, a530 3:71 Dietary Supplements Education
ADME, 6:273 Dicholoroisoproterenol, 6:27 and Health Act, 4422
allosteric effector, 2:314, Diclofenac Diethanolamine methoxycin-
2:315 classification in various coun- namate, 4471-472
anticonvulsant, 6:266, 6:267, tries, 4430 Diethylcarbamazine
6:298, a307 protein toxicity, 2:615 antihelmintic, 51091,
CYP2C19 substrate, 4627 Dicloxacillin, 5631 51095-1096
discovery, 6:547 Dicoumarol, 1:882 Diethylenetriamine pentaacetic
dose, 6:270 Dictionary of Natural Products, acid (DTPA), 3,3:507,
dose for anxiety, a529 1:597 3:508,3:514
dosing interval and age, 2:643 Dicumerol, 2:310, 3:311 formation constants with iron
side effects, 6:276 Dicyclomine and other metals, 3506
Diazoxide, 3:78 anticholinergic, e l 3 4 iron chelator, 3:511-512
Dibekacin, 2:207 influence of cyclic radicals on pM values, 3:484
Dibenzo(l,4)diazepineantipsy- anticholinergic activity, radiopaque chelating agent,
chotics 6:143 4:489-490
pharmacokinetics, biotrans- relative anticholinergic activ- Diethylmaleate
formation, and drug interac- ity, 6:156 radiosensitizer, 5190-191
tions, 6:636-637 8-(Dicyclopropylmethyl-)-1,3- Diethylnitrosamine
Dibenzofurans dipropylxanthine, reaction with nucleosides,
picornavirus antiviral agents, 3121-122 2:616
5403 Didanosine Diethylpropion, 6:171, a856
Dibenzosuberanes anti-HIV drug, 5471,5472 absorption and metabolism,
picornavirus antiviral agents, selective toxicity, 5267 6:863-866
5403 Dideoxyinosine, 1:717 dose, 6:845
Dibenz(l,4)oxazepineantipsy- Didesmethylsibutramine, 4450 metabolism, 6:177-179
chotics Didox pharmacological activities,
pharmacokinetics, biotrans- for sickle-cell anemia, 3464 a865
formation, and drug interac- Didrex, 6:171,6:186,6:845 structure-activity relationship,
tions, 6:635-636 Dielectric problem, 1:83-84 6:185,6:186,6:187
Cumulative Index

Diethylstilbestrol, 3:656 increased expression leading selective toxicity, 5264


biotransformation, to drug resistance in cancer X-ray crystallographic studies,
3:637-638 chemotherapy, 5:283-284 1:486
estrogen receptor affinity, interaction with methotrex- 1,4-Dihydropyridinecalcium
a659 ate, 1:120 channel blockers, 3:20-28
interaction with estrogen re- interaction with trimetho- recent developments, 3:46 - 47
ceptors, 3:646 prim, 1:151, 12183 1,4-Dihydropyridines ?
stereoisomer analogs, interaction with trimetrexate, chromatographic separation,
1:706-707 . 1:531,1:557-559 1:788, 1:789
Difenoxin target of structure-based drug combinatorial libraries, 2:18, -
dose, 6:334 design, 1:425-426 2:20
Differential mRNA display anal- X-ray crystallographic studies, Dihydropyrimidine dehydroge-
ysis, 2:42 1:486
nase
Dihydrofolate reductase inhibi-
Differential-scanningcalorime- gene expression effect on
tors, 1545, 1:717
try, 2:655 5-fluoruracil, 4:609
antimetabolites, 6:76-78
Differin, 4320 chemical-shift mapping of single nucleotide polymor-
Differin Gel, 4373 binding, l:545 phism~,4630
Diffuse androgen dependent alo- comparative molecular field Dihydroquinazolinone sulfon-
pecia, 4433 analysis, 1:153 amides, 3:85-86
Diffusion-filtered NMR screen- genetic algorithm study of ac- Dihydroquinine, 1:889
ing, 1570-571 tive site, 1:89 Dihydrostreptomycin, 2:172,
Diflorasone diacetate, 3:750, genetic algorithm study of 5:841
a752 docking, 1:88-89 5a-Dihydrotestosterone(DHT),
Difluoromethylornithine, 5 3 5 mass-spectrometric binding 1:36, 1:768,3:616, 3:618,
a-Difluoromethylornithine, assay screening, 1:604 3:621
1:717 molecular modeling, 1:114, binding, 3:686
Digestion, 6:111-114 1:115, 1:116, 1~147,1~151 esterification, 3:714
Digitalis QSAR studies, 1:5 and hair growth, 4435,4436,
cardiovascular effects, 3:28 QSAR studies of inhibition by 4439
discovery, 2:39 diamino, 5Y, 6-Z-quinazo- most potent endogenous an-
Digital Northern, 1:342 lines, 1:34-35 drogen, 3:680,3:681
Digitoxin, 3:32 QSAR studies of inhibition by relative androgenicity and re-
cardiovascular effects, 3:28 diamino-5X-benzylpyrimi- ceptor binding of analogs,
Diglucomethoxane, 3:66 dines, 1:39 3:702
Digoxin, 3:32 QSAR studies of inhibition by selective retention, 3:693
with bleomycin, 5116 triazines, 1:31-33 testosterone metabolite,
cardiovascular effects, 3:28, recombinant DNA technology 3:687,3:689
3:44-45 applications, 2:97 Dihydroxamic acid
multiple inhibitory mecha- selective toxicity, 5264 synthesis, 3524
nisms, 3:33 soft analogs, 2:565-566 2,3-Dihydroxy-W-dimethyl-
P-glycoprotein substrate, volume mapping, 1:140 benzamide (DHBA)
4:631 Dihydromorphine, 6:363 iron-specific ligand, 3:482-483
and P-gp pump, 2:658 Dihydromuscimol, 1:690 pM values, 3:484
volume of distribution, 2:640 4,5a-Dihydronorethindrone Diiodofluorescein
Dihydrexidine interactions with steroid re- influenza antiviral agent,
for Parkinson's disease, 6:727, ceptors, 3:633 5379
6:728 Dihydroorotate dehydrogenase Diiodophenyl alkanoate ra-
Dihydroartemisinin, 1:887, antimalarial target, 5925 diopaques, 4497
5:963,5:971-972 transition state analogs, 1:752 Diiodopyridone radiopaques,
dosage forms, 5935 Dihydroorotate dehydrogenase 4:497
Dihydrocodeine, 6:363 inhibitors Diisopropyl fluorophosphate
Dihydro-P-erythroidine X-ray crystallographic studies, (DFP), 6:92
nicotinic receptor antagonist, 1:486 2,6-Diketopiperazinederivatives
2:390, 2:395 Dihydropteroate synthetase in- influenza antiviral agents,
Dihydrofolate reductase hibitors, 1:717 5386-387
antimalarial target, 5:925 antimalarials. 5:925 Dilaudid, 6:334
Cumulative Index

Diliganded receptors Dimethyltubocurarine, 1:857 2,3-Diphosphoglycerate


nicotinic acetylcholine recep-DIMP, 3:720-721 (2,3-DPG)analogs, 1:103,
tors, 2:373374 Dinapsoline 1:104
Diliganded receptors nicotinic for Parkinson's disease, 6:727, Diphtheria toxin
acetylcholine receptors 6:728 selective toxicity, 5:259
(muscle-type),2:373-374 Dinestrol Dipivefin
Diller-Merz rapid docking ap- applications, 3630, 3632 applications, 6:10 'i
proach, 1:292, 1:295 Dinoprost, 4302 general adrenergic agonist,
assessment, 1:303 Dinoprosterone, 4301-302 6:3
combinatorial docking, 1:317 Diodone Dipolar electrostatic forces, -
Diltiazem, 3:32,3:160, neurotoxicity, 4555 1:172
3169-170 Dipole-dipole interactions, 1:6,
Diodrast, 4541
bioavailabiliiy and half-life, 318 1:82
Dioncolactone A
cardiovascular effects, Dipole-induced dipole interac-
316- 17,344 antimalarial, 5:994-995
tions, 1:173
CYP3A4/5/7 substrate, 4627 Dioncopeltine A
Diprenorphine, 6:371
dihydropyridines contrasted, antimalarial, $994-995
1,3-Dipropyl-8-[2-(5,6-ep-
327-28 Dioncophylline B oxy)norbornyllxanthine,
multiple inhibitory mecha- antimalarial, 5:994-995 3:122
nisms, 3:33 Dioncophylline C Diprotrizoate, 4497
nonclassical resolution, 1:803, antimalarial, 5:994-995 angiography application,
1:805 2,4-Dioxobutanoicacid deriva- 4:569
P-glycoprotein inhibitor, tives neurotoxicity, 4554, 4555
4631 influenza antiviral agents, properties, 4504
uses and side effects, 3:43 5:386 Dipyridamole, 3:285
Dimannosidostreptomycin, 2:172 Dioxybenzone clinical trials, 3:293
Dimension tables, 1:390, 1:403 structure-activity relationship, formula weight, mechanism of
Dimeric vinca alkaloids 4469 action, and route of admin-
antitumor natural product, sunscreen, 4460 istration, 3:287
5:139-143 Diphemanil mechanism and sites of action,
Dimethindene anticholinergic, 6:136 3:321-322
anticholinergic, a 1 3 1 relative anticholinergic activ- structure, 3:289
Dimethiodal sodium, 4497 treatment regimen, 3:298
ity, a157
N,N-Dimethyldopamine Directed tweak algorithm, 1:260
Diphenhydramine
alkyl chain homologation ana- Directionality, 1:140
logs, 1:701 over-the-counter status, 4:426
Directive 92/26/EEC, 4:428
bioisosteric analogs, 1:690, selective toxicity, 5:275
Direct-to-consumer advertising,
1:692 Diphenoxylate, a333
4422
semirigid analogs, 1:695 antidiarrheal, 6:338 Dirithromycin, $763
Dimethyl fumarate dose, &334 DISCO, 1:58, 1:60, 1:256
radiosensitizer, 5:193 Diphenyhydramine and molecular modeling, 1:147
for Parkinson's disease, 6:731, Discodermolide
6:732 genotoxicity prediction, 1:843
1,2-Dimethyl-3-hydroxypyridin- Diphenylacetyloxy-derivative Discovery, in patent infringe-
4-one, See Deferiprone anticholinergics, 6:132-133 ment cases, 2:748-749
1,l-Dimethyl-4-phenylpipera- Diphenylhydramine, 6:212, Discretes, 2:8
zinium 6:214 Diseases
cholinergic, 6:56 Diphenylmethane, 1:231 effects on pharmacokinetics,
nicotinic receptor agonist, privileged structures, 1:252 2:646,2:647
2:394 2,3-Diphosphoglycerate Human Genome draft map
Dimethylpyrindine (2,3-DPG),1:104, 1:421 and understanding of, 2:320
anticholinergic, 6:131 binding to sickle hemoglobin, and metabolism, 2:474-475
Dimethyl sulfoxide (DMSO) 3~445-446 molecular uniqueness of, 2:85
force field models for, 1:176 hemoglobin allosteric effector, relative limited number of,
radiosensitizer, $176 3:386,3:387,3:388-390, 2:706
solvent for compound stores, 3:395 Disinfectants, $539
2:57 radiosensitizer, 5:183-184 testing, 5:544
Cumulative Index

Disintegrants, 2:678 Dithiothreitol DK-35C, 5:706,5:708


Disintegrins, 1:652 radioprotective agent, D,L descriptors, for chiral mole-
recombinant DNA studies, 5~156-157 cules, 15'83
2:105 Dithromycin, 1:875 DMB-323
Disipal Diurazine, 3124 NMR binding studies with
for Parkinson's disease, 6:731, Diuretic agents, 355-61, HIV protease, 1:560-562
6:732 3:142-143. See also Urico- DMHB T
Disopyramide, 3:32,3:34, 316'7 suric agents structure-based design, 1:424
cardiovascular effects, 3 3 6 aldosterone biosynthesis in- DMP-450, 1:659
multiple inhibitory mecha- hibitors, 3:120-121 structure-based design, .
nisms, 3:33 animal studies, 3:62 1:438-439
uses and side effects, 3 3 5 aromatic sulfonamides, 3:68, DMP-504,3:369-370
3~70-73 DMP-696,6:578
Disorders
atrial natriuretic peptide, antidepressant, a518
relative limited number of,
3~133-138 DMP-840
2:706
carbonic anhydrase inhibitors, dual topoisomerase ID1 inhibi-
Disoxaril 366-70 tor, 5:68,5:75
picornavirus antiviral, 5:400 clinical aspects, 3:62-63 DMP-904,6:577-578
structure-based design, cyclic polynitrogen com- DMSO, See Dimethyl sulfoxide
1:454-455 pounds, 3:121-125 DMTl (Divalent Metal Trans-
Dispersive interactions, 1:82, and edema, 3:62-63 porter 1; NrampZ), 3:498
1:174. See also van der high ceiling, 388, 3:89-111 DMXAA
Wads forces hydrothiazides, 35'8-81 with tirapazamine, 6:85
Dissimilarity approaches, mercurial, 364-66 DNA, 4619. See also Recombi-
1:189-190, 1:206-208 metabolic and electrolyte dis- nant DNA technology
Dissociation constant, 1286 orders, 3:63 effect of oligonucleotide thera-
Dissolution rate osmotic, 3:63-64 peutics on, See Antisense
characterization, 2:658 pharmacological evaluation, oligonucleotides; Oligonu-
polyrnorphs, 2:652 3:61-62 cleotide therapeutics
salts, 2:651 potassium-sparing, 3:125-133 molecular modeling, 1:154
Distamycin steroidal aldosterone antago- NMR structural determina-
binding perturbations, 1:544 nists, 3:111-120 tion, 1:535
Distance geometry methods sulfonamides, aromatic, 3:68, noncovalent bonds in, 1:170
in molecular modeling, 1:126, 3:70-73 patentability, 2:718
1:142, 1:147 sulfonamides other than aro- supercoiling modeling, 1:95
in QSAR, 1:60 matic, 3:68,3:81-89 synthesis inhibition by phe-
in virtual screening, 1:263 thiazides, 373-78 nols, 1:40
Distance geometry QSAR tech- Diuril, 3:76 target of toxicity, 2:616
nique, 1:53 Divalproex as therapeutic agent, 2:117
Distance matrix, 1:135 anticonvulsant, 6266 in vitro evolution (SELEX),
Distance measures DiverseSolutions, 1:387 2:92-94
molecular modeling, for molecular similarityldiver- DNA-binding drugs. See also
1~135-137 sity methods, 1:193-194, Alkylating agents
molecular similarityldiversity 1:203-204 antitumor natural products,
methods, 1:201-202 Diversity analysis, 1:358 5:111-124
Distance range matrix, Diversity-based ligand libraries, chemical-shift mapping of
1:135-136 2350 binding to, 1:544-545
Distribution. See also Absorp- Diversity methods, See Molecu- chemotherapeutic agents and
tion, distribution, metabo- lar sirnilarityldiversity related tumor-activated
lism, and excretion (ADME) methods drugs, 6:51-94
prodrugs, 2:515-518 Diversity-property derived molecular modeling, 1:116
Distribution half-life, 2:643 (DPD) method, 1:201, 1203 NMR spectroscopy, 1:547-552
1,3-Disulfonamide, 3:70-71 Divisional patent applications, thermodynamics of binding,
Dital, 6:171 2:734 1:183
Ditercalinium Dixon plots, 1:731-732 DNA chips, 4:600
dual topoisomerase I/II inhibi- Dizocilpine DNA damage, a677
tor, 5:75 anticonvulsant, 6:306 and apoptosis, 6:677
Cumulative Index

DNA fragmentation, 6:677 DNA repair-deficiency diseases, DockCrunch project, 1:317


DNA gyrase inhibitors 5:32 Docking methods. See also Scoring
novel lead identification, 1:321 DNA sequencers, 4621 functions; various docking -
selective toxicity, 5:263 DNA topoisomerase 1, See Topo- programs; Virtual screening .
DNA helicase pcra isomerase I assessment, 1:303304
X-ray crystallographic studies, DNA topoisomerase 2, See Topo- basic concepts, 1:289-290
1:487 isomerase I1 combinatorial, 1:317-318 'i
DNA hypermethylation DNA viruses, 5294-295. See flexible ligands, 1:293-294,
and drug resistance, 5:289 also Antiviral agents, DNA 1:322
and epigenetic changes, DNAzymes and homology modeling, -
5:8-10 influenza antiviral agents, 1:305-306
DNA hypomethylation, 5:8 5:385-386 and molecular modeling,
DNA insertion/deletion muta- Dobutamine 1:113-118
agonist/antagonist, 6:5 and molecular size, 1:312313
tions, 4620
applications, 6:16 NOE docking in NMR,
DNA-intercalating topoisomer-
structure-activity relationship, 1:545-546
ase inhibitors, See Topo- 6:29 penalty terms, 1:313
isomerase I1 inhibitors; To- Dobutrex, 6:5 protein flexibility, 1:300-302,
poisomerase I inhibitors Docetaxel, 1:849, 1:863 1:322
DNA lesions, 5:4, 5:176 affinity for P-gp pump, 2:678 protein-ligand docking soft-
DNA ligase, 6:677 antimalarial, 5:990 ware, 1261
DNA methylation antitumor natural product, and QSAR, 1:304-305
accumulation, 5:3 5:110,5:137,5:138-139 searching configuration and
and drug resistance, 5:289 P-glycoprotein substrate, 4631 conformation space,
and epigenetic changes, DOCK 1:294300
5:8-10 anchor and grow algorithm, seeding experiments,
DNA methyltransferases, 5:8 1296 1:318-319
DNA microarrays, 2:43, assessment, 1:303, 1:304 special aspects, 1:300-306
2:621-624 combinatorial docking, 1:318 in structure-based virtual
fabrication, 4600-601 consensus scoring, 1266 screening, 1260-267
for gene expression analysis, empirical scoring, 1:310 as virtual screening tool,
4:600-606 force field-based scoring, 1:308 12266-267
for genotyping, 4622, force-field scoring, 1964 water's role, 1:302-303,
4624-625 geometric/combinatorial 1:313314
interpretation and bioinfor- search, 1295 Docking problem, 1:289
matics, 4:605-606 ligand handling, 1293 DockIT, 1 2 6 1
DNA polymerase epsilon, 6:677 molecular modeling, 1:112, Dockvision, 1261
DNA polymerase inhibitors, 1:113, 1:115, 1:116 Doctrine of equivalents,
1:342, 1:717 molecular modeling of small 2:743-744,2:749
antisense oligonucleotides, cavity, 1:106, 1:107 Dofetilide, 3:32, 3:41, 3167
2:119 penalty terms, 1:313 cardiovascular effects,
DNA polymerases, 5995-296, performance in structure pre- 3:42-43
a677 diction, 1:314 potassium channel subtype
DNA radicals, 5176-180 protein and receptor model- selective, 3:45
DNA repair ing, 15267 uses and side effects, 3:40
and apoptosis after stroke, protein flexibility, 1:301 Dolabella auricularia, 1:868
6:677 receptor representation in, Dolastatin-10, 1:868, 1:869
and carcinogenesis, 5:4,5:5 1:291 Dolastatin 10,5:140
and drug resistance in cancer rigid docking, 1:262-263 Dolichol, 3353
chemotherapy, 5:287 sampling/scoringmethods Dolsamate, 2:206,2:212
enhancement by radioprotec- used, 1:261 DoMCoSAR approach, 1:305
tive agents, 5169-170 seeding experiments, 1:319 Donepezil
inhibition by radiosensitizers, with site-based pharmaco- for Alzheimer's disease, a762
5:191-193 phores, 1:236 anticholinesterase, 6:96
and PARP (poly(adenosine DOCK4.0 for cognition enhancement,
5'-diphosphateribose)poly- PMF scoring, 1265 6:781,6:782
merase), 6:677-679 weak inhibitors, 1:319 structure-based design, 1:449
Cumulative Index

Donor bone marrow Dopamine transporter, 6:498, selective a,-antagonist, 6:2,6:4


organ transplant rejection ap- 6:499 structure-activity relationship,
plications, 5524 inhibition by antidepressants, 6:31
L-Dopa, 1:785, a674 6:500 Doxcyclin, 5935
analogs, 1:690 Dopamine-transporter inhibitors Doxefazepam, 6:207
interaction with vitamin B, pharmacophore model, 1:256, Doxepin, 1:692-693
family, 4399-400 1:258 affinities for monoamine re- .T
metabolism and Parkinson's virtual screening, 1:267-269, ceptors, 6:495
therapy using, 6:720, 1:270 antidepressant, 6:485,6:486,
6:721-725 Dopascan 6:487
and norepinephrine synthesis, Parkinson's disease diagnostic inhibition of serotonin, norepi-
6:22 radioligand, 6:735 nephrine, and dopamine
for Parkinson's disease, D-Optimal designs, 1:65-66 transporters, a500
6:712-736 Doral, 6:207,6:549-550 pharmacokinetic parameters,
prodrugs, 2:525 6:497
Doriden, a 2 1 1
selective toxicity, 5273
Dorimide, 6:211 selective toxicity, 5268-269
Dopamine
Dormicum, a207 side effects profile, 6:493
and addiction, 6:336-337
antipsychotic drug discovery Dormonocot, 6:553 Doxercalciferol, 4377,4378
strategies based on, Dorzolamide, 3:67 DOX-GA3, 5 9 0
6:640-651 Dosage forms. See also Oral dos- Doxorubicin, 2:96
and body weight, 6:855 age form with amsacrine, 5 6 8
inhibition by depressants, a500 challenges of, 2:650 antibody conjugates, 5:92
and neurotensin, 3:230 patentability, 2:718 antitumor natural product,
and Parkinson's disease, Dose adjustment, 2:641 5:83,5:110,5:124,5:128,
6:712-736 Dose reduction factor, radiopro- 5:129
role in CNS stimulant effects, tective agents, 5:154 P-glycoprotein substrate,
6:180-182 Dose-response curves, 1:8 4631
and schizophrenia, 6:602-603 vitamins, 4362 resistance to, 5288
semirigid analogs, 1:697 Dose-response relationship, tumor-activated prodrug,
TSH modulation, 3568 2:635 5:88, 589-90
Dopamine agonists, 6:725 Dose-to-solubility ratio, 2:666 Doxycin, 5740
struduralmodeling, a728-729 Doxycycline, 2:185,2:186,5:740,
Dosing interval, 2:641
Dopamine D, receptor agonists, 5742
Dosing rate, 2:636,2:641
6:726-728 antimalarial, 5:935,5:982
Dosmalfate, 2:206,2:212
Dopamine D, receptor agonists, Doxylamine, 2:618,6:212,6:214
Dostinex DPC-368, a 5 8 1
6:725-726
for Parkinson's disease, a722 DPC-423,3:324,3:325
Dopamine D, receptor antagonists
antisense, 2:136 Dothiepen, 1:692-693 DP-VPA
toxicity, 2:619 affinities for monoamine re- anticonvulsant, 6:311
Dopamine Dl receptors, 6:713, ceptors, 6:495 DragHome method, 1:305
a726 antidepressant, 6:485,6:486, DRAGON, 1:388-389
Dopamine D, receptors, 6:713, 6:487 Dramamine
a725 inhibition of serotonin, norepi- selective toxicity, 5:275
Dopamine D, receptors, 6:713 nephrine, and dopamine DREAM+ +, 1:318
Dopamine D, receptors, 6:713 transporters, 6:500 DRF-2725,3:370
Dopamine potentiating agents pharmacokinetic parameters, DRF-4832,3:370
for Parkinson's disease, 6:497 Drill-down, 1:391, 1:403
6:729-731 Double minute chromosomes, Dronabinol, 1:849
Dopaminergic receptors 520 dose, 6:854
and selective toxicity, 5259 Double prodrug concept, 2:517 metabolism, a866
Dopamine-selective reuptake Double-strand breaks, a677 structure-activity relation-
inhibitors Dovenex, 4378 ships of analogs, 6:877-880
antidepressants, 6:494,6:515 Doxans, 6:207 for wasting, 6:858,6:860
combined with norepineph- Doxazosin Dronedarone, 3:41
rine-selective, for eating dis- applications, 6:15-16 potassium channel subtype
orders, 6:885 metabolism, 6:19 selective, 3:45
Cumulative Index

Drostanolone, 3:709 bile acid sequestrants/choles- and E m methyltransferases,


anabolic activity, 3:716 terol absorption inhibitors, 2:22-23
Drotrecogin alfa, 2:209,2:212 3:355 essential pathways versus sin-
Drug Abuse Control Arnend- estrogen modulator antihyper- gle enzyme inhibitor, 1:495
ments of 1965,2:686 lipidemics, 3:355 HBV virus antiviral agents,
Drug-antibody conjugates, 2:506 estrogen-replacement therapy, 5:333-334
Drug availability, 2:636 - 637 3:355,3631-633 herpes virus antiviral agents, 7
Drug characterization fibric acid antihyperlipidemic 5:309310
DNA microarray application, agents, 3:354-355 to p-lactams, 5613-623
4:604 nicotinic acid antihyperlipi- linezolid, 5:590
Drug databases, 1:385-386. See demic agents, 3355 macrolide antibiotics,
also Databases plant sterols, 3:355
5:774-776
Drug Data Report, 1:379, 1:386 probucol, 3355
mutagenesis technique appli-
Drug delivery. See also Drug for- statins, 335.2-354
vitamin B, family, 4399-400 cation, 2:89-90
mulation; Oral dosage form pathogens, 1:770
vitamin D family, 4:379-380
salts, 2:651 quinolones, 5:586
Drug interaction studies, a647
self-emulsifyingsystems, Druglikeness screening. See also sulfonamides and sulfones,
2:673-674 Lipinski's "rule of 5" 5~572-573
Drug detoxification, 5286-287 molecular similarityldiversity tetracyclines, 5:743-746
Drug development, 1:509-510 methods, 1:191 toxicological studies, 2:622
approval time frame, similarity searching, 1:383 Drugscore function, 1:311,
2:696-697 virtual screening, 1245-250 1:312
and intellectual property, Drug-lipid conjugates, assessment, 1:303
2:706-707 2:509-510 performance in structure pre-
new toxicology paradigm: toxi- Drug metabolism, See Metabo- diction, 1:314
cology problem prevention lism seeding experiments, 1:319
rather than toxicology prob- Drug metabolizing enzymes in virtual screening, 1:315
lem solving, 2:611 polymorphisms in, 4:626-631 Drug screening, See Screening
reasons for failure in product Drug preparation methods Drug synthesis, 2:407-408. See
development stage, 2:634 patentability, 2718 also Multiple parallel syn-
serial design costs, 1:359 Drug Price Competition and thesis
toxicology's role in improving Patent Term Restoration, bench-scale experiments,
speed and success rate of, 2:687 2:408,2:411-414
Drug product, 2:502 bench to pilot plant, 2:409,
2:611-612
Drug reaction reporting, 2:686 2~414-417
Drug discovery. See also Lead
Drug-receptor complexes, chiral product requirements,
discovery; Lead identifica-
1:170-179 2~411-412
tion low energy state of, 1:5 commercial-scale operations,
accelerated pace of, 2:706 Drug receptors, 2:334335 2:417-420
chemistry-driven, 2:82-83 Drug regulation environmental controls, 2:413,
intellectual property chal- chronology of, 2:684-688 2:420
lenges, 2:705-708 Drug resistance in-process controls, 2:412,
and toxicology, 2:610-611 aminoglycoside antibiotics, 2:418
Drug Efficacy Study Implemen- 5:753-757 nevirapine example, 2:408,
tation, 2:687,4424 antibacterial agents, 5:543, 2:412,2:420-429
Drug Enforcement Administra- 5:572-573,5:586,5:590 scale-up, 2:408-420
tion (DEA),2:687 antibiotic resistant pathogens, synthetic strategy, 2:408-411
Drug formulation 1:770 Drug-target binding forces,
consideration in synthesis de- antifungal agents, $884-885 1~170-171
velopment, 2:408 anti-HIV drugs, 5:478-479 association thermodynamics,
patentability, 2:718 antimalarial agents, 5:921, 1~170-171,1:177-179
Drug Importation Act of 1848, 5:928-930 energy components for inter-
2:684 antimycobacterial agents, molecular noncovalent in-
Drug interactions 5:860-861 teractions, 1:171-174
antihyperlipidemic agents, in cancer chemotherapy, example drug-receptor inter-
3352-355 5281-290 actions, 1:181-183
Cumulative Index

Drug-target binding forces (Con- Durham-Humphrey Amendment Echogen, a399


tinued) (to Food and Drug Act), Econazole, 5893-897
free energy calculation, 2:686,4424,4426 formulations and indications, -
1:180-181 Dutasteride 5891
molecular mechanics force experimental hair growth Ecothiophate, 6:91,6:93
fields, 1:174-177 drug, 4440,4:441 Ecotrin, 3:287
Drug target genes Dutonin, 6:485 Ecteinascidia turbinata, 1:868 ;z
polymorphisms in, 4632-636 DX-8739,5:682 Ecteinascidin-743, 1:848,
Drug targets DX-8951f 1:867-868
allosteric proteins, 2:313-315 antitumor natural product, ECTL (Extracting, Cleaning, -

and bioinformatics, 1:351-352 5133 Transforming, and Loading)


estimated number of, 1:50 Dyclonine data, 1:377-379, 1:403
relative limited number of, gene expression profiling Ectopic beats, 3:5
2:706 study, 4613 ED,,, 2:613
b=s Edatrexate
x-ray crystallography of pub-
topical antibacterials, antimetabolite, 576, 5 7 8
lished structures, 1:482-493
5553-554 Edecrin, 3:88
Drug transport, 2:249-251. See DYLOMMS, 1:107 Edema, 3:9
also Passive diffusion; Per- Dymelor, 4 1 2 and renal excretion, 3:62-63
meability DYN 12,2:219,2:226 Edman degradation
active transport, 2:257-265, Dynorphin A, 6:356,6:357, performing in peptide arrays,
3:57-60 6:358,6:418 2:7
facilitated transport, Dynorphin A analogs, Edman sequencing, 1:518
2:257-265 6:418-422 Edronax, a485
strategies to enhance perme- Dynorphin analogs Edrophonium, 1:58
ability, 2:251-255 constrained, 6:420-421 anticholinesterase, 6:85
Drug transporter genes linear, 6:418-420 EDTA, See Ethylenediaminetet-
polymorphisms in, 4631-632 Dynorphin B, 6:358 raacetic acid
DRY6, 4159 Dynorphins, 6:331,6:656-658 Efaproxiral, 1:422,3:391394
Drying Dyrenium, 3:124 radiosensitizer, 5184-190
in large-scale synthesis, Dyrexan-OD, 6:171 Efavirenz
2:416-417 Dyslipidemia, 3:340-341 anti-HN drug, 5:472
DS 210,3:128 selective toxicity, 5:267
DS 511,3:128 E. Coli Effective concentration range,
DTIC iron uptake by, 3:494-495 2:636
alkylating agent, 5:54,5:65 mutagenicity prediction, 1:829 Effexor, 6:485,6:529
DTPA, See Diethylenetriarnine E. coli 0157 vaccine, 2:226 Eflornithine, 1:768, 1:769,4433
pentaacetic acid Eadie-Hofstee plot, 1:727, 1:729, adverse effects, 4434,4435
DU-86 1:731 for African trypanosomiasis,
alkylating agent, 5:61 and allostery, 2:304 51043-1045
DU-257 Early afterdepolarizations, development of, 4440
tumor-activated prodrug, 3:159-160 mechanism of action,
5:83,594 Early endosomes, 4662 4436-437
Duchenne muscular dystrophy Eating disorders, 6:838-839, Efonidipine, 3:21
plasmid DNA-mediated gene 6:840-842 bioavailability and half-life,
therapy study, 4654,4655 guidelines for treatment, 323
Duocarmycin 6:842-843 cardiovascular effects, 3 2 4
for arming antibodies, 5:94 physiology and pharmacology, Eglodipine, 3 2 1
DuP-697,4234,4239 a874 bioavailability and half-life,
DuP-721 Ebola virus, 5432-434 3:23
antimycobacterial, 5859 E-cadherin, 5:8,5:10,5:14 EICAR
DuP-747 hypermethylation, 5:9 flavivirus antiviral, 5428
analgesic, 6:389, a 3 9 1 ECEPP force field, 1:118 Eicosanoids, 4204-205
DuP-996 Echinocandins, 1:877-878 biosynthesis, 4205
acetylcholine-release modula- antifungals, 5:900-903 cycloxygenase-derived, 4233
tor, 6:97-98 discovery, 2:39 Eigenvector following method,
Duragesic, a334 Echinocytes, 4548 1:292, 1:301
Cumulative index

Einstein-Sutherland equation, Elgodipine for plasmid DNA-mediated


1:24 cardiovascular effects, gene therapy, 4658,
Elan, 1:387 3:24-25 4666-667
Elavil, 6:485 Elimination algorithms, 1907 En, 6207
dose for eating disorders, ELISA-type assays, 2:73 Enablement, patents, 2:707-708,
a851 for epitope mapping, 2 8 8 2:722-723
Eldepryl for single base primer exten- provisional applications, P
for Parkinson's disease, 6:730 sion detection, 4623 2:727-728
Elecon, 3:767 Elixir Sulfanilamide poisonings, Enactin
Electrocardiogram (ECG),3:4, 2:685 inhibitor df amyloid P-peptide -
3:5 Elkpain, 3:110 aggregation, a 7 5 9
Electron-affinic drugs, Ellence Enalapril, 1:650, 1:747, 1:881,
6:180-183 antitumor natural product, 3:198
Electron cryomicroscopy, asymmetric synthesis, 1:807,
5:128
1:809
1:611-628 Ellman resin, 2:30
conformationally restricted
image processing and 3D re- Elorine, a139
peptidomimetics, l:64O - 641
construction, 1:624-628 Elutherobin impact of ACE polymorphisms
image selection and prepro- antitumor activity, 5139 on effectiveness, 4634
cessing, 1:623-624 EM-574,2:213,2:220 prodrug, 2:510
three-dimensional, 1:615-616 EM-652,3664 and snake venom peptides, 2:6
Electron-donating substituents, EM-800, 3664 Enalaprilat, 1:650,1:747,2:510
1:12-15 EM 250 conformationally restricted
growth inhibition by, 1:41 experimental hair growth peptidomimetics, 1:640-641
Electronic parameters drug, 4441 covalent joining to thiazide
in QSAR, 1:ll-15,150 EMBL Nucleotide Sequence Da- diuretics, 3:86-87
Electronic reading rooms (Free- tabase, 1:335 ENA 78 ligand
dom of Information Act), Embryonic stem cells, 5:524 and CXCR2,4161
a701 Embryo tail defects, 1:40 Enamelysin, 5 1 3
Electron lenses, 1:612 EMD 60400 Enantiomeric excess, 1:784
Electron probability distribu- analgesic, 6:394 enrichment by crystallization,
tion, 1:101 EMD 61753 1:800-802
Electron-topological matrix of analgesic, 6:394, 6:395 Enantiomers, 1:365, 1:366. See
congruence, 1:147 EMD 121974 also Chirality
Electron-withdrawing substitu- antiangiogenic agent, with agonist-antagonist prop-
ents, 1:ll-15 5:218-219 erties at same receptor,
growth inhibition by, 1:41 EMD 122946,1:676 1:705
Electrophysiology, 3:3-4 endothelin receptor antago- chromatographic separations,
Electroporation nist, 3:206 1:787-793
for plasmid DNA-mediated EMD 128130 defined, l:783-785
gene therapy, 4:656-657 for Parkinson's disease, 6:733, Enantioselective metabolism,
Electrospray FTICR mass spec- 6:734 1:786-787
trometry, 1:601-603 Emergency Use Investigational Enantioselectivity, 1:784
Electrostatic interactions, New Drugs application, Enbrel, 4182,5229,5234
1:171-172, 1:285 2:690 Encainide, 3:32,3:34, 3:167
charge parameterization, Emerging pathogens, 5:713 cardiovascular effects, 3 3 7
1:lOl-102 Emivirine increased mortality from, 3 4 5
and docking scoring, 1:308 anti-HIV drug, 5:472 multiple inhibitory mecha-
enzyme inhibitors, 1:721, Empirical scoring, 1264, 1:307, nisms, 3:33
1:723 1:308-310 uses and side effects, 3 3 5
long range, 1:177 Emtricitabine Encapsulated hemoglobins,
molecular modeling, 1:81-85, for hepatitis B virus, 5:327, 3:398,3:420-421
1:108-110, 1:140 5:329 Encoding
and molecular property visual- Emulsion No. II,3:422 and genetic algorithm, 1:88
ization, l:137 Emulsions, 2:672-673 natural products with mass
and QSAR, 1:6-7, 1:52 iodinated suspension ra- spectrometry, 1:596-597
Electrotopological indices, 1:4 diopaques, 4575576 Encryption, 1:403
Cumulative Index

Endocytosis, See Receptor-medi- Enduron, 3 7 7 Enterococcus


ated endocytosis ENERGI approach, 1:127 bridge in peptidoglycans,
Endogenous opioid peptides, Energy driven/stochastic search 5612
6:356-358 strategies, 1:292, methicillin-resistant, 5618
Endogenous vasoactive peptides, 1:296-2300 penicillin-binding protein,
3:193-195 Energy homeostasis, 6:869-872 5:615
Endomorphins, 6:357,6:358, Energy of association, 1:177 porin loss in, 5:621 f
6:422-425 Ene jets, 6:170 Enterohepatic circulation, 2:278
Endoplasmic reticulum Enforcement Enterotoxin, 2:234
adaptive toxic response, 2:617, patents, 2:740-751 Enthalpy of association
2:618 trademarks, 2:761,2:763-764 drug-receptor complexes,
@-Endorphin,6:331,6:356, trade secrets, 2766 1:170-171
6:357, a 3 5 8 England, See United Kingdom Entoviruses
Endorphins, 1:634, 1:850-851, English yew, paclitaxel from, target of structure-based drug
6:356-358 1:861-862 design, 1:454-456
model receptor site, 1:149 Enhanced damages, patent in- Entrainment, 1:802
Endosomal acidic insulinase, 4 8 fringement, 2:747 Entropy, 1:94
Endostatin, 5:45 Enkephalin analogs Entropy of association
Endothelial cells, 5:216 with antagonist activity at drug-receptor complexes,
and blood-brain barrier, 6:676 delta receptors, 6:416-417 1:170-171
cytoskeleton disruptors, conformationally restricted Enumerated structure, 1:368
5219-220 peptidomimetics, 1:129, Enumeration, 1:401, 1:403
inhibitors of migration, 5:219 1:637, 1:639 Enviradene
Endothelial nitric oxide syn- delta-selective constrained, picornavirus antiviral, 5 4 1 1
thase, 6:695-708 6:414-416 Environmental controls
Endothelin-l,3:202-208 delta-selective linear, in large-scale synthesis, 2:413,
substance P opposes, 3223 6:412-414 2:420
Endothelin-2,3:202,3:203 dimeric, 6:417-418 Enviroxime
Endothelin-3, 3:202, 3:203 leading to receptor-specific picornavirus antiviral agent,
Endothelin antagonists, 1:211, ligands and nonpeptide li- 5411-413
1:672-674, 1:675, 1:676, gands, 470-75 Enzymatic hydrolysis,
3:206-208 mu-selective constrained, 2:537-539
Endothelin-convertingenzyme, 6:411-412 Enzyme-based genotyping tech-
3:203, 3:208 mu-selective linear, nologies, 4:622-624
degrades amyloid P-peptide, 6:410-411 Enzyme-induced inactivators,
a760 Enkephalins, 1:634, 1:850-851 1:756
Endothelin-convertingenzyme discovery, a 3 3 1 Enzyme-inhibitor complexes,
inhibitors, 3208 model receptor site, 1:149 1:721-722
Endothelin peptide family and Parkinson's disease, 6:715 Enzyme inhibitors, 1:715-720,
biological actions, 3:203-205 Enovid, 3:632 2:72. See also specific En-
biosynthesis and metabolism, Enoxaparin, 2:210,2:212,3:309 zymes
3202-203 clinical trials. 3:292 affinity labels, 1:756-759,
conformationally restricted formula weight, mechanism of 1:760-764
peptidomirnetics, 1:637,1:639 action, and route of adrnin- coadministration with drugs,
NMR spectroscopy, 1:523-524, istration, 3286 2:677
1:526-527 Enrasentan design of covalently binding,
pathological roles, 3205-206 endothelin receptor antago- 1~720,1:754-756
structure, 3:201-202 nist, 3:206 design of noncovalently bind-
Endothelin peptide receptors, Ensemble, 1:94 ing, 1:720-754
3:203 Entacapone examples used in disease
Endothelium for Parkinson's disease, 6:730, treatment, 1:717
and sickle-cell anemia, 6:731 ground-state analogs, 1:720,
3458-459 Entecavir l:74O -741
Endothelium-derived relaxation for hepatitis B virus, inactivation of covalently
factor, 3:205. See also Nitric 5331-332 binding, 1:756-760
oxide Enterobactin, 3:482-483,3:490 mechanism-based, 1:759-760,
nitric oxide as, 3:12 pM values, 3:484 1:764-771
Cumulative Index

multisubstrate analogs, 1:720, general adrenergic agonist, Epothilone D, 1:865


12741-748 6:3 Epothilones
pseudoirreversible, 1:771-774 as lipolytic agent, 6:857 alkylating agents, 5:52
rapid, reversible, 1:720, metabolism, 6:17 antitumor activity, 5139
1:728-734 structure-activity relationship, Epoxides
recombinant DNA technology 6:30, e l 8 7 filtering from virtual screens,
applications, 2:97-100 Epiallomuscarine, 6:57 1:246 P
slow-, tight-, and slow-tight- Epibatidine, 1:819-820, 1:821 topical antibacterials,
binding, 1:720,1:734-740, analogs as cognition enhanc- 5:550-551
1:749 ers, 6:806-808 Epoxymexrenone, 3:117,3:120 -
transition-state analogs, cholinergic, 6:52-53 4,5P-Epoxymorphinananalge-
1:720, 1:748-754 nicotinic receptor agonist, sics, 6:334
Enzyme-mediated asymmetric 2:394 structure-activity relation-
synthesis, 1:804-807 Epicillin, 5632 ships, 6:361-364
Enzyme replacement Epidermal growth factor structure-activity relation-
carbohydrate-based drugs to decreased dependence on in ships of N-substituted,
market last decade, 2:211 carcinogenesis, 5:11 6:364-370
Enzymes. See also Receptors plasmid DNA-mediated gene Epristeride, 3:723-724,4438
basic concepts, 2:322-327 therapy studies, 4658, Epstein Barr virus, 5:296-297,
kinetics, 1:725-728 4666 5:299
major drug metabolizing fami- radiosensitizer, 5:194 Eptifibatide, 3:29,3:285, 3318
lies, 2:437 Epidermal growth factor recep- ADME, 3297
metabolism induction, tor, 5:11,5:23 clinical trials, 3993, 3294
2:476-478 Epidermal growth factor recep- formula weight, mechanism of
metabolism inhibition, tor-2,2:87-88 action, and route of admin-
2:475-476 3"-Epidihydrostreptomycin, istration, 3287
pathways and inhibitor de- 2:176 structure, 3289
sign, 1:495 Epigenetic changes for thrombolytic therapy,
reagents for carbohydrate- and carcinogenesis, 5:7-10 3167
based drugs, 2:229-230 and drug resistance in cancer treatment regimen, 3298
and structural genomics, chemotherapy, 5289 Equilenin, 3:599,3:644
1:352 Epilepsy, 6:264-265. See also Equilin, 3:635, 3:644
Enzyme targets, 1:5 Anticonvulsants dose for eating disorders,
and recombinant DNA tech- new causative agent for, a320 6:853
nology, 2:96-100 porcine embryonic GABAergic for eating disorders, 6:858
Eosinophilic granulocytes, cell transplants, 6:320 estrone compared, 3:658
3252, 3:253 Epimuscarine, 6:57 Equine estrogens, 3:631,3:632
and granulocyte-colony stimu- Epinephrine, See Adrenaline fate of conjugated, 3:635-636
lating factor, 3263 Epipodophylloxins genesis of, 3:644-645
and granulocyte-macrophage alkylating agents, 5:52 Equipmentlsystems qualifica-
colony stimulating factor, Epirubicin tion, 2:419
a259 antitumor natural product, Equivalence class, 1:403
Eosinophils 5:110,5:124, 5:128 Erb-B1 growth factor receptor,
chemokinelcytokine receptors, tumor-activated prodrug, 5 8 9 5:22,5:23
4:133 Epithelial transport, 2:250 Erb-B2/HER2/neu growth factor
Eotaxin Epitope mapping, 2:88-89 receptor, 5:22,5:23
and CCR3,4148-152 Epitope scanning mutagenesis, Erectile dysfunction, 4445-446,
Eotaxin 1,4:149 2271 4448
Eotaxin 2,4148,4149 Eplerenone, 3:112,3:117,3:120 Erections, 4444- 445
Eotaxin 3, 4:148 EPO, See Erythropoietin Ergocalciferol, 4:362,4:374,
Ephedra, 1:885, 6:10, Epoetin alfa, 3258 4376
6~168-169,6:857 EPOGEN, 3:258 Ergosterol, 3594
Ephedrine, 1:884-886, Epoprostenol, 4302-303 biosynthesis by fungal patho-
6:168-169,6:171 Epothilone A, 1:864 gens, 5:886-888
applications, 6:10,6:12, 6:172 toxicological profile prediction, Erimin, 6:207
dose as anti-obesity agent, 1:838-839 Erm methyltransferade inhibi-
6:846 Epothilone B, 1:864-865 tors, 2:22-23,295
Cumulative Index

Ersentilide ES 37,3135-136 enterohepatic recycling, 3:640


potassium channel subtype E, constant (Taft), 1:23-24 estrogen receptor affinity,
selective, 3 4 5 E-selectin 3:635
Erythrocytes, 3:252-254, cloning, 2:106 fate of l7a-ethynyl analogs,
3256-257 and sickle-cell animal models, 3:634-635
contrast media effects on, 2:216,2:223-225,2:241 metabolism, 3621, 3622
4547-550 E-selectin inhibitors, 2:223-224, nonsteroidal analogs of, P
exosome secretion, 5:241 2:240 3~659-666
in malaria, 5:920-926 NMR screening binding stud- steroidal analogs, 3656-659
sickle, 3:445,3:451-452, ies, 1:572 testosterone metabolite, 3:687 .
3453, 3454 Eserine blue Estradiol valerate
Erythro-9-(2-hydroxy-3-nonyl) anticholinesterase, 6:88 applications, 3:630,3:632
(EHNA) Eseroline
Estranes, 3597, 3:598
high-affinity adenosine deami- anticholinesterase, 6:88
Estrenol, 3:712
nase ligand, 1:604 Esidrix, 3:76
anabolic activity, 3:716
Erythroid krupple-like factor Esilgan, 6:207
Esmolol, 2:541-542,3:32 Estriol
(EKW
and sickle-cell anemia, 3:467 P-antagonist, 6:5 estrogen receptor affinity,
Erythromycins, 1:870, 1:871, applications, 6:16 3:635
1:874-876,2:188,5:763 cardiovascular effects, 3:39, Estrogen modulator antihyper-
antimycobacterials, 5:855-858 3:40 lipidemics
CYP3A4/5/7substrate, 4627 computer-aided drug design clinical applications, 3351
discovery, 2:39 (CADD), 2574-576 side effects, adverse effects,
genetic engineering, 2:92 uses and side effects, 3 3 8 drug interactions, and con-
hydrophobic interactions, Esophagography, 4567. See also traindications, 3:355
2:195 Radiopaques Estrogen-progestin combina-
macrolide binding, 2:193-194 Essential amino acids, 4:362 tions, 3:630, 3:631,
mechanism of action, Essential fatty acids, 4362 3654-655
2:188-189 E-State index, 1:26, 1 5 4 currently marketed, 3632
P-glycoprotein inhibitor, Estazolam, 6:207 Estrogen receptor a, 3:645-647,
4631 Esterone 3:669
prodrugs, 2:510 prodrugs, 2:505 X-ray crystallographic studies,
selective toxicity, 5:261-263 Ester prodrugs, 2:504-505 1:487
structure-activity relationship, Esters Estrogen receptor P, 3:351,
2:189-193 and obviousness of patent 3:645-647,3669
Erythropoietin, 2:237, claims, 2:732 Estrogen receptor modulators,
3:255256,4:130 pharmacophore points, 1:249 See Selective estrogen re-
androgen effects on, 3:682, Estimated Average Require- ceptor modulators
3705706 ment, 4:363,4368 Estrogen receptors
bioactivity, 3256 folic acid, 4411 activity assessment,
and decline in need for trans- niacin, 4397 3:648-649
fusions, 3272 vitamin A, 4371 affinity assessment,
with hydroxyurea for sickle- vitamin B,, 4389 3:648- 649
cell anemia, 3:464 vitamin B,, 4392 distribution of isoforms, 3648
preparations, 3:258 vitamin B,, 4400 electrophilic metabolites,
role in blood cell development, vitamin C, 4418 3638-639
32252-254,3:445,3:447 vitamin E, 4384 hypermethylation and carcino-
secretion in kidneys, 3:56 Estinyl, 3:632 genesis, 5:9
with stem cell factor, 3268 l7p-Estradiol, 1:706, 1:771, mass-spectrometric binding
therapeutic implications, 3599 assay screening, 1:604
3:272,3:273 biosynthesis, 3:617, molecular endocrinology,
therapeutic indications, side 3:618-620, 3:633-634, 3:648
effects, and pharmacokinet- 3:642-645 topography, 3:645-648
ics, 3:256-258 chemical delivery system, Estrogen-replacement therapy,
Erythro- prefix, 1:784 2:583-586 2:553,3:350-351,3:630
Erythrose in contraceptives, 3:654 for eating disorders, a858
enantiomers, 1:784 CYP3A4/5/7 substrate, 4627 and SERMs, 3:655
Cumulative Index

side effects, adverse effects, Ethacrynic acid, 3:142 promotion of Fenton reaction,
drug interactions, and con- animal studies, 3:62 3503
traindications, 3:355, antisickling agent, 1:421 radiopaque chelating agent,
3:631-633 diurectic, 3:88, 3:89-92 4489-490
Estrogen response elements, sickle hemoglobin modifier, radioprotective agent, 5:163
3648, 3:653 3:461 N-Ethylmaleimide
P
Estrogens, 3:595,3:598-599 Ethambutol, 5:839-840 radiosensitizer, 5:177
for Alzheimer's disease, drug interactions, 5:864 Ethylpropion, 6:863-864
6:765-766,6:768 efficacy and dosage, 5:810, pharmacological activities,
5:863 6:865 -
androgen conversion to,
3690-692 side effects, 5:840 Ethyl triiodostearate
biosynthesis, 3:617, Ethamide, 3:7O radiopaque material, 4493
3:618-620 Ethanol Ethyndiol diacetate, 3:632,
adaptive responses caused by, 3:666
currently marketed, 3:632
2:618 Ethynyl estradiol, 3634
for eating disorders, 6:853,
Ethclorvynol, 6:208, 6:209 applications, 3:631,3:632
6:858 ADME, 6:221 in contraceptives, 3:654
environmental and dietary, Ethidium bromide dose for eating disorders,
3:651-652 thermodynamics of binding to 6:853
fate of conjugated equine, DNA, 1:183 for eating disorders, 6:858
3~635-636 Ethiodol enterohepatic recycling, 3:640
for female unwanted hair emulsified, 4:575 steroidal analogs, 3:656,3:657
growth, 4:434 liposome encapsulated, 4575 5-Ethynylnicotine, 6:52
first antiandrogens, 3:718 radiopaque material, Etiocholane
genesis of equine, 3:644-645 4:493-494 testosterone metabolite, a687
metabolism, 3:620-622 Ethionamide, 5:835-836 Etizolam, a554
oxidation and reduction, efficacy and dosage, 5:810, Etodolac, 4242-243
3:633- 634 5:863 classical resolution, 1:796-797
radioprotective agent, 5:165 side effects, 5:836 Etodroxizine, 6:212,6:214
side effects, 3:631-633 Ethnic differences Etomidate, 2538
soft drugs, 2553-554 in metabolism, 2:472-473 Etonitazene
temperature-dependent up- Ethnomedicine, 239 analgesic, 6:308
take, 3:686 Ethopropazine Etopophos, 5:135
tissue-selective, 3652-654 for Parkinson's disease, 6:731, Etoposide, 1:717,1:867
Estrone, 3594 6:732 with amsacrine, 5:71
biosynthesis, 3:633-634 Ethosuximide antitumor natural product,
dose for eating disorders, ADME, 6:282 5:110,5:134-135
6:853 anticonvulsant, 6:265, 6:267, gene expression profling
for eating disorders, 6:858 6:297,6:298 study of drug response,
enterohepatic recycling, 3:640 clinical efficacy, 6:273 4:609
equilin compared, 3658 dose, 6:270 P-glycoprotein substrate,
estrogen receptor affinity, side effects, 6:277 4631
3635 Ethotoin resistance to, 5:288
with medroxyprogesterone, ADME, 6:273 with tirapammine, 5:85
3650 anticonvulsant, 6:266 tumor-activated prodrug, 5:87
metabolism, 3:621,3:622 dose, 6:270 Etoricoxib, 4235, 4236
Estrone sulfate, a 6 2 1 Ethoxzolamide, 3:69,3:70 Etorphine, 1:851
Estropipate Ethyldienolone, 3708 e-Tox, 2:620
applications, 3:630,3:632 Ethyl diiodostearate Etozolin, 3:109-110
Etanercept, 4:182,4:183,5:229, radiopaque material, 4493 Etrinate, 4373474
5:234-235 Ethylenediaminetetraaceticacid Eucatropine
Etanidazole (EDTA) anticholinergic, 6:136
radiosensitizer, 5: 178 formation constants with iron mydriatic and cycloplegic ac-
ETC-216,3:374 and other metals, 3506 tivity, e l 5 3
ETC-588,3374 history of use for iron chela- relative anticholinergic activ-
Eterobarb tion, 3:514 ity, 6:157
anticonvulsant, 6:306-307 pM values, 3:484 Euclidean distance, 1:68, 1:202
Cumulative Index

EUDOC Exifone Ezetimibe, 3:343,3:348-349,


assessment, 1:303 antimalarial, 5987 3366
ligand handling, 1293 Exna, 3 7 6 metabolism, 3:357
Eulexin, 3:717,3:719-720 Exons, 4619 side effects, a355
Eunephran, 3:76 Exosite, 2:95 E,Z system, 1:365, 1:399
Euphthalmine, 6:136 Exosomes, 5 2 4 1
Eurodin, 6207 Ex parte patent proceeding, F12511,3:370 ?
European Bioinformatics Insti- 2:739,2:745-746 Fabry's disease, 2:211,2:218
tute (EBI), 1:335 Experimental drugs, 2:687 Facilitated transport, 2:257-265
sequence databases, 1:387 Expert Protein Analysis System, Factor I1 -
European Patent Convention, 1:335 hemostatic preparations,
2:752 Expert systems 3292
European Patent Office, 2:720, plasma concentrations and
to predict metabolic biotrans-
2:756 half-life, 3296
formation, 2:481-483
European Union Factor V
Export licenses, 2:772 in clotting, 3:301-308
over-the-counter classification
in, 4428-430 Expressed sequence tags, 1:338 plasma concentrations and
patent enforcement, 2:740 expression level significance, half-life, 3296
patent protection, 2:751 1:342-344 Factor Va
Europium-cryptates, 2:48 patentability, 2:719 in clotting, 3:300-308
Evaporation profiling, 1:341-342 Factor VII
for production of amorphous Expression analysis/profiling, in clotting, 3:300-308
solids, 2:653 1:334 hemostatic preparations, 3.292
Evernimycin, 5793 branched DNA analysis for impact of polymorphisms on
Everninomycin, 2:214,2:220 toxicity testing, 2:623-624 acute coronary syndrome,
Everolimus, 1:849 DNA microarrays for analysis, 4637,4638
Evista, 3:343,3:632 4:600-606 plasma concentrations and
selective toxicity, 5276 gene function determination half-life, 3296
Evolutionary algorithms, 1:299 by, 2:43 Factor VIIa
with QSAR, 1:53-54, 1:61 genome-wide, 1:344-345 in clotting, 3299-308
Evolutionary chemistry profiling applications in drug hemostatic preparations,
and receptor target drugs, research, 4606-614 3:292
2:350-351 for target discovery, Factor VIIa inhibitors, 3:325
Exact match search, 1:378, Factor VIII
l:34O -345
1:379-381, 1:403 in clotting, 3:301-308
and toxicity, 2:621-624
Exaprolol and hemophilia A, 3291
Expression vectors, 2:95 hemostatic preparations, 3292
membrane function disrup-
tion, 2:614 Extended-spectrum p-lactam- plasma concentrations and
Exchange repulsion energy, ases, 5619 half-life, 3296
1:172-173 Extended stereochemistry, Factor VIIIa
Excimer fluorescence, 2271 1:365, 1:404 in clotting, 3:299-308
Excipients, 2:671,2:673 External guide sequences Factor M
to minimize aggregation, influenza antiviral agents, in clotting, 3:299308
2:674 5385386 and hemophilia B, 3991
permeation enhancers, 2:675, External registry number, hemostatic preparations,
2:676 1:379, 1:404 a292
selection, 2:678-679 Extraction plasma concentrations and
Excitation, in heart, 3:4-6 of natural products, 2:57 half-life, 3996
Exelderm, 5891 Extraction ratio, of an organ, Factor Ma
Exelon 2:636 in clotting, 3:299308
for Alzheimer's disease, a762 Extrapyramidal symptoms, of Factor Ma inhibitors, 3:325
for cognition enhancement, antipsychotics, 6:600, Factor X
6:781 6:605-607 in clotting, 3299-308
Exemestane, 1:770, 1:771, Extrathermodynamic relation- hemostatic preparations,
3:632,3:643,3:728 ship, 1:26 3292
Exertional angina, 3:9 Extrinsic tenase complex, plasma concentrations and
Exhaustive mapping, 1:398 3999-300 half-life, 3296
Cumulative Index

Factor Xa, 3:285 Fansimef, kg34 Federal Food, Drug, and Cos-
in clotting, 3:299-308 Fareston, 3:343,3:632 metics Act of 1938,2:684,
hemostatic preparations, Farglitazar, 429-30 2:685-686,2:689,2:697,
3:292 Faropenem, 5:659,5:660 2:698
Factor Xa inhibitors, 1:103, Fas-associated death domain, and over-the-counter drugs,
1:738, a 3 2 4 3 2 5 5:17 4424
3D pharmacophores, 1:199 Fas ligand Fedotozine P
non-peptide peptidomimetics, and adaptive immunity, 5:225 analgesic, 6:394,6:395
1:662, 1:665 plasmid DNA-mediated gene Feiba
site-based pharmacophores, therapy study, 4654 hemostatic preparation, 3:292 -
1:235-236 Faslodex, 3:6O5- 606 Felbamate
target of structure-based drug FASTA, 1:347 ADME, 6:284-285
design, 1:442
Fastin, e l 7 1 anticonvulsant, 6:265, 6:268,
Factor XI
Fast ion bombardment, 1:586, (3269, 6:295,6:298
in clotting, 3:301-308
1:587 clinical efficacy, 6:273
plasma concentrations and
half-life, a296 Fastsearch index, 1:376-377, development, 6:302
Factor XIa inhibitors, a308 1:399, 1:404 dose, 6:270
Factor XIII, a285 Fast Track programs, FDA, pediatric indications, 6:274
in clotting, 3:303 2:689,2:697 removedlrestricted by FDA,
Factor XIIIa, 3:284, a285 Fat-absorption inhibitors, a844 4:642
in clotting, 3:303 clinical applications, 6:843 side effects, a278
Factor XIIIa inhibitors, Fat soluble vitamins, 4368 Felodipine, 2:567,3:21
3329-331 Fattiviracin A1 bioavailability and half-life,
Factor XIIa influenza antiviral agent, 3:23
and bradykinin production, 5:390 cardiovascular effects, 3:25
3:225 Fatty acids vascular-to-cardiac selectivity
in clotting, 3:299-308 as absorption enhancers in ratio, 3:172
Factorial designs, 1:65-66 lipid formulations, Female-pattern baldness, 4433,
bioassays, 2:46 2:673-674 4435
Factory Inspection Amendment and insulin resistance, 4 2 8 Female sex hormones, 3:598,
of 1953,2:686 in lipid formulations, 2:671 3:629-630. See also Contra-
Fact tables, 1:390, 1:401, 1:404 permeation enhancers, 2:675, ceptives; l7p-Estradiol; Es-
FAD, 4393,4394,4397 trogens; Progesterone
2:676
nitric oxide synthase binding aromatase inhibitors,
role of insulin in metabolism,
site, 6:698 3:642- 645
42-3
FADH, 4394 biosynthesis, 3:617,
FADH,, 4394 target of toxicity, 2:616 3642-645
Fadrozole, 3:643,3:668 Faverin, 6:485 clinical applications,
Failed Reactions database, 1:385 FBSS, 1:202 3:630-633
Famciclovir FCE 22101,5:659,6:660 discovery of SERMS,
for hepatitis B virus, FCE 22891,5:659 3:655-656
6:330-331 FCE 29464,5:660 drug metabolism, 3:633-642
for herpes virus, 5:309,5:310 FDA, See Food and Drug Admin- nonsteroidal analogs of estra-
selective toxicity, 5:267 istration diol, 3:659-666
Famiciclovir, 2:508 Fd4C nonsteroidal analogs of pro-
Familial hypercholesterolemia, for hepatitis B virus, 6:327, gesterone, 3:667-668
3:11 5:329,5:333 physiology and pharmacology,
Families, 1:93 FeatureTrees, 1:316, 1:321 3:645-655
Family competition evolutionary Febrifugine recent and future develop-
algorithm, 1:299 antimalarial, 5:996,5:997 ments, 3:668-669
Famotidine Federal Anti-Tampering A d of steroidal analogs of estradiol,
classification in various coun- 1982,2:687 3:656-659
tries, 4:430 Federal Courts Improvement steroidal analogs of progester-
Fananserin, 6:651 Act of 1982,2:741 one, 3666-667
Fanconi's anemia, 6:32 Federal Declaratory Judgments structure-activity relationship,
Fansidar, kg34 Act of 1934,2:741 3:656-668
Cumulative Index

Female sexual dysfunction, "sparing" effect in sickle-cell Field effects, 1:140


4440,4441-442 anemia, 3:456-457 Field mapping, 1:107
Femara, 3632 Fetal stem cells, 5:524 Fields, 1:404
Femstat, 55591 Fexofenadine Fiflucan, 5890
Fendiline, 3:17 P-glycoprotein substrate, Fight or flight response, a526 '

bioavailability and half-life, 4631 Filgrastim, 3:263, 3:264


3:18 selective toxicity, 5275 Filtercascade, 1:267 P
cardiovascular effects, 3 1 9 FG 7142 Filters, for searching,
Fenfluramine cognition enhancer, 1:315-316, 1:376, 1:380,
dose, 6:847 6:794-795 1:392, 1:404 -
removed from market, 6:843, Fiber-optic biosensor arrays, Filtration
6:856 4614 in large-scale synthesis, 2:416
Fenofibrate, 3:343, 3347 Fibonacci search method, 1:11 Final monograph, over-the-
for angina treatment, 311 Fibric acid antihyperlipidemic counter drugs, 4425-426
enzyme activity, 3:365 agents Finasteride, 1:717, 1:768-770,
metabolism, 3:357 ADME, 3:357 3:717, 3:722, 4433
side effects, 3:354 for angina treatment, 3:11 adverse effects, 4434-435
Fenozan-50F clinical applications, development of, 4:439-440
antimalarial, 5985-986 3346347 mechanism of action, 4436
Fenlphen, 6:856 marketed agents, 3:343 reactions of, 3:604,3:605
Fenpropimorph, 5:903 right shifters for hemoglobin, structure-activity relationship,
Fenquizone, 3:86 3:389-394 4437-438
Fentanyl, 2:544,6:332,6:333 side effects, adverse effects, Fingerprint Generation Pack,
analogs, a 3 8 1 3 8 4 drug interactions, and con- 1:388
cytochrome P,,, isozyme sub- traindications, 3:354-355 Fingerprints, 1:376,1:378,
strate, a339 structure-activity relationship, 1:399, 1:404
dose, 6:334 3~364-365 molecular similarity methods,
Fentanyl Oralet, 6:334 Fibrillation, 3:4, 3:31 1:188
Fenton reaction, 3:499, and reentry, 3:30 FIRM, 1:67
3502-503 Fibrin, 3:165-166,3:284-285 First-pass effect, 2:639
Ferricenium salts in clotting, 3:299308 degree of, and feasibility of
radiosensitizers, 5196 t-PA stimulation, 2:84-85 candidate drugs, 2:646
Ferrichrome, 3:490 Fibrinogen, 3:285,3:303,3:318 First-pass metabolism,
pM values, 3:484 binding to contrast agents, 2:677-678
Ferric hydroxide, 3:481 4558 First to market, 2:4
Ferrimycin, 3:514 t-PA stimulation, 2:84-85 Fitness functions, 1547-88
Ferrioxamine B, 3:514 virtual screening studies, FK-143,3:724
pM values, 3:484 1:212-213 FK-463,5:888,5:902,5:903
Ferrioxamine E Fibrinolysis, 3:299-308 FK-3311,4:241-242
pM values, 3:484 Fibrinolytic agents FK 506
Ferrioxamines, 3:514 bleeding and other adverse for Alzheimer's disease, 6:766
Ferriprox, 3507 effects, 3291-294 binding to FKBP, 1:552-555
Ferrites clinical uses, 3:284-299 clinical use for organ trans-
radiopaque, 4487,4489 marketed, 3290 plants, 5494-500
radiopaque, ultrasmall, 4487, treatment regimens, cytokine IL-1 downregulation,
4490-492 3:298 -299 4173
Ferritin, 3:495-496,3:498-499 Fibrinopeptide A, 2:303 cytokine IL-2 downregulation,
regulation, 3:499-501 Fibrinopeptide B, 2:303 4173
Ferrochloroquine Fibroblast growth factor, cytokine IL-5 downregulation,
antimalarial, 5:992 5217-218 4177
Ferroportin 1, 3:501 Fibroblast growth factor inhibi- NMR spectroscopic binding
Fest Corp v. Shoketsu Kinzoku tors studies, 1:539
Kogyo Kabushiki Ltd., antiangiogenic agents, pharmacokinetics, 5:495
2:744-745 5218-219 pharmacology, 5:495-499
Fetal hemoglobin, 3452-453 Fibronectin, 5:12,5:216, 5219 side effects, 5:500
hereditary persistence of, Fick's diffusion laws, 2:256 structure-activity relationship,
3:457 Field-based descriptors, 1:201 5:499-500
Cumulative Index

FK-506 binding protein, 5:496 performance in structure pre- Fluocinonide, 3:750,3:752,


FK-506 binding protein inhibi- diction, l:314 3:803,3:824
tors, 1:552-555 protein and receptor model- Fluocortin butyl, 2:550-552 .
de nouo design, 1:113 ing, 1:267 9a-Fluorcortisol, 3:749,3:776,
flexible docking studies, 1:265 receptor representation in, a802
hydrogen bonding in, 1:288 1:291 Fluorescence correlation spec-
recombinant DNA studies, sampling/scoring methods troscopy, 2:47 -?
2:99-100 used, 1:261 Fluorescence polarization,
target of NMR screening stud- seeding experiments, 1:319 2:47-48
ies, 1:565-566, 1:571 F l e a c extension, 1:318 Fluorescence resonance energy _
weak inhibitor screening, Flickering cluster model, of hy- transfer (FRET), 2:75
1:319 drophobic interactions, 1:15 bioassays, 2:47,2:48-49
X-ray crystallographic studies, FLIPR, 2:51-52 detection for genotyping,
1:487 Flo, 1:256 4622,4:623, 4625
Flat database storage, Flobufen, 1:41-42, 1:42 Fluorescence spectroscopy,
1:362-363, 1:404 FLOG 1:592
Flat file storage, 1:360-362, explicit water molecules, Fluoroamide residues
1:404 1:303 in pseudopeptide arrays, 2:12
Flaviviruses, 5:427 ligand handling, 1:293 para-Fluoroamphetamine, 6:187
antiviral agents, 5:427-430 and molecular size, 1:312-313 4-Fluorobenzenesulfonamide
Flecainide, 3:32,3:167 seeding experiments, 1:318 binding to carbonic anhy-
cardiovascular effects, 3:37-38 Flomax, 6:4 drase, 1:538
enantiomers, 1:786 Flomoxef, 5:652-653 6a-Fluorocortisol,3:750,3:800,
multiple inhibitory mecha- Flonatril, 3:83 3:802
nisms, 3:33 Flosulide, 4242 Fluorodonepezil
increased mortality from, in viuo models, 4:246 anticholinesterase, 6:96
3:45 Flow cytometry, 2:77-79 6a-Fluoro-16a-hydroxycortisol,
uses and side effects, 3:35 Flucloxacillin, 5:609,5:631 3:750
Flesinoxan, 6:568-569 Fluconazole, 5:893-897 Fluoromethalone, 3:750,3:753,
Flestolol, 2:543 formulations and indications, 3:803,3:828
FlexE, 1:301 5:890 5-Fluoroorotate
FlexibaselFLOG, 1:263 intrinsic resistance to, 5:885 antimalarial, 5:987,5:988
Flexible ligands selective toxicity, 5:268 9a-Fluoroprednisolone, 3:751,
in docking methods, Flucytosine, 5:903-905 3:797,3:800,3:802
1:293-294, 1:322 formulations and indications, Fluoroquinoline combinatorial
and geometric/combinatorial 5:890 libraries, 2:18-19,2:21
search, 1:295 Fludara Fluoroquinoline K-12
in virtual screening, antimetabolite, 5:76 anti-HN drug, 5:474
1:263-264 Fludarabine Fluoroquinolones
Flexmatch index, 1:376 antimetabolite, 5:76,5:81-82 antimycobacterials, 5:853-855
Flexmatch search, 1:404 Fluid-energy mill, 2:674 selective toxicity, 5:263
FlexS, 1:316 Flumazenil, 6:563-564 side effects, 5:855
novel lead identification, cognition enhancer, 6:796 5'-p-Fluorosulfonylbenzoyl aden-
1:320, 1:321 Flumethasone, 3:751,3:796, osine (5'-FSBA), 1:763-764
FlexX 3:802-803 5-Fluorouracil, 1:717, 1:718
assessment, 1:303, 1:304 Flumizole, 4234-235 antimetabolite, 5:75, 5:76,
consensus scoring, 1:266, Flunarizine, 3:160,3:170 5:77,5:79-81
1:320 Flunet and DPD polymorphisms,
empirical scoring, 1:264, 1:310 structure-based design, 1:451 4630
explicit water molecules, Flunisolide, 3:750,3:753, 3:821 effect of dihydropyrimidine
1:302 Flunitrazepam, 6:207, a550 dehydrogenase expression
hydrogen bonding, 1:319 Fluocinolone, 3:750,3:752, on, 4:609
incremental construction, 3:761, 3:784,3:797,3:803 with ionizing radiation, 5:195
1:295-296 Fluocinolone acetonide, 3:750, with irinotecan, 5:131
molecular modeling, 1:115 3:752,3:761,3:797,3:803, with oxaliplatin, 5:60
novel lead identification, 1:320 3:824, a834 for papillomavirus, 5338
Cumulative Index

5-Fluorouracil (Continued) pharmacokinetic parameters, Food, Drug, and Insecticide Ad-


P-glycoprotein substrate, 6:497 ministration, 2:684
4631 side effects profile, 6:493 Food and Drug Administration -
prodrug, 2:515 Fluxon, 3:423 (FDA), 2:684. See also In-
resistance to, 5284, 5:288 FMN, 4393,4394,4397 vestigational New Drugs;
tumor-activated prodrug, nitric oxide synthase binding New Drug Application
5:44,5:90-91 site, 6:698 accelerated developmentlre- 7
Fluosol, 3:398,3:421-422 FMNH, 4394 view, 2:687,2:696-697
emulsion stability, 3:428 FMNH,, 4394 approvals for drugs, 2:705
pharmacokinetics, 3423 Fms growth factor receptor, and delay of marketplace en- -
pharmacology, 3:425-426 522 try of new drugs, 2:705
radiosensitizer, 5:183 FNQ3 delays in patents caused by,
side effects, 3:423 flavivirus antiviral, 5:429-430 and term extension, 2:714
Fluoxetine, See Prozac FOCUS-2D method, 1:68-69 drug development and ap-
Fluoxymesterone, 3697, Focused drug discovery, 2:54-56 proval time frame,
3:699 -700 Fodor photolithographic 2:696-697
Flupenthixol, 2:512 method, 2:s drug submission package, and
Fluphenazine, 2:512 Folate synthesis planning, 2:410
dose, 6:601 receptor-mediated endocyto- Fast Track programs, 2:689,
receptor binding and side ef- sis, 2:264 2:697
fects, 6:606 Folate analog antimetabolites, meetings with during IND
Flurandrenolide, 3:750, 3:752, 5~76-79 process, 2:695-696
3:803 Fold compatibility methods, over-the-counter drugs,
Flurazepam, 6207 1:353 4424- 428
Flurbiprofen, 1:763,4244 Fold patterns patent term extension, 2:708
Flurithromycin, 5:763 limited number of, 1:353 pioneer drug requirements,
Flutamide, 3:717,3:719-720, Foldsome, 3:778 2:742
3721,3:722 Folic acid, 4:399,4:405 pre-IND meeting, 2:690
Fluticasone propionate, 2:553, and cobalamin, 4415 Process Risk Analysis, 2:411
3:750, 3753, 3:827, deficiency, 4407-411 and solid-state requirements
35432-833 Dietary Reference Intakes, of synthesis, 2:414
Flutimide 4401
structure, 2:688
influenza antiviral agent, hypervitaminosis folic acid,
sunscreen regulation history,
Ex386387 4411
uptake and metabolism, 4467,4470-472
Fluvastatin, 1:744, 1:879-880, and trade secrets, 2:764
4405-407
3:343344, 3:345 and United States Pharmaco-
vitamin status assays, 4367
ADME, 3:356 peia and National Formu-
Follicle-stimulating hormone,
for angina treatment, 3:11 3:616 lary, 2:700-701
enzyme activity, 3:364 and androgen synthesis, Food and Drug Administration
D-Fluviabactin, 3:489, 3492 3~682-683 Modernization Act of 1997,
L-Fluviabactin, 3:483, 3:485, and estrogen synthesis, 3:642, 2:688,2:689,2:690,2:697,
3:490,3:495 3:654-655 2:698
synthesis, 3522 X-ray crystallographic studies, Food and Drugs Act of 1906,
Fluvoxamine, 6:530 1:488 2:685
affinities for monoamine re- Fomivirsen Foradil, 6:4
ceptors, 6:495 for herpes virus, 5309 Force fields
antidepressant, 6:485,6:486, Fondaparinux, 2:210,2:212, drug-target binding forces,
6:488 3:285 1:170-183
dose for anxiety, 6:529 clinical trials, 3:292,3:294, molecular modeling, 1:79-81
dose for eating disorders, 3310 parameter derivation,
6:850 formula weight, mechanism of 1:102-103
for eating disorders, 6:857 action, and route of admin- Force-field scoring, 1264,
inhibition of serotonin, norepi- istration, 3286 1:306-308
nephrine, and dopamine structure, 3:288 Formadicins, 5:664
transporters, 6:500 Fonsecaea, 5883 Formestane, 1:770, 1:771,3:727
Cumulative Index

Formidacillin, 5636-637 FR-173657 Friedreich's ataxia


in vitro antibacterial activity, bradykinin antagonist, 3:227 role of iron, 3504, 3505
5635 FR-181877,3:328,3:329 Frontal affinity chromatogra- .
Formoguanamine, 3123 FR-191512 phy-mass spectrometry,
Formoterol influenza antiviral agent, 1:601
P-agonist, 6:4 5390 Frontotemporal dementia and
applications, 6:14 FR-228352,4235-236 parkinsonism linked to
Formula table, 1:376 FR-900098 chromosome 17 (FTDP-171,
Formulation, See Drug formula- antimalarial, kg89 6:745
tion FR-901379,5:902 Fructose-1,6-biphospatase -
5-Formyl tetrahydrofolate poly- FR-901533 allostery, 2:306
glutamate, 4407 endothelin-converting enzyme 5-FSA
10-Formyltetrahydrofolate poly- structure-based design, 1:424
inhibitor, 3:208
FTDOCK, 1:115
glutamate, 4:406,4:407, Fractalkine, 4:132
Ftrees-FS algorithm, 1:221
4410 Fractional factorial designs, 1:66 FTY 720, k489
Fosamax Fractionation clinical use for organ trans-
selective toxicity, 5:273 of natural products, 2:57 plants, 5506-509
Foscarnet Fraction unbound, 2:637 side effects, 5:509
for herpes virus, 5308 Fragment analogs, 1:707-710 Fujita-Ban equation, 1:4
selective toxicity, 5267 Fragment-based ligand docking, Fujita-Nishioke analysis, 1:13
Fosinopril 1:294 Fullerene C,,
impact of ACE polymorphisms Fragmin, 3286 influenza antiviral agent,
on effectiveness, 4634 France 5390
Fosinoprilat, 2:674-675 patentable subject matter, Fumigation, 5539
Fosinorpil 2:720 Functional assays, 2:341342
prodrug of fosinoprilat, trade secret protection, 2:769, Functional genomics, 1:338340
2:674-675 2:782 and receptor target validation,
Fosmidomycin FRED 2:336-338
antimalarial, 5989 ligand handling, 1:293 Functional group filters
Fosphenytoin sampling/scoringmethods in druglikeness screening,
ADME, 6:275 used, 1:261 l:246-247
anticonvulsant, 6:266,6:304 Freedom of Information Act, Functionalization reactions
dose, 6:270 2~767-768 in metabolism, 2:431-4352:
Fos protein, 5:22,6:25 electronic reading rooms, 437-465
FOUNDATION, 1:112-113 2:701 Functional mimetics (peptidomi-
Fourier transform ion cyclotron Free energy of association, 1:286 metics), 1:636
resonance (FTICR) mass calculating, 1:180-181 Fungal cell wall, 5:888-889
spectrometry, 1:585, drug-receptor complexes, 1:5, Fungal diseases, 5:882-884. See
1:601-603 1:170-171 also Antifungal agents
4-Point pharmacophores, 1:408 enzyme-inhibitor complexes, diagnostic and microbiological
molecular similarity methods, 1:722 issues, 5885-886
1:189, 1:196-198, 1:205 Free energy perturbation, 1:307, trends in incidence, 5884
privileged, 1:231 1:308 Fungal efflux pump inhibitors,
virtual screening, 1:210 Free radicals 5:909
FPlGCM, 2:552 inhibition by radioprotective Fungal natural products, 1:848,
FP16CMAc, 2:552 agents, 5:168 1:893,2:39
FPL-55712,4:221 production by ionizing radia- Fungal pathogens, 5882-884
FPL-66564,2:564 tion, k153 biosynthesis and function of
FPL-67047 Free rider, 2:705 ergosterol, 5:886-888
structure-based design, 1:453 Free-Wilson approach, in QSAR, opportunistic filamentous,
FPL-55712-derived compounds, 1:4, 1:2930 5884
4221-222 Freeze drying Fungal squalene epoxidase in-
FR-139317 for production of amorphous hibitors, 1:717
endothelin receptor antago- solids, 2:653 Fungal sterol 14a-demethylase
nist, 3:206 and solid state structure, inhibitors, 1:717
FR-171113,3:327,3:328 2:669 Fungi, 5882
Cumulative Index

Fungizone, 5:890,5:891 pediatric indications, a274 GALT (gut-associated lymphoid


Furosemide, 2:510-511,3:88, side effects, a278 tissues), 2261, 2:264
3:94-95,3:142 GABA receptors, 6:95-297 Gamanil, 6:485
animal studies, 3:62 binding-gating problem, 2:369 Gambler
selective toxicity, 5264 GABA transporter, 6:498 consensus scoring, 1:266
Fusidic acid, 5792 Gadobenate dimeglumine flexible ligands, 1263
Fusin, 4166 radiopaque material, 4492 seeding experiments, 1:319 ;r
Fuzzy bipolar pharmacophore Gadobutrol Gamma rays
autocorrelograms, 1:197 radiopaque material, 4492 antiradiation testing, 5:154
Fuzzy clustering technique red blood cell effects, 4549 Ganaxolone
with molecular similaritytdi- Gadodiamide anticonvulsant, 6:314-315
versity methods, 15205 radiopaque material, 4492 Ganciclovir
Gadolinium chelates chemical delivery system,
Fuzzy distance, 1:57-58
radiopaque, 4490-492,4535 2:583
Fuzzy searches, 1:376
Gadolinium-DTPA for hepatitis B virus,
radiopaque material, 4:490, 5330331
G-3139,2:139,2:140 4491- 492 for herpes virus, 5307-308
G-4120, 1:663 red blood cell effects, 4549 with HSV-based suicidal gene
GABA, 1:766,2:391 Gadopenamide therapy, 5 4 4
analogs, 1:690 radiopaque material, 4492 tumor-activated prodrug,
and anticonvulsants, Gadopentetate dimeglumine 5:83, 5 9 0
6292-297 radiopaque material, 4492 Ganglionic blocking drugs, 6:110
and anxiety, 6:537-541 Gadoteric acid Gantanol, 5934
geometric isomer analogs, radiopaque material, 4492 Gantrisin, 5934
1~705-706 Gadoteridol Gap junctions, 3:3
molecular modeling, 1:149 radiopaque material, 4492 Gas chromatography, 1:592
and Parkinson's disease, 6:713 Gadoversetamide for enantiomer separation,
GABA,/benzodiazepine receptor radiopaque material, 4492 1:787
complex, 6:538-541 Gadoxetic acid Gas chromatography-mass spec-
and cognition enhancement, radiopaque material, 4492 trometry (GC-MS),
6:782-797 Gadozelite 1~585-586
GABA aminotransferase radiopaque material, 4492 GASP (Genetic Algorithm Simi-
(GABA-T)inhibitors, 1:718, Gain-of-function mutations larity Program), 1256
1:766-767 nicotinic receptors, 2:376 in molecular modeling, 1:147
X-ray crystallographic studies, Galactopyranosyl-a-D-mannopy- Gas phase association, 1:177,
1:488 ranoside, 2226 1:178
GABA analog anticonvulsants, P-D-Galactoside Gastric acid secretion inhibitors,
6271 saturation transfer difference 486-88
ADME, 6:282-284 in binding to agglutin I, Ach-muscarinic-receptor-me-
GABA, receptor, 6:295,6:537 1:569 diated secretion, 4:97
anion-selective receptor, 2:360 Galantamine (galanthamine), acid production, 488-90
and anticonvulsants, 1:848, 1:849, 1:892-893 CCKJgastrin-receptor antago-
6295-296 allosteric effectors, 2:314, nists, 4119
GABAA/benzodiazepinecom- 2:315 H.Pylori, 493-94
plex, 6:538-541 for Alzheimer's disease, 6:762 histamine H,-receptor-medi-
GABA, receptor, 6295, a537 for cognition enhancement, ated secretion, 497-103
and anticonvulsants, 6:296 6:781,6:782 hormones regulating, 489-90
GAB& receptor, 6:295,6:537 nonclassical resolution, 1:802, physiology, 4:90-91
anion-selective receptor, 2:360 1:803 proton-pump inhibition,
Gabapentin Gallopamil, 3:17 42103-117
ADME, 6:284 bioavailability and half-life, receptor-mediated processing
for ALS, a674 3:18 regulating, 497-103
anticonvulsant, 6265, 6268, cardiovascular effects, 3 1 9 reflux esophagitis, 494-95
6:296,6:298 Gallotannin reversible proton-pump inhibi-
clinical efficacy, 6273 NAD glycohydrolase inhibitor, tors, 4117-119
development, 6:300-301 a686 targets under investigation,
dose, 6270 GALOPED, 1:218 4117-119
Cumulative Index

ulcer disease, 4:91-92 Gemfibrozil, 3:343,3:346,3:347 Gene Ontology project, 1:337


in vitro assays for, 495-96 for angina treatment, 3:11 General Agreement on Trade
in vivo assays for, 496-97 enzyme activity, 3:365 and Tariffs (GATT)
Zollinger-Ellison syndrome, metabolism, 3:357 patent legislation, 2:712-716 .
492-93 side effects, 3:353,3:354 Generalized anxiety disorder,
Gastric juice, 6:111-112 Gemonil, 6:205 a526
Gastric secretion, 6:110, Gemoprost, 4303 Generally regarded as efficaciour
6:111-114 Gemtuzumab, 5:228,5:231-233 (GRAE), 4424
Gastrin, e l 1 2 Gemtuzumab ozogamycin Generally regarded as safe
Gastrin-releasing peptide, tumor-activated prodrug, (GRAS), 4:424
3:229-230 5:83,5:92 Generic Drug Enforcement Act
Gastritis, 4 8 6 Gemzar of 1992,2:688
Gastroesophageal reflux disease, antimetabolite, 5:76,5:80
Generic structures, 1:367, 1:368,
Genatropine, e l 1 7
486 1~404-405
GenBank, 1:335
Gastrointestinal absorption Genescopolamine
growth of, 1:339
and apical sodium-dependent X-ray crystallography applica- therapeutic use, 6:117
bile acid transporter, 2:283 tion, 1:481 Geneseq database, 1:346
prodrugs, 2:510-514 Gender differences Gene sequences. See also Ex-
Gastrointestinal system in metabolism, 2:472-473 pressed sequence tags
carbohydrate-based agents in Gene array chips, 2:5 patentability, 2:718-719
research, 2:219 GeneChips, 1:344,4624,5:35 Gene sequencing
carbohydrate-based drugs to fabrication, 4:601 provisional patent applica-
market last decade, 2:206 hybridization, 4604-605 tions, 2:776
carbohydrate-based therapeu- Gene cloning, See Cloning Gene silencing
tics in development, Gene clusters, 2:92 and carcinogenesis, 5:8
2:212-213 Gene deletions, 4620 Gene subtraction
Gatekeepers, 5:26 Gene-directed enzyme-prodrug gene function determined by,
Gaucher's disease, 2:211,2:218 therapy (GDEPT), 5:83, 2:43
GCP-2 ligand 590-92 Gene therapy, 4652
and CXCRlICXCR2,4:161, Gene duplication, 4620 Gene therapy, plasmid DNA-
4162 Gene expression, 1:351. See also mediated, See Plasmid
GCS-100,2:218,2:220 Expressed sequence tags; DNA-mediated gene therapy
G-CSF 3 Expression analysislprofil- Genetic algorithms
X-ray crystallographic studies, ing; Pharmacogenomics; and combinatorial library de-
1:488 Single nucleotide polymor- sign, 1:217, 1:218
G-CSF signal transduction path- phism~(SNPs) with docking methods, 1:292,
way activator, 2:72 deregulation, 2:76-77 1:298-299
Gd0039,2:218,2:220 and drug response, 4608-610 with FOCUS-2D method,
GDEPT (gene-directed enzyme- Gene family approaches, 1:188, 1:68-69
prodrug therapy), 5:83, 1:244 inverse folding and threading,
5:90-92 subset selection, 1:190-191 1:124-125
Gedunin Gene family databases, Lamarckian, 1:299
antimalarial, 5:996,5:998 1:347-349 in molecular modeling,
Gelatin GeneFlex, 4624 1:87-89, 1:117
for plasma volume expanders, Gene function determination with QSAR, 1:53, h61-
3:429-430, a 4 3 1 antisense drugs as tools for, in vir@mlscreening, 1:263
Gelatinase, 5:13 2:128-129 Gen&ically engineered animals
NMR binding studies, 1:555 DNA microarrays for, 4604 patentability, 2:720
Gel permeation chromatogra- in high-throughput screening, Genetically engineered drug dis-
phy-mass spectrometry, 2:43 covery tools, 2:91-106
1:599 Gene gun Genetic engineering, See Recom-
GEM-91,2:134 for plasmid DNA-mediated binant DNA technology
Gemcitabine gene therapy, 4657-658 Genetics, 4618
antimetabolite, 576,580-81 Gene knockout studies, 2:43 Genetic superfamilies,
with permetrexed, 5:78 Gene mapping, 2:42 2:267-269
radiosensitizer, 5:195 Gene nomenclature, 1:337 GeneTox, 1:829
Cumulative Index

Gene transfer structure-activity relationship Glibenclamide, 2:206,3:176-178


recombinant globin gene vec- of rings I11 and N of the 4,5 and extracellular potassium,
tors, 3:468-469 subclass, 2:183 3:162-163, 3164
technology improvements, toxicity, 2:184-185,2:615 Gliclazide, 413, 4 1 6
3:470 Gentamicin B, 2:182 Glidants, 2:678
Genie Control Language, 1:378 Gentamicin Cla, 2:176-177 GLIDE
Genistein, 3647, 3652 Gentamycin, 5:748 sampling/scoring methods 7
Genitoxants, 1:840 selective toxicity, 5:260-261 used, 1:261
Genome, 2:621,2:622,4619 GEOCORE, 1:124 Glimepiride, 411,413,416,420
Genome annotation, 1:481, Geodon, 6:601 binding parameters, 418
1:494 Geometric atom-pair descrip- CYP2C9 substrate, 4627
Genome-wide expression analy- tors, 1:210 selective toxicity, 5264
sis, 1:344-345 Geometric/combinatorial search Glinide insulinotropic agents,
Genomics, 2:38,2:42. See also 411,414- 20
strategies, 1:292, 1:295
Gliotoxin
Functional genomics; Phar- Geometric hashing, 1:262
hepatitis C antiviral, 5426
macogenomics; Structural Geometric isomer analogs, Glipizide, 4:11, 413, 415, 416,
genomics 1:704-707 420
and DNA microarrays, 4600 Gepirone, 6:581 binding parameters, 4 1 8
and increased demand of con- Germany CYP2C9 substrate, 4627
sumers for control of their over-the-counter classification, selective toxicity, 5264
health, 4:422 4:428 Global stereochemistry, 1:398
and increases in potential tar- patentable subject matter, a-Globin chain, 3:445
gets, 2:62-63 2:720 P-Globin chain, 3:445
phylogenomics, 1:347-349 trade secret protection, 2:769 y-Globin chain, 3:456,3:457
simulating effects of drugs, Gerodorrn, 6:207 P-Globin gene
4612-614 Gestodene, 3:641, 3:658 abnormal, 3:445-446
toxicology implications, Geysen pins/wells, 2:7 geographic distribution in Af-
2:621-623 GG-745,4440 rica, 3:452, 3455
Genotype relative risk, 4643 Ghost membranes recombinant vectors,
Genotyping, 4600. See also Sin- EPR signal changes by ROH, 3:468-469
gle nucleotide polymor- 1:27 regulation, 3466-469
phism~ Ghrelin, 1:671, 1:674, 6:873 Globo H vaccine, 2:217,2:220
combined enzymatichybrid- GHRPS, 1:671, 1:674 a2pGlobulin, 2:618
ization approaches, GI-181771,6:884, a886 Glomerular filtrate, 3 5 7
GI-198745,4:440 Glomerulus, 3:57-58
4625-626
Gibbs-Helmholtz equation, Gloximonam, 5:666,5:668
costs, 4:644
1:286 Glucagon
hybridization-based, Gigabyte, 1:405 and gastric secretion, 43112
4624-625 Gingko role in insulin regulation, 4 2
polymerase chain reaction- for Alzheimer's disease, 6:674, Glucagon-like polypeptide 1 , 4 3 4
restriction fragment length 6:675,6:768 Glucoamylase-maltase, 433-36
polymorphism, 4622-623 Ginkolides, 6:674 Glucocorticoid y-lactones, 2:552
pyrosequencing, 4:624 Glabranine Glucocorticoid receptors, 3:749
single base primer extension, flavivirus antiviral, 5:429 structure, 3:776
4623-624 Glass-transition temperature, X-ray crystallographic studies,
use in clinical trials, 2:655 1:488
4642- 644 Glatiramer Glucocorticoid response ele-
when to use, 4 6 2 1 for MS, 6:674, a 6 7 5 ments, 3:749,3:778-779
Gentamicin, 2:176-177,2:185, Glaucine fumarate and oncogenes, 5:25
5748 picornavirus antiviral, 5:414 Glucocorticoids, 3:612. See also
structure-activity relationship Glaucoma Anti-inflammatory steroids
of ring I11 of the 4,6 sub- cholinergics for, 6:40 antiglucocorticoids, 3:837-845
class, 2:183-184 P-1,6-GlcNAc-branched N-gly- biosynthesis and metabolism,
structure-activity relationship cans, 2:226 3:773-776
of rings I and I of both sub- Gleevec, 5:110,5:284 cytokine IL-1 downregulation,
classes, 2:177-183 selective toxicity, 5257 4172,4:175
Cumulative Index

cytokine IL-5 downregulation, Glutamate dehydrogenase, 1:764 Glycine receptors


4177 allostery, 2:306-307,2:308 anion-selective receptor, 2:360
functions of, 3748 Glutamate NDMA agonists, binding-gating problem, 2:369 -
non-steroidal, 3845-846 1:150 M2-M3 loops, 2:367
P-glycoprotein substrate, Glutamate NDMA antagonists, Glycine transporter, 6:498
4631 1:150 Glycobiology, 2:236-242
temperature-dependent up- F
Glutamate receptor 1 Glycoconjugates, 2237-239
take, 3686 X-ray crystallographic studies, Glycogen
Gluconeogenesis 1:488 role of insulin in synthesis, 4 2
insulin's role in regulating, Glutamate transporter, 6:498 Glycogenolysis
-
4:2 Glutamic acid insulin's role in regulating,
Glucophage, 4:22
chemical modification re- 42
Glucosamine-6-phosphate
agents, 1:755 Glycogen phosphorylase
deaminase
nonclassical bioisostere ana- allosteric protein target,
allostery, 2:306
Glucose, 1:784. See also Diabe- log, 1:694 2:314,2:315
tes mellitus; Insulin and rigid analogs, 1:699 Glycolipids, 2:237,2:616
hypoglycemic agents 6'3)-Glutamic acid, 6:296 Glycol residues
normal range of plasma, 4 4 Glutamine-5-phospho-1-pyro- in pseudopeptide arrays, 2:12
osmotic diuretic, 3 6 4 phosphatase Glycophorin A
for prevention of ventricular allostery, 2:306 potential smoothing study of
remodeling, 3:181 Glutamine-PRPP amidotrans- TM helix dimer, 1:86
thyroid's effect on metabo- ferase inhibitors, 1:717 Glycoprotein IB
lism, 3:571 Glutathione interaction with sickled cells,
transport mechanism in renal radiosensitization by depletion 3:4583:458
tubules, 357-58 of, 5:190-191 Glycoprotein IIb/IIIa (GpIIb/
utilization by insulin, 42-4 and vitamin E, 4381,4383 IIIa) inhibitors
Glucose 6-phosphate dehydroge- Glutathione conjugation and calcium channel blockers,
nase redox reactions, 2:461-464 3:29
inhibition by carbonic anhy- Glutathione peroxidase non-peptide peptidomimetics,
drase, 3:68 hydrogen peroxide manage- 1:662-665
and malaria, 5:931 ment, 3:502 recombinant DNA studies,
Glucose toxicity, 4:s
X-ray crystallographic studies, 2:105
a-Glucosidase inhibitors,
1:488 template mimetics, 1:129,
431-37
Glutethimide, 6:210,6:211 1:643, 1:645
a-Glucosidases, 4 3 3 3 7
Glucosidation ADME, 6:221 for thrombolytic therapy,
in metabolism, 2:453-456 Glyburide, 411,413,415-16, 3166-167
Glucosulfone sodium, 5:829 4:19-21,426 Glycoprotein IIIa
Glucotrol, 4 1 3 binding parameters, 4 1 8 impact of polymorphisms on
Glucuronidase, 3:640 selective toxicity, 5:264 acute coronary syndrome,
Glucuronidase tumor-activated Glycerides 4637,4638
prodrugs, 5:89-90 as absorption enhancers in Glycoproteins, 2:231,2:238
Glucuronidation, 3:640 lipid formulations, 2:674 therapeutic, 2:237
in metabolism, 2:453-456 in lipid formulations, 2:671 Glycopyrrolate, 2:58
Glucuronide conjugation permeation enhancers, 2:675, anticholinergic, 6:137
androgens, 3:687-688 2:676 relative anticholinergic activ-
estrogens, 3:638,3:639-640 Glycerine ity, 6:156
Glutamate, 2:391 osmotic diuretic, 3:64 stereoisomers, 1:784-785
and anxiety, 6:546 Glycerol, 2:616 Glycosphingolipids, 2:237
gating of anion-selective chan- Glycerol trinitrate, 3:13-14 N-Glycosylation, 2:271
nels, 2:360 pharmacokinetics, 3: 15 N-Glycosylation consensus se-
release during ischemia, 6:689 Glycinamide ribonucleotide quences, 2:271
and schizophrenia, 6:603-604 formyltransferase inhibi- Glycosylphosphatidyl-inositols,
Glutamate antagonists tors, 1:742-743 2237
for Parkinson's disease, target of structure-based drug Glycylcyclines, 2:185
6:733-734 design, 1:429-432 Glynase, 413
Cumulative Index

Glyphosate reporter gene assays, 2:50-51 Granulocyte-macrophage colony


antimalarial, 5:988-989 transfeded, 2:74 stimulating factor,
Glypressin, 3200 Gpl20-CXCR4 binding, 5:462 3258-259
Glyset, 4 3 2 inhibitors, 5467-468 bioadivity, 3259
GM 237354,5:907-908 Gp130 cytokines preparations, 3 2 6 1
Gmelin database, 1:386 and interleukin-6, 3269 role in blood cell development,
GMK vaccine, 2:217,2:220 and interleukin-11,3265 3252-255 P
Goiters, 3:565 GPR-CY4,4159 therapeutic implications,
GOLD G proteins, 523-24. See also 3:272,3:273
assessment, 1:303, 1:304 GPCRs (G-protein-coupled therapeutic indications, side -
empirical scoring, 1:309 receptors) effects, and pharmacokinet-
flexible ligands, 1 2 6 3 GPR14 receptor ics, 3959-261
genetic algorithm, 1:299 urotensin-I1 as ligand for, X-ray crystallographic studies,
protein flexibility, 1:300
3213 1:488
sampling/scoring methods
GR-68755 Granulocytes, 3952-255,3263,
used, 1:261
Gold cognition enhancer, 6:816 3264
radiopaque material, 4486 GR 10361,6:643 and adaptive immunity, 5225
GOLEM, 1:67 GR 69153,5:643,5645 and innate immunity, 5:224
GOLPE, 1:54, 1:60 GR 89696 Granulokine, 3264
Gonadotropin releasing hor- analgesic, 6:391, a 3 9 2 Grapafloxacin
mone, 3:654,3:683,3:698 GR 103545 removed/restricted by FDA,
Gonanes, 3:597, 3598 analgesic, 6:391,6:392 4642
Good Laboratory Practices, GRAB-peptidomimetic (Group- Graphical representation, 1:371
2:611,2:612,2:693 Replacement Assisted Bind- Graph isomorphism problem,
Good Manufacturing Practices, ing), 1:636, 1:658-659, 1:380, 1:405
2:420,2:686 1:677 Grave's disease, 3:574
Goodwill, 2:704 GRAMM (Global Range Molecu- Great Britain, See United King-
Gossypol, 3728-729 lar Matching), 1:115 dom
Gossypolone, 3729 Gram-negative bacteria GREEN
Gp100,5237-238 action of p-ladams against, force-field scoring, 1264
Gp120-CCR5 binding, 5:462 5:611-613 GRID, 1:58, 1:315
inhibitors, 5468 cell wall, 5610-611 3D pharmacophores, 1:198
Gp120 coreceptors, 5:467 p-lactam indications, 5625 empirical scoring, 1:309
GPCR libraries penicillin-binding protein, explicit water molecules,
3D pharmacophore finger- 5614 1:303
prints for, 1205 Gram-positive bacteria hydrogen bonding, 1:107
GPCR-likeness, 1251, 1252 action of p-lactams against, and molecular modeling, 1:138
GPCRs (G-protein-coupledre- 5:611-613 Gridding and Partitioning (Gap)
ceptors), 1:229-234, 1:668 cell wall, 5:610-611 approach, 1:199,1:200
adrenergic receptors, 6:25 p-lactam indications, 5625 GRIDIGOLPE analysis,
arrestin binding to, 2:75 penicillin-binding protein, 1:304-305
assays for, 2:74-75,2:79 5:615 Grid tyranny, 1:91, 1:144
and chemokines, 4:131,4:132, Grand mal seizures, 65464 Grimatin, 3264
4:135 Granule enzymes, 5 2 2 5 GRIND, 1:60
defined, 2:331-332 Granulocyte-colony stimulating Grinding
focused screening libraries factor, 3261-262 in large-scale synthesis, 2:414
targeting, 1:209, 1250 bioadivity, 3262 Griseofulvin, 5905-906
homology modeling, 1:123, preparations, 3264 formulations and indications,
1:150 role in blood cell development, 5:891
molecular modeling, 1:122 3952-255 GROa ligand
opioid receptors, 6:342-343 with stem cell fador, 3:268 and CXCR2,4:161
peptidomimetics, 1:644, 1:677 therapeutic implications, GROp ligand
prostanoid receptors as, 3:272,3:273 and CXCR2,4161
4277-278 therapeutic indications, side GROr ligand
recombinant DNA studies, effects, and pharmacokinet- and CXCR2,4:161
2:lOl-102 ics, 3262-264 Groove-binding ligands, 1:5
Cumulative index

Ground-state analog enzyme GV129606X, 5:687,5:689,6:694, Halofantrine


inhibitors, 1:720, 1:740-741 6:708 antimalarial, 5946-949
Group contribution approaches GV143253X, 5:687,5:690,5:694, dosage forms, 5:934
aqueous solubility, 2:657 55'05 Halogenated ketone hydrate res- .
ionization constant, 2:662 GW 532, 3369 idues
melting point, 2:655 GW 707, 3369 in pseudopeptide arrays, 2:12
partition coefficient, 2:656 GW 5638,3663 Halogenated sedative-hypnotics ir
Growth hormone GW 7604,3:663 ADME, 6220-221
role in insulin regulation, 4 2 GW 150013,6:574,6:581 currently used drugs,
Growth hormone receptor GW 320659 6:208-209 -
X-ray crystallographic studies, experimental smoking cessa- discovery, 6235
1:488 tion agent, 4:459 side effects and drug interac-
Growth hormone secretagogues, GW 468816 tions, 6:208-210
Halogenated topical antibacteri-
1:671-672, 1:675 experimental smoking cessa-
als, 5:545-547
GS-4071 tion agent, 4459
Haloperidol
for influenza, $370, 5:371, GW 501516,3:370,3:372 discovery, 6:6l7- 618
5:473 GW 590735, 3370 dose, 6:601
structure-based design, 1:452 GYKI-46903 HlV protease inhibitor, 1:111,
GS-4104 cognition enhancer, 6:816 1:112
for influenza, 5368 Gymnochrome D pharmacokinetics, biotrans-
GT-102279,3:370 flavivirus antiviral, 5:429 formation, and drug interac-
GTPase, 5 2 4 tions, 6:637-639
GTPase-activating protein, 5 2 5 H-961 receptor binding and side ef-
GTS-21 for herpes virus, 5:321 fects, a 6 0 6
for Alzheimer's disease, a764 for poxviruses, 5:341 Haloprogin, 5:906
cognition enhancer, Habitrol, 4452 formulations and indications,
6~808-809 Haemophilus b vaccine, 2:209, 5891
Guanabenz 2:212 Halopyrimidines
a,-agonist, 6:3 Haemophilus influenzae filtering from virtual screens,
applications, 6:14 penicillin-binding protein, 1246
metabolism, 6:18-19 6:614,5:616, &617 Halotestin, 369'7, 3:699-700
structure-activity relationship, Hair growth disorder drugs, Halotex, 5:891
6:31 4433 Hammerhead ribozymes, 2:119
Guanadrel adverse effects, 4:434 Harnmett constants, 1:11, 1:50
antiadrenergic, 6:4 chemistry and structure-adiv- Hammett equation, 1:12, 1:13,
applications, 6:14 ity relationship, 4:437-438 126, 1:50
Guanethidine clinical use, 4433-435 Hamming distance, 1:202
antiadrenergic, 6:4 hair growth physiology, 4435 Hammond postulate, 1:748
applications, 6:14 history and future trends, Hanes-Woolf plot, 1:727, 1:729,
Guanfacine k438-440 1:731
a,-agonist, 6:3 pharmacokinetics, 4434-435 Hansch approach, to QSAR,
applications, 6:14 physiology and pharmacology, 126-27, 1:30
structure-activity relationship, 4435-437 for anti-inflammatory ste-
6:31 role of 5-a-reductase, 4435 roids, 3:788-791
Guanidines, 6:4 Hairpin ribozymes, 2:119 Hansch-F'qjita-Ban analysis,
metabolism, 6:18-19 Halbetasol propionate, 3750, 1:31
pharmacophore points, 1249 3:752 Hansch parabolic equation, 1:3
structure-activity relationship, Halcinonide, 3:750,3:752, Hansch-type parameters, 154
6:30-31 3:803,3:823-824,3:831 Haplotypes, 4:620
Guanine, 4619 Halcion, 6:207 Haptoglobin, 3:403
Guanine nucleotide exchange Haldol, 6:601 Ha-ras gene, 6:4
factors, 5:22,5:24 Halfan, 5:934 Hard drugs
Gulonolactone oxidase, 4417 Half-life, 2:636,2:641-644 soft drugs contrasted,
Gusperimus, 1:849,5:490 characterization for IND pro- 2:536-537
Guy's Hospital pill, 3:65 cess, 2:645 Harkoseride
GV104326,6:684,5:685 Hall databases, 1:387 anticonvulsant, 6:311312
Cumulative Index

HARPick program, 1:218, 1:221 Hematopoiesis, 3252-255 Hemoglobinopathy database,


Harrison Narcotic Act of 1914, Hematopoietic agents, 3:453
2:685 3:251-255. See also specific Hemoglobins, conjugated,
Hash code, 1:376, 1:380, 1:405 agents 3:417-420
and combinatorial library de- investigational agents, Hemoglobins, crosslinked, 3:397,
sign, 1:223 3:268-272 3406-408
molecular fragment based, 1:54 Hematopoietic stem cells, 3252, autooxidation, 3:405
Hashimoto's thyroiditis, 3:574 3:253 Hemoglobins, encapsulated,
Haflick limit, 5:11 response modification as sickle- 3:398,3:420-421
Haystack compound storage and cell therapy, 3:469-470 Hemoglobins, modified
retrieval system, 2:58 Heme iron, 3501 clinical use, 3:398-420
HBB Hemicholinium development, 3:396
picomavirus antiviral, $413 recent developments,
interatomic distance analogs,
HBED, See N-$7'-Bis(2-hydroxy- 3~420-421
1:710-711
benzy1)ethylenediamine- Hemoglobins, polymerized,
N-JV-diacetic acid Heminevrin, 6:2 11
3:397,3:412-417
HBOC-201,3:398,3:400, Hemochromatosis, 3504,3:514
Hemoglobins, recombinant,
3:413-414 Hernocyanin 3:396,3:397-398,
HCMV (cytomegalovirus),6:298 allostery, 2:306 3408-412
HDL, See High density lipopro- Hemofil Hemoglobin S (HbS; sickle he-
teins hemostatic preparation, 3292 moglobin),See Sickle hemo-
Head injury HemogFetal hemoglobin globin
and Alzheimer's disease, therapeutic induction, Hemolink, 3:400, 3:412,
6:748-749 3463-465 3415-417
Heart Hemoglobin. See also Blood sub- Hemophilia, 3:291
anatomy, 32-6 stitutes; Fetal hemoglobin hepatitis vaccine recom-
thyroid hormones effect on, abnormal, in sickle-cell ane- mended, 3295
3571-572 mia, See Sickle hemoglobin Hemopure, 3:397,3:400, 3:412,
Heartbeat, 33-4 allosteric effectors, 3386, 3413-414
Heart block, 39,3:29-30 3:388394 clinical trials, 3399
Heart transplantation, 5:487 allosteric protein, 2:296, Hemorrhage, 3:284
Heating and cooling 2:301-306 Hemospan, 3:419
in large-scale synthesis, 2:415 autooxidation, 3404 Hemostatic plugs, 3284
Heat shock proteins, 5:819 digestion, 3501 Hemostatic preparations
Heat transfer glycosylated fraction as indica- ADME, 3:295-298
in large-scale synthesis, 2:415 tor of glycemic control, 4 4 adverse effects, 3294-295
Heavy metals left shifters, 3:386,3:388 challenges, 3284
radiopaques, 4486-493 molecular mechanisms of al- clinical use, 3284-299
topical antibacterials, lostery, 2:305-306 marketed, 3292
5:552-553 molecular modeling of crystal HemoZyme, 3:405
Hedoral, 4378 structure, 1:105, 1:107 Hepabarbital, 6:205
Helical computer-assisted to- molecular size and nonideal- Heparin, 2:209-210,2:215-216,
mography, 4:495, 4568 ity, 3:446-447 2:221, 3:285
Helicobacter Pylori, 4:93-94, oxygen binding curve, 3:387 activated partial thromboplas-
6:740 p50,3:386 tin time, 3291
metronidazole-resistant, 5712 right shifters, 3:386, ADME, 3:295
and ulcers, 6:119 3388394 clinical trials, 3:291-292,
Helminths, 5:1090 structure, 2:302, 3:387-388 3:294
antihelmintics for, target of structure-based drug formula weight, mechanism of
5:1090-1096 design, 1:419-425 action, and route of admin-
Hemagglutinins, 2:240 Hemoglobin A (HbA; normal istration, 3286
plasmid DNA-mediated gene hemoglobin), 3444445 limitations of use, 3:323
therapy study, 4:657 oxygen binding to, 3:386, mechanism and sites of action,
viral, 2:263 3:446 3308-0
HemAssist, 3:397,3:400, Hemoglobin C,3:457 property-encoded nomencla-
3:406-408 Hemoglobin F, See Fetal hemo- ture/MALDI sequencing,
clinical trials, 3:399 globin 2:235-236
Cumulative Index

and proteoglycans, 2:238 Hepatitis C virus NS3 protein, Herpes viruses, 5:294-295,
structure, 3:288 5:417-418 5297-299
synthesis, 2:235 Hepatocyte growth factor adiva- a-Herpesviruses, 5298
for thrombolytic therapy, tor inhibitor 1 P-Herpesviruses, 5298
3:166 mariptase inhibitor, 1:269, y-Herpesviruses, 5:298,5:299
trend to lower molecular 1:271 Herpes virus protease inhibitors,
7
weight, 2:204,2:210 Hepatography, 4567. See also 5324-325
Heparinase I, 2:215-216,2:220 Radiopaques Herpes zoster, 5:298
Heparin cofactor II,2:302 Hepatolienography, 4567. See Hesperidin
rotavirus antiviral, 5431 -
Heparin-induced thrombocyto- also Radiopaques
penia, 3:294 HEPES ligand HE-State index, 1:26
Heparin-induced thrombocyto- nicotinic acetylcholine recep- Heterochiral molecules, 1:782
penia with thrombosis, Heterocyclic antidepremmts, 6:486
tors, 2:363,2:364,
Heterocyclic compounds
3:294 2:375-376
radioprotective agents,
Heparin-linked fibroblast Hephaestin, 3:501
5163-165
growth factor (FGF), HEPT Heterocyclic sedative-hypnotics
2:235-236 allosteric effector, 2:314, ADME, 6:221-223
Heparin rebound, 3:308 2:315 clinical pharmacology,
Heparin sulfate proteoglycans, Heptylphysostigmine 6:234-235
521, 5:216 anticholinesterases related to, currently used drugs,
Hepatic clearance, 2:637 6:89 6:210-211
Hepatic extraction ratio, Herbal remedies, 2:39 discovery, 6:235
2~637-638 Herceptin, 2:87-88,5228,5:230 pharmacologic effects, 6:230
Hepatitis B virus, 5:297, selective toxicity, 5:257 side effects and drug interac-
5299-301 Hereditary persistence of fetal tions, 6:210-211
Hepatitis B virus antiviral hemoglobin, a457 6-Heterocyclylmethylenepen-
agents, 5326 HERG protein cardiotoxicity ems, 5:698-699
antisense oligonucleotides, screening, 2:76,2:628 Heteronuclear multiple bond
5:337 Heroin, 1:849-850 correlation spectroscopy
combination treatments, as "accidental" prodrug of natural products, 1518
5334-335 morphine, 2500 Heteronuclear single quantum
purines, 5330-333 synthesis, 6:360,6:362 correlation spectroscopy,
pyrimidines, 5:326-330 Herpes simplex virus 1512
resistance, 5:333-334 chemokine receptors, Hexahydrosiladifenidol
targeting drugs to liver, 4170-171 anticholinergic, 6:132
5335337 in suicidal gene cancer ther- Hexamethonium
Hepatitis C virus, 5:361362 apy, 5 4 4 nicotinic receptor antagonist,
and HBV infection, 5300 Herpes simplex virus-l,5:297, 2:397
model systems to study repli- 5298 Hexestrol, 1:707
cation, 5:427 Herpes simplex virus-2, 5298 electrophilic metabolites, a638
Hepatitis C virus antiviral Herpes virus antiviral agents, estrogen receptor affinity,
agents 5:305 3:659
inhibitors of HCV 5' untrans- compounds under develop- Hexobarbital, a204
lated region and core gene, ment, 5:310326 CYP2C19 substrate, 4:627
5415-417 currently approved drugs, Hexocyclium, 6:139
inhibitors of NS5B RNA-de- 5:305-310 relative anticholinergic activ-
pendent RNA polymerase, immune modulators, ity, 6:157
5:425-426 5325-326 HHS-8 virus, 4:171
inhibitors of NS3 helicase, nonnucleoside inhibitors and HHV-6,5298-299
5425 other targets, 5321324 HHV-7,5:298-299
inhibitors of NS3 protease, prodrugs increasing oral avail- HHV-8, 5299
5418-425 ability, 5:309 Hib vaccines, 2:209,2:239
interferon-a applications, prodrugs under development, Hierarchical clustering, 1:220,
5:361364 5318-321 1:401, 1:405
Hepatitis C virus inhibitor resistance to, 5:309310 with molecular similaritytdi-
antisense drug, 2:120 selective toxicity, 5:267 versity methods, 1:205
Cumulative Index

High ceiling diuretics, 3:88, and combinatorial chemistry, Histamine receptor antagonists
3:89-111, a142 2:32 molecular modeling, 1:143
High-content metabolic assays, compound deck construction Histamine1 receptors, e l 1 2 -
2~72-79 and screening for hits, reporter gene assays studies, .
High-content toxicity screening, 2:54-59 2:51
2:626 following the competition, Histamine2 receptors, 6:112
High density lipoproteins 2:54 Histamine3 receptors, &I12 *
(HDL),2:616,3:340-341 lead discovery process, Histidine
and Alzheimer's disease, 2~41-62 chemical modification re-
6:748-749 mass spectrometry applica- agents, 1:755 -
and coronary artery disease, tions, 1:591, 1:592-596 gating of anion-selectivechan-
3:lO miniaturization, 2:66-67 nels, 2:360
current drugs to raise,
and molecular modeling, 1:155 Histone deacetylases, 5:8
3:342-352
molecular similarity/diversity Histoplasma capsulatum, 6:883
new treatments for raising
methods, 1:191 Histoplasmosis, 5:883
while lowering TG,
3:370-372 profiling hits, 2:59-62 Hit list, 1:380, 1:405, 1:411
transport, 3:359-361 raw data points obtained by HIV-DNA polymerase (reverse
High density oligonucleotide ar- companies, 1:50 transcriptase), 5462-463
rays, 1:344 for receptor target lead discov- HIV fusion proteins
Higher osmolality intravascular ery, 2:344 allosteric protein target,
contrast agents, 4495, screening hits analysis, 2:59 2:314,2:315
4538 screen validation and reagent and CXCFM, 4166-170
Highly active antiretroviral scale up, 2:53-54 HIV integrase inhibitors, 5:464
therapy (HAART), 6:884 target discovery and valida- HIV protease, 6:464
HIVIAIDS, k479 tion, 2:42-43 HIV protease inhibitors, 1:717,
High performance liquid chro- and toxicology, 2:610 2:610,6:475-477
matography (HPLC), ultra-high-throughput, 2:40 binding-site molecular models,
1:586-589 with virtual screening, 1:316 1:130
for combinatorial library X-ray crystallography applica- comparative molecular field
screening, 1:592-596, 1:598, tion, 1:472 analysis, 1:153
1:599, 1:607 Himbacine consensus scoring study,
denaturing, 4:622 anticholinergic, 6:116, a133 1:266
fast, 1:596 HIN file format, 1:369 3D CoMFA, 1:59
for hydrophobicity determina- HINT descriptors, 1:56 de novo design, 1:113
tion, 1:16-17, 1:23 for studying allostery, fluorescence polarization stud-
for separation of chiral mole- 2:309-312 ies, 2:48
cules, 1:783, 1:788-792 Hint!-LogP, 1:389 force field-based scoring study,
High pressure liquid chromatog- HipHop, 1:60, 1:256 1:307
raphy (HPLC),4 4 8 Hippocampus homology modeling, 1:123
High-throughput chemistry, nicotinic acetylcholine recep- knowledge-based scoring
1:358, 1:405 tors, 2:389, 2:391 study, 1:311
chemical libraries for, 1:367 Hirsutism, 4:433,4:440 molecular modeling,
and natural product screen- Hirudin and analogs, 3:29, 1:103-104, 1:105, 1:108,
ing, 1:848 3:285,3:316-318 1:109, l:lll, 1:117, 1:120,
High Throughput Crystallogra- marketed antithrombotics, 1:122
phy Consortium, 1:418 3:286 nevirapine synthesis,
High-throughput pharmacology, Histamine 2:420-429
25'2-79 role in gastric secretion, NMR binding studies, 1:533,
High-throughput pharmacology 6:112-113 1:559-562
system, 25'3-74,2:78-79 role in spasms, 6:111 non-peptide peptidomimetics,
High-throughput screening, and ulcers, 6:119 1:659-660
1:283,2:37-41 Histamine H2 receptor antago- novel lead identification by
automation, 2:40, 2:63-66 nists, 6:112-113 virtual screening, 1:320
bioassay design and screen antiulcer application, 6:155, reagents for screening, 2:91
construction, 2:43-54 6:158 recombinant DNA technology
candidate selection, 2:59-62 discovery, 2:40 applications, 2:97-99
Cumulative Index

seeding experiments, structure and molecular biol- Homolog-scanning mutagenesis,


1:318-319 ogy, 5:460-461 2:88-89
selective toxicity, 5267 targets for drug design, Homology, 1:348
target of structure-based drug 5:464-477 gene function determined by, -'

design, 1:433-442 viral budding out of host cell, 2:43


transition state analogs, 5:464 and X-ray crystallography,
P
l:647- 649 HIV-1 virus, 5:459 1:494
and water, 1:302 CCR5 and CXCR4 receptors, Homology modeling, 1:261-262
HIV reverse transcriptase, 4154-155 and docking methods,
5:462-463 1:305-306 -
and malaria, a 9 3 0
H N reverse transcriptase en- vector for cancer gene ther- molecular modeling, 1:123
zyme, 5:469 apy, 5:41 L-Homoparabactin, 3:489, 3490
HIV reverse transcriptase inhib- Homopoietin, 3:255
HIV-2 virus, 5:459
itors, 1:717,2:610,5:465, Homosalate
HJCFIT program, 2:372-373,
5:469-470 structure-activity relationship,
allosteric protein target, 2:378,2:380,2:381
4468
2:314, 2:315 H+,Kf-ATPase inhibitors, 1:718
sunscreen, 4460
nonnucleoside reverse tran- HKL suite, 1:478 Homo Sapiens
scriptase inhibitors, HMG-CoA reductase, 3667 genome sequencing, 1:344
5:472-473 HMG-CoA redudase inhibitors, Hormone replacement therapies,
nucleoside reverse transcrip- See Statins 5:250-251. See also Estro-
tase inhibitors, 5470-472 hMLH1, 5:27, 5 3 2 gen replacement therapy;
X-ray crystallographic studies, hypermethylation, 5:9 Insulin
1:488-489 HMPA Hormone-responsive elements,
HIV ribonuclease inhibitors, for poxvimses, 5:341 3623
5:465,5:473 HMR 1098,3:163,3:177, 3:178 Hot flashes, 3:631
HIV vaccines, 5:465 HMR 1453,3369 Hot-stage microscopy, 2:655
HIV virion, 5:460 HMR 1883,3:177,3:178-179 Hounsfield Unit, 4567
inhibitors of assembly, hMSH2,5:27,5:32 HP 522,3:93
5:474-475 HOE-140 HPMPA
HIV virus, 5:458-459 bradykinin antagonist, 3:226 for adenoviruses, 5:340
assembly of viral proteins: Hoechst 33258 for polyomaviruses, 5340
virion formation, 5464 binding to DNA, 1:544, hPMSl gene, 5:27
binding to host cell mem- 1:547-552 hPMS2 gene, 5:27
brane, 5:462 Homatropine, 6:124-125 HQSAR, 1:4
cellular picture of infection, mydriatic and cycloplegic ac- H-ras protein, 5:22,5:24
5:459-460 tivity, e l 5 3 and COX-2,5:34
clinical picture of infection, relative anticholinergic activ- HS-142-1
5:460 ity, e l 5 6 binding to atrial natriuretic
DNA entry to host cell nu- therapeutic use, 6:117 peptide receptor, 3:217
cleus, 5:463-464 Homeopathic Pharmacopeia of 3P-HSD, 3:614-615
DNA formation by reverse the United States, 2:700 5-HT, See Serotonin
transcriptase, 5:462-463 Homing receptors, See Selectins HT-SOB, 6:572
fusion with host cell cyto- Homochiral molecules, 1:782 HTLV I (Human T Leukemia
plasm and its uncoating, Homocysteine, 4399, 4408, Virus I), 5:459
5:462 4412 HTLV I1 (Human T Leukemia
genome, 5:461 L-Homofluviabadin, 3489, Virus 111, k459
integration of viral DNA into 3:490 HTLV I11 (Human T Leukemia
host genome, 5:464 Homogeneous non-radioisotopic Virus 111:HIV virus), 5:459.
life cycle, 5:461-464 assays, 2:46-49 See also HIV virus
maturation, 5:464 Homogeneous radioisotopic as- HTML (HyperText Markup
migration of viral mRNA to says, 2:46-47 Language), 1:371, 1:405
cytoplasm, 5:464 Homogeneous time-resolved flu- HUGO Gene Nomenclature
mode of viral transmission, orometry, 2:47,2:48 Committee, 1:337
5:459 HOMO (Highest Occupied Mo- Humalog, 4:7
splicing of viral mRNA into lecular Orbital) energy, Human Genome Database
host genome, 5:464 l:ll, 1:14, 1:54 protein classes, 1:262
Cumulative Index

Human Genome Project, 2:42 Hydration Hydromorphone, 6:332,6:363


draft map and understanding in metabolism, 2:449-450 dose, a334
of diseases, 2:320,3:2 Hydrochlorothiazide, 3:76, Hydromox, 3:83
driving force for carbohydrate- 3:78-81, 3:84,3:142 Hydroperoxy-eicosatetraenoic .
based drug development, metabolism, 3:80 acid, 4205
2:236-237 MK-196 compared, 3:92 Hydrophobic bond, 1:15
and genetic superfamilies, Hydrochlorothiazide-amiloride, Hydrophobic effect, 1:178, 1:182 *
2:267-269 3:78 Hydrophobic interactions, 1:50,
and pharmacogenomics, Hydrochlorothiazide-triam- 1:286, 1:287-288
4618,4619 terene, 3:78 discovery of importance of, 1:3 -
Human genome sequencing, and empirical scoring, 1:310
Hydrocodone, a 3 6 3
1:344,4:618 enzyme inhibitors, 1:724
dose, 6:334
and gene expression analysis, hydrogen bonding contrasted,
Hydrocordone
4:600 1:319
Human growth hormone, recom- cytochrome P,, isozyme sub-
molecular modeling, 1:85,
binant, 2:6 strate, a339
1~108-110
dose for wasting diseases, a854 Hydrocortisone,See Cortisol
and QSAR, 1:6, 1:7, 1:15-19,
for wasting diseases, 6:858 Hydrocortisone esters, 3:749, 1:23, 1:52
Human growth hormone-somato- 3:752,3:791,3:803,3:808 Hydrophobicity, 1:16-17
genic receptor interactions, effect of structural changes on determination by chromatog-
2:88-89 activity, 3:796-837 raphy, 1:17-18, 1:23
Human herpesvirus-8 virus, HydroDiurit, 3:76 Hydrothiazide diuretics, 3:78-81
5:296 Hydrofinasteride, 1:768, 1:770 Hydroxamate iron chelators,
Humanized antibodies, 5:226 Hydroflumethiazide, 3:77 3483, a486
for organ transplant rejection, Hydrogenation synthesis, 3:524-530
5509 agitation issues in large-scale Hydroxamate residues
selective toxicity, 5257 synthesis, 2:415 in pseudopeptide arrays, 2:12,
Human leukocyte antigens, Hydrogen bonds, 1:285-286, 2:13
5236-237 1:365 19-Hydroxyandrostenedione,
Humans acidic protons and .rr-systems, 3690
nonpatentability, 2:719 1:313 Hydroxy bupropion
Human serum albumin, See Se- and empirical scoring, experimental smoking cessa-
rum albumin 1:309-310 tion agent, 4459
Human stem cells enzyme inhibitors, 1:722, (S)-3-Hydroxy-y-butyrolactone,
for toxicity testing, 2:626-627 1:724 1:808, 1:810
Human tissue studies hydrophobic interactions con- Hydroxychloroquine, 1:891,
throughput limitations, 2:72 trasted, 1:319 5938
Humate molecular modeling, 1:81, for Alzheimer's disease, a767
hemostatic preparation, 3:292 1~107-108 dosage forms, 5:934
HUMSTR, 4166 and QSAR, 1:6 1,5-Hydroxycholecalciferol
Humulin, 4 7 and structure-based design, secretion in kidneys, 3:56
Huperzine-A 1:409 N-,N'-(2-Hydroxycyclohexy1)eth-
anticholinesterase, 6:97 Hydrogen peroxide ylene-diaminediaceticacid
H029953XX, 3:330,3:331 reaction with iron(II), 3502 radiopaque chelating agent,
Hyaluronic acid, 2:210-211, Hydrolapachol 4489
2:212,2:505-506 antimalarial, 5976 2-Hydroxycyclohexylethyl-
Hybridization-based genotyping, Hydrolases enediaminetriaceticacid
4624-625 and drug metabolism, 2:439 radiopaque chelating agent,
Hybridomas, 5:226 target of structure-based drug 4489
Hydantoin anticonvulsants, 6:270 design, 1:449-454 6R-Hydroxy-l,6-dihydropurine
ADME, 6:273-275 Hydrolysis riboside. 1:752
structure-activity relationship, enzymatic, 2:537-539 Hydroxy-eicosatetraenoic acid,
a304305 enzyme-mediated asymmetric, 4:205
Hydrates, 2:651 1:805-806 P-Hydroxyethylethylene di-
metastable, 2:669 in metabolism, 2:449-450 aminetriacetic acid
moisture sorption, 2:663 prodrugs, 2510 radiopaque chelating agent,
pseudopolymorphs, 2:653 Hydrolytic liability, 2:574 4:489
Cumulative Index

Hydroxyethyl starch Hyoscyamine Hypothalamus


for plasma volume expanders, dissociation constant, &I51 regulation of energy ho-
3:429, 3:430, 3431, 3:432, relative anticholinergic activ- meostasis by, 6:869-872
a433 ity, 6:156 Hypothetical descriptor pharrna- -
Hydroxyethylurea,1:153 in solanaceous alkaloids, cophore, 1:63
Hydroxyhexamide, 4 1 6 6:120-126 Hypothyroidism, 3:565,3:574,
P
Hydroxylamine stereoisomerism, 6:148, 6:149 3:576
radioprotective agent, &I62 therapeutic use, &I17 Hypoxanthine, 3:141
Hydroxyl-containing compounds HYPER, 1:727 Hypoxanthine aminopterin-thy-
midine, 5226 -
radioprotective agents, 5:163 Hypercarotenosis, 4371
Hydroxylketone residues Hypercholesterolemia,3:11 Hypoxanthine phosphoribosyl
in pseudopeptide arrays, 2:12 and Alzheimer's disease, transferase, 6:226
Hydroxylpropyl methylcellulose 6:748-749 Hypoxia
(HPMC) and multistep carcinogenesis,
single gene pharmacogenetic
3392
for precipitation inhibition, studies in genes influencing
nitroimidazole binding for de-
2:668, 2:669 progression, 4:639-641 tection, 6:180
for solid dispersions, 2:670 Hyperglycemia, 2:618,42-4 radioprotective agents utiliz-
R-(-)-11-Hydroxy-10-methyla- Hyperinsulinemia, 4 3 ing, 5154,5167-168
porphine, 1:705 Hyperprolactinemia, 2:618-619 and VCAM-1,3:459
Hydroxymethylglutaryl-CoA Hypertension Hypoxia-activated prodrugs,
(HMG-CoA)reductase in- and coronary artery disease, 583-87
hibitors, See Statins 3:lO Hypoxia inducible factor-la,
2-Hydroxy-2-phenylnonanamide, Hyperthyroidism, 3:565,3:574, a256
6:304-305 3:575 and carcinogenesis, 5:20
3-(3-Hydroxypheny1)-N-n-pro- Hypertriglyceridemia, 2:342 Hysterosalpinography, 4567.
pylpiperidine (3-PPP), Hyperuricemia, 3:56 See also Radiopaques
1:704-705 Hypervitaminosis A, 4319, Hytrin, 6:4
17a-Hydroxyprogesteronecap- 4370-371 HZ2
roate, 3:641 Hypervitaminosis biotin, 4405 analgesic, 6:393
8-Hydroxyquinoline Hypervitaminosis C, 4:417
radioprotective agent, 5:163 Hypervitaminosis D, 4379 I-309,4:161
14-Hydroxy-4,14-retro-retinol, Hypervitaminosis E, 4384 IAZGP
4327-328 Hypervitaminosis folic acid, radiosensitizer, 5:180
4:411 Ibuprofen
Hydroxystreptomycin, 2:172,
Hypervitaminosis K, 4387 for Alzheimer's disease, 6:767
2:176,5:840
Hypervitaminosis niacin, CYP2C9 substrate, 4627
4-Hydroxytamoxifen, 3:647, 4395-397 first tier of cancer pain treat-
3:662 Hypervitaminosis pantothenic ment, 6:332-333
5-Hydroxytryptophan acid, 4401 Ibuterol, 2:504
radioprotective agent, 6:165 Hypervitaminosis pyridoxine, Ibutilide, 3:32, 3:41,3:167
Hydroxyurea 4:400 cardiovascular effects, 3:42
for herpes, 6:322 Hypervitaminosis riboflavin, potassium channel subtype
5-lipoxygenase inhibitors, 4389 selective, 3:45
4213-216 Hypervitaminosis thiamine, uses and side effects, 3 4 0
radiosensitizer, 5195 4389 IC-351,4450
for sickle-cell anemi.a, 3:464 Hypervitaminosis vitamin B,,, Iceberg model, of hydrophobic
D,L-3,5-Hydroxyvalerate, 1:745 4415 interactions, 1:15
Hydroxyzine, 6:212,6:214 Hypnotics, See Sedative-hypnot- ICI 118,552,3:180
Hygromycin, 2:195,2:196 ics ICI 147,798,3:131
Hygroscopicity HypoGen, 1:256 ICI 164,384,3:585, 3:635, 3:657
amorphous solids, 2:653 Hypoglycemia, 4 2 ICI 182,780,3:635,3:657,3:668
characterization, 2:662-664 side effect of insulin replace- molecular endocrinology,
polymorphs, 2:652 ment therapy, 4 5 3648
salts, 2:651 Hypoglycemic agents, See Insu- reactions of, 3:604,3:605-606
Hygroton, 3:82 lin and hypoglycemic agents ICI 197,067
Hylorel, 6:4 Hypogonadism, a698 analgesic, 6:392
Cumulative Index

ICI 198,615,4225-226 IL-1R accessory protein, 4:173 inhibition of serotonin, norepi-


ICI 199,441 Imagent, 3:399 nephrine, and dopamine
analgesic, 6:392,&406-407 Imatinib transporters, a500
ICI 204,219,4225-226 selective toxicity, 5:257 pharmacokinetic parameters,
ICI 204,448 Imavist, 3:399 a497
analgesic, 6:394 Imidacloprid, &51-52 radioprotective agent, 5:165
ICI 206,970, 3:131 selective toxicity, 5278 side effects profile, a 4 9 3 .T
ICM Imidapril Immediate release products
affinity grids, 1:293 impact of ACE polymorphisms dissolution rate criteria, 2:666
homology modeling, 1:305 on effectiveness, 4634 Immobilized enzyme inhibitors, -
ligand handling, 1:294 Imidazoles 1:720
Monte Carlo minimization, nitric oxide synthase inhibi- Immortality, 5:lO-11
1:298 tors, 6:704-705 Immune system, 5:224-226
novel lead identification, 1:320 Imidazolines, 6:3,6:4 Immunity, 5224-226
ICS, values, 1:731-732 metabolism, 6:18-19 Immunoadhesins, 2:85
QSAR, 1:s structure-activity relationship, Immunodeficiency, 5:294
ID3,1:67 6~30-31 Immunogens, 2:239-240
Idarubicin Imiglucerase, 2:211,2:212 Immunoglobulins, 2:239-240
antitumor natural product, Imines and adaptive immunity, 5225,
5:110,5:124,5:128 filtering from virtual screens, 5:227
IDEA, 1:390 1:246 RSV antiviral agents, 5395
Ideal bile acid binding protein, Iminobiotin transport, 2:261-262
2:278 binding to avidin, 1:181, 1:182 Immunomodulation, 543-44
IDEALIZE, 1:255 Iminostilbene anticonvulsants, herpes virus antiviral agents,
Ideas 6:270 5325-326
nonpatentability, 2:718 ADME, 6:275 Immunophilins
Idebenone structure-activity relationship, chemical-shift mapping of
for Alzheimer's disease, 6:305-306 binding to, 1:545
6:758-759,6:768 Imipenem, 1:872-873, 1:874, FK506 binding to FKBP,
Identification. See also Lead 5:671 1~552-555
identification antimycobacterial application, recombinant DNA studies,
combinatorial library com- 5:858 2:100,2:101
pounds, mass spectrometry coadministration of cilastin, Immunosuppressive drugs,
application, 1:596-597 5623-624 5:486. See also Cyclospor-
mass spectrometry applica- discovery, 5:668-669 ine; FK 506; Organ trans-
tion, 1:594-596 indications, 5625 plant drugs
Idiopathic hirsutism, 4433, p-lactamase classification for Alzheimer's disease, 6:766
4440 based on activity, 5620, Immunotherapy
Idoxuridine, 1:717 5:621 antibody-directed, 5226-235
Idraparinux, 3:310 MIC 90,5:685 anti-inflammatory therapeutic
IES-40 pharmacokinetics, 5:624 antibodies, 5:233-235
radiopaque material, 4577 side effects and interactions, chimeric antibodies, 5226
IESdOO 5625 dendritic cell, 5:235-243
radiopaque material, 4577 use recommendations, 5:626 humanized antibodies, 5:226
Ifetroban, 3:326,3:327 in vitro activity, 5:692, 5693 inhibitors for Alzheimer's dis-
Ifex in vivo efficacy in systemic ease, 6:766
alkylating agent, 5:54 murine infections, 5:685 Immunotoxins, 5 9 2
IFN-a, See Interferon a Imipramine Imodium A-D, 4:427,6:334
IFN-y, See Interferon y affinities for monoamine re- Imovane, 6:211
Ifosfamide, 1:783 ceptors, &495 Implantable cardioverter defi-
alkylating agent, 5:53,5:54, analogs, 1:692-693 brillator, 3:46
555 antidepressant, 6:485,6:486, Importance sampling, 1:98
IL-la, 4173 6:487 Impotency, 4:432,4:440-450
IL-lp, 4173 CYP2D6 substrate, 4627 Imprinting
Ile-2-AM (actinomycin C), 5:111 dose for eating disorders, and carcinogenesis, 5:8
Iletin II,4:7 6:850 Inactivation theory, receptors,
Iloprost, 3:328,4304-305 for eating disorders, 6:858 2:326
Incontinence, 4432 Infliximab, 4182-183,5:229, seeding experiments,
Increased pulmonary relative 5:233-234 1:318-319
volume, 3:424 Influenza A virus, 5:364 target of structure-based drug
Incremental construction Influenza B virus, 5364 design, 1:446-447
in docking, 1:292, 1:295-296 Influenza hemagglutinin inhibi- Inosine monophosphate dehy-
in virtual screening, 1:262, tors, 5:377-384 drogenase 2
1~317318 Influenza M2 protein inhibitors, X-ray crystallographic studies, T
Incretins, 4 3 4 5388 1:489
Indacrinone, 392-93 Influenza neuraminidase inhibi- Inositol hexaphosphate
ia Indapamide, 3:83,3:84 tors, 5:364-377 allosteric effector of hemoglo- -
1 metabolism, 3 8 0 Influenza RNA transcriptase bin, 3:388
j Indene-derived anticholinergics, inhibitors, 5384-388 Inositol hexasulfate
Influenza virus antiviral agents,
! 6:131-132 allosteric effector of hemoglo-
5364
Inderal, See Propranolol bin, 3:388
inhibitors of influenza hemag-
Indexes, 1:376-377, 1:405 Inositol triphosphate, 3158
glutinin, 5:377-384
Indinavir, 1:648, 1:659 In-process controls, 2:412,2:418
inhibitors of influenza M2 pro-
anti-HIV drug, 5:475-476 tein, 5388 In re Durden, 2:732-733
CYP3A4/5/7substrate, 4627 inhibitors of influenza neur- Insecticides
P-glycoprotein substrate, aminidase, 5364-377 selective toxicity, 5277-279
4:631 inhibitors of RNA transcrip- soft drugs, 2:555-558
structure-based design, tase, 5:384-388 In silico screening, 1:191, 1:244.
1:438-439, 1:440, 1:441 other inhibitors, 5:388-390 See also Virtual screening
Indocin selective toxicity, 5:267 In silico toxicology, 2:620-621
selective toxicity, 5274 Influenza virus neuraminidase Inspections, in patent infringe-
Indolotropane, 4146 inhibitors, 1:717 ment cases, 2:749
Indomethacin, 1:453,4:243 InfoChem ChemReact/Chem- Institutional Review Board,
binding to serum albumin, Synth database, 1:386 2:691, 2:698
2131 InfoChem SpresiReact database, Insulin
selective toxicity, 5:274 1:386 and adiposity signals,
in vivo models, 4:246 Information Disclosure State- 6~872-873
Inducible chemokines, 4134 ment, 2:733 controlled substance, 4:423
Inducible nitric oxide synthase, Informetrics radiosensitizer, 5:194
6:695-708 multiple parallel synthesis,
Insulin, animal, 4 5
Inductor variables, 1:25-26 2:30
Indunox, 6:214 Insulin, [AspBlOI-, 4:lO-11
Infrared spectroscopy, 1:592
Infection Inhibin, 3683 Insulin, genetically engineered,
carbohydrate-based agents in Inhibitors. See also Enzyme in- 2:6,2:83,45
research, 2:221-223 hibitors; specific inhibition Insulin Amendment of 1941,
carbohydrate-based drugs to targets: i.e., Dihydrofolate 2:686
market last decade, reductase inhibitors Insulin analogs, 44-11
2~207-209 finding weak by virtual Insulin and hypoglycemic
carbohydrate-based therapeu- screening, 1:319 agents, 41-11,5250-251
tics in development, not all are drugs, 1:408 biguanides, 421-24
2:213-215 structure of free, and struc- formulations for subcutaneous
Inflammation ture-based design, 1:409 injection, 4 7
animal models, 4:246 In-house databases, 1:387-388 a-glucosidase inhibitors,
carbohydrate-based agents in Initiation, in carcinogenesis, 431-37
research, 2:223-225 59-5 for prevention of ventricular
carbohydrate-based drugs to Injunctive relief, patent in- remodeling, 3:181
market last decade, fringement, 2:747-748 prodrugs, 2505
2:210-211 Innate immunity, 5:224 thiazolidinediones, 4:24-31
carbohydrate-based therapeu- Innohep, 3:286 Insulin aspart, 4 6 , 4 : 7 , 4 9
tics in development, 2:216 Inosine monophosphate dehy- development of, 4:11
role of chemokines, 4131-132 drogenase receptor binding affinities,
Inflammatory bowel disease, consensus scoring study, 410
2:216 1:266 Insulin-degrading enzyme, 4 8
Cumulative Index

Insulin dependent diabetes mel- Interatomic distance variant an- modulator studies, 4174-175
litus, See Diabetes mellitus, alog~,12710-712 role in blood cell development,
type 1 Intercalated disk, 3:3 3253
Insulin detemir, 411 Intercalation, $67 X-ray crystallographic studies,
Insulin glargine, 4:6,47,49 Intercellular adhesion molecule 1:490
development of, 411 1 Interleukin-3,3:268-270,
receptor binding affinities, antisense inhibitors, 2:126, 3~271-272 V
410 2:127,2:138 role in blood cell development,
Insulin lente, 4 6 , 4 7 recombinant DNA studies, 3:253,3:254-255
Insulin-like growth factor 1 2:105 with stem cell factor, a268 -
insulin binding, 49-10 X-ray crystallographic studies, X-ray crystallographic studies,
radiosensitizer, 5:194 1:489 1:490
X-ray crystallographic studies, Interdigitation-fusion vesicles, Interleukin-4
1:489 4573 and adaptive immunity, 5:225
Insulin-like growth factor 2 Interference, with patents, modulator studies, 4:175-176
X-ray crystallographic studies, 2:735-738 plasmid DNA-mediated gene
1:489 Interferon therapy study, 4656
Insulin lispro, 4:6, 4 7 , 4 9 dosing interval, 2:643-644 radioprotective agent, $171
development of, 411 induction by polyribosine: role in blood cell development,
receptor binding affinities, polyribonocytidine, 2:117 3:253
410 radioprotective agents, 5:171 X-ray crystallographic studies,
Insulinotropic agents, 411-20 Interferon-a 12490-491
Insulin overdosing, 2:618 dosing interval, 2:644 Interleukin-5
Insulin receptor, 4 9 for hepatitis B virus, 5:326, and adaptive immunity, 5:225
Insulin resistance, 4 3 5:334 glucocorticoid downregulation,
and free fatty acids, 4 2 8 for hepatitis C virus, 5:361, 4:172
Insulin-sensitizing agents, 5:362-364 modulator studies, 4176-178
420-31 for papillomavirus, $337-338 role in blood cell development,
Insulin ultralente, 46,47,4:9 volume of distribution, 2:640 3:253
Integrase, 5:616 Interferon a1 X-ray crystallographic studies,
Integrilin, 3:29, a287 X-ray crystallographic studies, 1:491
Integrin a4pl 1:490 Interleukin-6,3:268-270
interaction with sickled cells, Interferon y and adaptive immunity, 5:225
a458 and adaptive immunity, 5:225 with IL-11,3:265
Integrin aM IL-5 modulator, 4177 modulator studies, 4178-180
X-ray crystallographic studies, modulator studies, 4183-184 plasmid DNA-mediated gene
1:489 plasmid DNA-mediated gene therapy study, 4657
Integrins, 5:13 therapy study, 4656, radioprotective agent, Ex171
recombinant DNA studies, 4669-670 role in blood cell development,
2:105 X-ray crystallographic studies, 3:253,3:254-255
Integrin aVp3 1:490 with stem cell factor, 3:268
interaction with sickles cells, Interleukin-1,4656 X-ray crystallographic studies,
3:458 enhances IL-11,3:264 1:491
Integrons modulator studies, 4:173-174 Interleukin-7
and p-lactam resistance, radioprotective agent, 5:171 role in blood cell development,
5:614-616 role in blood cell development, 3:253
Intellectual property, 2:703-708. 3:253,3:254-255 Interleukin-8
See also Patents; Trade- and stem cell factor, 3:267 and CXCRl/CXCR2,
marks; Trade secrets X-ray crystallographic studies, 4161-164
and gene hnction, 2:43 1:490 mutation and chimera studies,
other forms of protection (be- X-ray crystallographic studies 4137
sides patents, trademarks, of receptor, 1:490 X-ray crystallographic studies,
and trade secrets), Interleukin-2 1:491
2:770-771 and adaptive immunity, 5:225 Interleukin-10
Intent-to-use applications, trade- glucocorticoid downregulation, and adaptive immunity, 5:225,
marks, 2:760 4:172 a226
Cumulative index

plasmid DNA-mediated gene Interrogatories, in patent in- review flow chart, 2:694
therapy study, 4656 fringement cases, 2:749 types of, 2:689-690
X-ray crystallographic studies, Interstitial collagenase, 5:13 Investigator Investigational New -
1:490 Intestinal metabolism, Drugs application,
Interleukin-ll,3:264-265, 2:677-678 2:689-690
3:269,3:272 Intestinal peptide transporter, In vitro assays, 2:72
bioactivity, 3:265 2274-275 gastric acid secretion inhibi- r
preparations, 3:266 Intestinal permeability, See Per- tors, 495-96
role in blood cell development, meability In vitro cell-based toxicity test-
3253 Intestine transplantation, 5:487 ing, 2:611,2:624-628 -

therapeutic indications, side Int-2 growth factor, 5:22 In vitro evolution (SELEX),
effects, and pharmacokinet- Intoplicine 2:92-94
dual topoisomerase ID1 inhibi-
In vitro studies
ics, 3:265-266
shortcomings of, 3:62
Interleukin-12, 4656 tor, 5:68,5:73,5:74
In vitro toxicology
glucocorticoid downregulation, Intracellular adhesion molecule
phosphorothioate oligonucleo-
4172 1 (ICAM-1) tides, 2:139
modulator studies, 4180-181 target of NMR screening stud- In vitro uptake
role in blood cell development, ies using SAR-by-NMR, phosphorothioate oligonucleo-
3253 1:566-567 tides, 2:121,2:132-133
X-ray crystallographic studies, Intracellular receptors, 2:334 In vivo assays
1:490 Intraepithelial neoplasia, 5:35 gastric acid secretion inhibi-
Interleukin-13 Intrahepatic anion-binding Y tors, 496-97
modulator studies, 4181-182 protein In vivo pharmacokinetics
X-ray crystallographic studies, binding to contrast agents, phosphorothioate oligonucleo-
1:490 4557 tides, 2:133-135
Interleukin-17 Intratransguanylation, 5:158 In vivo pharmacological activi-
role in blood cell development, Intrinsic tenad complex, ties
a253 35299-300 phosphorothioate oligonucleo-
Interleukin-lp-convertingen- Invader assay, 4625 tides, 2:136-138
zyme (ICE) Invadopodia, 5: 13 In vivo toxicity testing, 2:611,
transition state analog inhibi- Invasins, 2:262-263 2:619-620
tors, 1:655 Invasive cleavage assays, 4625 In vivo toxicology
Interleukins, 4130 Invention disclosure, 2:711-712 phosphorothioate oligonucleo-
role in blood cell development, Inventory data, 1:405 tides, 2:139-142
3:252-255 Inverse folding, 1:123-125 Inward rectification
Intermediate density lipopro- Inverse QSAR, 1:4 nicotinic acetylcholine recep-
teins (IDL), 3:340-341 Inverted keys, 1:405 tors (neuronal), 2:388
Intermolecular forces, 1:6 Investigational New Drugs Ap- Inward-rectifying K+ current,
Internal ribosome entry signal, plication Process, 2:72 3:7
5:41 guidance documents, Iobenzamate
International cell depository au- 2:690-691 biotransforrnation, 4:566
thority, 2:723 information submitted with, Iobenzamic acid, 4497
International Conference on 2:691 properties, 4506
Harmonization of Technical meetings with FDA, Iobitridol, 4497
Requirements for Registra- 2~695-696 excretion, 4564
tion of Pharmaceuticals for over-the-counter drugs, 4428 nephrotoxicity, 4552
Human Use, 2:701 parallel track, 2:689-690 properties, 4506
International patent agree- pharmacokinetic data submis- Iobutoic acid, 4497
ments, 2:751-752 sion, 2:645 properties, 4:506
Internet Phase I, 2:691-693 Iocarmate
increased availability of medi- Phase II,2:693-695 excretion, 4565
cal information on, 4423 Phase III,2:695 pharmacokinetics, 4562
Inter partes patent proceeding, Phase IV, 2:695 Iocarmic acid, 4497
2:739 pre-IND meeting, 2:690 angiography application,
Interpro, 1:349 resources for application prep- 4:569
InterProScan, 1:349 aration, 2:690-691 hyperosmolality, 4543
Cumulative Index

Iocarmic acid (Continued) Iodixanol, 4497,4538 Iodoxamate meglumine, 4497


myelography application, cardiovascular effects, 4551 Iodoxamic acid, 4:497
4571 cations used with, 4:542 cholangiography application, -
properties, 4:508 development of, 4495 4570
synthesis, 4514, 4:515 excretion, 4564 excretion, 4562,4563
Iocetamic acid, 4:497 isomerism, 4516 pharmacokinetics, 4559
cholecystography application, liposome encapsulated, 4574 properties, 4508 7
4570 nephrotoxicity, 4552 Iodoxyl, 4:497
excretion, 4563 neurotoxicity, 4554,4555, properties, 4511
isomerism, 4515 4556 Iofratol, 4497 -
properties, 4506 osmolality, 4539 neurotoxicity, 4:555
synthesis, 4:512, 4513 pharmacokinetics, 4562 osmolality, 4539
Iodamide, 4497 properties, 4:510 properties, 4510
angiography application, protein binding, 4556 Ioglicic acid, 4497
4:569 red blood cell effects, 4:548, properties, 4504
excretion, 4564 4549 Ioglucol, 4497
neurotoxicity, 4:554 Iodized oil radiopaques, properties, 4507
pharmacokinetics, 4561 4493-495 Ioglucomide, 4497
properties, 4504 Iodoalphionate properties, 4507
urography application, 4571 biotransformation, 4565, Ioglunide, 4497
Iodamide meglumine, 4497 4566 neurotoxicity, 4:555
Iodecol, 4497 Iodoalphionic acid, 4495,4:497 properties, 4508
osmolality, 4538,4:539 cholecystography application, Ioglycamic acid, 4497
properties, 4510 4570 biotransformation, 4565
spiral CT application, 4569 isomerism, 4515 cholangiography application,
Iodinated particulate suspen- properties, 4511 4570
sions meta-Iodobenzylguanadine excretion, 4562, 4:563
radiopaques, 4572677 NAD glycohydrolase inhibitor, properties, 4509
Iodinated polymer radiopaques, 6:686 protein binding, 4556,4557
4577 5-Iododeoxyuridine Ioglycamide
Iodine radiosensitizer, 6:194 biotransformation. 4566
incorporation in thyroid hor- 6-Iodoethylated starch, 4577 cholangiography application,
mone biosynthesis, Iodohippurate sodium, 4:497 4570
3:568-569 urography application, 4571 histamine release, 4559
and thyroid gland, 3:565 Iodomethamate pharmacokinetics, 4559-560
x-ray cross-section, 4486 angiography application, Iogulamide, 4:497
Iodine organic radiopaque com- 4569 properties, 4508
pounds, 4495-512 neurotoxicity, 4555 Iohexol, 4494,4:497,4531
pharmacology, 4540 -566 urography application, 4571 adverse reactions, 4546
potential nonionic, 4518-535 Iodophendylate, 4497 analysis, 4539
structure-activity relationship, properties, 4511 angiography application,
4517,4531-539 Iodophenyl alkanoate ra- 4569
synthesis, 4:512-517 diopaques, 4497 cardiovascular effects, 4:550
Iodine topical antibacterials, Iodophthalein, 4497 cations used with, 4541,
6:547 Iodopyracet, 4497,4541 4542
Iodipamide, 4497 angiography application, development of, 4:495
adverse reactions, 4544 4569 excretion, 4563-564
biotransformation, 4566 biotransformation, 4566 histamine release, 4559
cholangiography application, myelography application, isomerism, 4515
4569-570 4570 liposome encapsulated, 4:573
excretion, 4562,4563 pharmacokinetics, 4:561 nephrotoxicity, 4551,4552
histamine release, 4558 properties, 4511 neurotoxicity, 4:554,4555,
liposome encapsulated, 4573 protein binding, 4557 4556
pharmacokinetics, 4559-562 urography application, 4571 osmolality, 4538,4539
properties, 4508 Iodoxamate particulate, 4576
protein binding, 4556-557 biotransformation, 4566 pharmacokinetics, 4:561
urography application, 4571 pharmacokinetics, 4559-561 pharmacology, 4540
Cumulative Index

properties, 4506 development of, 4495 Iophenoxate


protein binding, 4556, excretion, 4564 biotransformation, 4566
4557-558 histamine release, 4559 Iophenoxic acid, 4497
red blood cell effects, 4548, isomerism, 4515 biotransformation, 4:565-566 :
4:549 liposome encapsulated, 4573, cholecystography application,
spiral CT application, 4568 4:574 4:570
synthesis, 4:513,4514 myelography application, excretion, 4563 P
Iolidonic acid, 4:497 4:571 isomerism, 4515
biotransformation, 4565 nephrotoxicity, 4551,4552 properties, 4:505
properties, 4505 neurotoxicity, 4554455, protein binding, 4556 -
Iolixanic acid, 4497 4556 Iopidine, 6:3
properties, 4505 osmolality, 4538 3H2-Iopiperidol-A,4:497
Iomeglamic acid, 4:497 pharmacokinetics, 4561 properties, 4507
biotransforrnation, 4566 pharmacology, 4540 Ioprocemic acid, 4497
properties, 4506 properties, 4506 properties, 4505
Iomeprol, 4:497 protein binding, 4:556, 4558 Iopromide, 4497
cardiovascular effects, 4551 red blood cell effects, 4:548, cardiovascular effects, 4:551
neurotoxicity, 4554 4549 liposome encapsulated,
osmolality, 4538 Smiles rearrangement, 4514 4573-575
properties, 4506 spiral CT application, 4569 nephrotoxicity, 4551,4552
red blood cell effects, 4:549 synthesis, 4512,4513 neurotoxicity, 4555
Smiles rearrangement, urography application, 4571 osmolality, 4538
4513414 Iopanoate pharmacokinetics, 4:561
Iomorinic acid, 4497 biotransformation, 4565466 properties, 4507
properties, 4505 excretion, 4562-563 red blood cell effects, 4549
Ionamin, 6:171,6:844 liposome encapsulated, 4575 Iopronic acid, 4497
Ion channel gates, 3:6-7 pharmacokinetics, 4561 biotransforrnation, 4565
Ion-channel pharmacology, Iopanoic acid, 4497 properties, 4506
2~75-76 adverse reactions, 4:544 Iopydol, 4497
Ion channels, 3:6-8 biotransformation, 4565, properties, 4:511
allosteric protein target, 4566 Iopydone, 4497
2:314, 2:315 cholecystography application, properties, 4511
anion- and cation-selective, 4570 Iosarcol, 4497
2:360 excretion, 4562,4563 properties, 4508
and anticonvulsants, 6292 isomerism, 4515 Iosefamic acid, 4497
formed by nicotinic receptors, properties, 4:505 properties, 4509
2:358 protein binding, 4556, 4557 Ioseric acid, 4497
Ionic bonds, 1:6, 1:170, 1:365 Iopax properties, 4505
Ion-induced dipole interactions, properties, 4511 Iosimide, 4497,4535
1:173 urography application, 4571 analysis, 4:539
Ionization constant Iopentol, 4:497 properties, 4507
characterization, 2:660-662 analysis, 4539 Iosulamide. 4497
Ionizing radiation. See also Ra- cardiovascular effects, 4551 cholangiography application,
dioprotective agents cations used with, 4542 4570
and carcinogenesis, 5:4,5:33 isomerism, 4515 properties, 4:509
damage from, 5:153-154 neurotoxicity, 4554, 4555 Iosumetric acid, 4:497
p53 activation, 5:28 osmolality, 4:538 properties, 4506
Ionotropic state, 3:9 pharmacokinetics, 4561-562 Iotasul, 4497
Ion pairing, 2675-676 properties, 4507 osmolality, 4538
Iopamidol, 4497,4531,4535 protein binding, 4557 properties, 4510
adverse reactions, 4546 red blood cell effects, 4548, Iotetric acid, 4497
analysis, 4539 4549 properties, 4509
angiography application, Iophendylate Iothalamate
4:569 biotransforrnation, 4566 adverse reactions, 4544
biotransformation, 4566 excretion, 4565 angiography application,
cardiovascular effects, 4551 myelography application, 4569
cations used with, 4:542 4570 biotransformation, 4566
Cumulative Index

Iothalamate (Continued) pharmacokinetics, 4561 Ipamix, 3:83


cations used with, 4541 properties, 4507 Ipconazole, 1:41
excretion, 4562,4563,4565 red blood cell effects, 4:549 IP-10 ligand
histamine release, 4558, Smiles rearrangement, 4514 and CXCR3,4165,4166
4559 synthesis, 4512 Ipodate
hyperosmolality, 4542,4543 Ioxabrolic acid, 4497 biotransformation, 4:566
myelography application, properties, 4510 cholecystography application, 7
4570-571 Ioxaglate 4570
neurotoxicity,4553-554, adverse reactions, 4546, excretion, 4563
4555 4547 Ipodic acid, 4497
pharmacokinetics,4561 cardiovascular effects, 4551 properties, 4505
pharmacology, 4540 cations used with, 4542 Ipral, 6:204
protein binding, 4556,4557 histamine release, 4559
Ipratropium, 6:125,a158
urography application,4571 hyperosmolality, 4543
therapeutic uses, 6:117
Iothalamic acid, 4497 liposome encapsulated, 4573,
particulate, 4576 4574 Iproniazid, 5:834
properties, 4505 nephrotoxicity,4551,4552 Irbesartan
Iotranic acid, 4497 pharmacokinetics, 4562 CYP2C9 substrate, 4627
properties, 4509 protein binding, 4557 Iressa, 5:12
Iotriside, 4497,4:535 red blood cell effects, 4548, Irinotecan, 1:849,1:861
properties, 4507 4549 antitumor natural product,
Iotrizoic acid, 4497 Ioxaglate meglumine, 4494, 5:110,5:131
properties, 4504 4497,4533 IRL 1038
Iotrol, See Iotrolan asymmetric bis compound, endothelin receptor antago-
Iotrolan, 4494,4497,4:531 4537 nist, 3206
cardiovascular effects, 4:551 development of, 4495 IRL 3630
cations used with, 4542 osmolality, 4:538,4539 endothelin receptor antago-
development of, 4495 pharmacology, 4:540 nist, 3206
histamine release, 4558, synthesis, 4514 Iron
4559 Ioxaglic acid, 4497 absorption, 3501
isomerism, 4515 properties, 4509 in biosphere, 3480-481
liposome encapsulated,4573 Ioxilan, 4497 chalate effect, 3481-483
nephrotoxicity, 4551,4552 isomerism, 4515 dynamics in humans,
neurotoxicity, 4553,4554, neurotoxicity, 4554 3:495-503
4555 particulate, 4576477 dynamics in microorganisms,
osmolality, 4537-538,4:538, properties, 4507 32481-495
4539 red blood cell effects, 4548 molecular control of uptake,
pharmacokinetics, 4562 synthesis, 4513 processing, and storage,
properties,4510 Ioxitalamic acid, 4:497 3:499401
red blood cell effects, 4549 adverse reactions, 4546, non-transferrin bound, 3:501
Iotroxate 4547 oxidation states, 3:480-481
cholangiography application, angiography application, siderophores, 3:483-488
4570 4569 storage and transport,
Iotroxic acid, 4497 cations used with, 4541 3:495-499
biotransformation,4566 properties, 4505 Iron chelators. See also Desferri-
pharmacokinetics, 4559 red blood cell effects, 4549 thiocin
properties, 4509 Ioxithalamate animal models, 3534-540
Ioversol, 4497 histamine release, 4558, clinical use, 3505-514
adverse reactions, 4546 4559 future developments,
analysis, 4539 neurotoxicity, 4:554 3522451
cardiovascular effects, 4551 pharmacokinetics,4562 HBED, 3:515-522
excretion, 4564 Ioxotrizoic acid, 4497 history of chelation therapy,
isomerism, 4515 properties, 4504 3:514-515
liposome encapsulated, 4573 Iozomic acid, 4497 pM values for selected ligands,
nephrotoxicity, 4:551 angiography application, 3:484
neurotoxicity, 4:554,4555 4569 recent developments,
osmolality, 4538 properties, 4509 3:515-522
Cumulative Index

synthetic approaches, structure-activity relationship, Isotope editing and filtering, in


3:522-534 628-29 NMR, 1:545, 1546
Iron(II), 3:480-481 Isofamic acid Isotretinoin, 4:320,4373
absorption, 3:501 protein binding, 4557 Isoxazole
reaction with hydrogen perox- Isofebrifugine cognition enhancer, 6:801
ide, 3:502 antimalarial, 5:998 Isoxsuprine, 3:13,3:14
Iron(III), 3:480-481 Isomaltase-sucrase, 433-36 agonistlantagonist, 6:5 -?
absorption, 3:501 Isomers applications, 6:16
Iron-mediated damage, iodinated radiopaques, Isoxyl, 5810
3:501-503 4515-516 Isradipine, 3:21 -
Iron-mediated dtseases, and obviousness of patent bioavailability and half-life,
3~503-505 claims, 2:732 323
Iron overload disorders, Isomer search, 1:388, 1:405-406 cardiovascular effects, 395-26
Isomethadone, 6:385 Isuprel, 6:4
R503-505
Isometheptene, 6:158 I-TAC ligand
animal models for, R534-540
Isoniazid, 5:833-834 and CXCR3,4:165
Iron-processing proteins, 3:495 activity and mechanism of ac- Italy
Iron regulatory proteins, tion, 5:834-835 patentable subject matter,
3:500-501 drug interactions, 5:862, 2:720
role in Alzheimer's disease, 5:864 trade secret protection, 2:769,
3~504-505 efficacy and dosage, 5:810, 2:782
Iron-responsive elements, 5863 Itasetron
3:499-501 interaction with vitamin B, cognition enhancer, 6:816
Irreversible inhibitors, 1:755 family, 4399, 4400, 4401 Itavastatin, 3:343
Ischemia, See Myocardial isch- and NAT2 polymorphisms, Iterative cyclic approaches
emia; Stroke 4630 and combinatorial library de-
Isepamicin, 2:182-183 peripheral neuropathy from, sign, 1:217
ISIS 1939,2:126-127 4618 Itraconazole, 5:893-897
ISIS 2105,2:133,2:139 selective toxicity, 5266 formulations and indications,
ISIS 2302,2:134,2:138,2:139, side effects, 5:835 5:890, 5:891
2:142 Isopodophyllotoxins P-glycoprotein inhibitor,
ISIS 2503,2:139,2:140,2:143 antitumor natural products, 4631
ISIS 3521,2:138-139,2:140, 5:110,5:134-136 selective toxicity, 5:268
2~142-143 Isoprenaline, 1:885,2:554 Itrocinonide, 2:552
ISIS 5132,2:139,2:140,2:141, Isopropamide Ivermectin, 1:849,1:891,1:892
2:142,2:143 anticholinergic, 6:135 antihelmintic, 6:1091,
ISIS 14803,2:141 relative anticholinergic activ- 5:1093-1094
ISIS 104838,2:155 ity, 6:157
ISISBase, 1:377, 1:387 Isoproterenol, 6:27 J-111,225, 5:682,5:684,5:708
ISIS databases, 1:373, P-agonist, 6:4 in vivo efficacy in systemic
1:376-377,1:387 applications, 6:14 murine infections, 5685
descriptors, 1:192 structure-activity relationship, 5-111,347,5:682,5:683,5:684
exact match searching, 1:380 6:29 5-113,397
similarity searching, Isoquinazolinone PARP inhibi- opioid analgesic, 6:447,6:449
1~382-383 tors, 6:686 5-114,870, 5:682,5:684,5:685
substructure searching, 1:382 Isosorbide 5-114,871, 5:683,5:684,5:685
ISISPirect, 1:387 osmotic diuretic, 3:64 J-115,814,6:886-887
ISISPraw, 1:387 Isosorbide dinitrate, 3:13,3:14 Janus kinase, 4130
Ismelin, 6:4 Isosorbide mononitrate, 3:13, chemokine interaction, 4:135
Ismotic 3:14 Japan
osmotic diuretic, 3:64 Isosulfazecin, 5:664 over-the-counter classification
Isoartemisitene, 5:965 Isothiazoles in, 4430-431
Isobombycol picornavirus antiviral agents, patentable subject matter,
radioprotective agent, &I67 5:403 2:720
Isoetharine Isothioureas trade secret protection, 2:769
P-agonist, 6:4 nitric oxide synthase inhibi- Japanese encephalitis virus,
applications, 6:14 tors, 6:705-706 5:427,5:429-430
Cumulative Index

Japanese Patent and Trademark signal transduction, Ketones


Documents database, 1:386 a342343 pharmacophore points, 1:249
Jarvis-Patrick algorithm, 1205, structure and molecular biol- Ketoprofen
1:401 ogy, 6:350-354 classification in various coun-
and combinatorial library de- Kappa-selective opioid receptor tries, 4430
sign, 1:220, 1:222 agonists, 6:348, e355-356 Key-based similarity searching,
Java, 1:396, 1:406, 1:407 centrally acting, 6:387-393 1:382-383 -?
JG-365, 1:121, 1:122 peripherally acting, 6:393-395 Key field, 1:406
Jimsonweed, 6:120 Kappa-selective opioid receptor Keys, 1:363
JM-83 antagonists, 6:348, encryption, 1:403 -
alkylating agent, 5 5 4 6:365-367 molecular similarity methods,
Karplus relationship, 1:525 1:188
JM-216
KB-R7943,3:173-175 Khat, 6:168-169, 6:172
alkylating agent, 5:54,5:60
KC 399
JM-473 Khellin, 1:883, 1:884
experimental hair growth
alkylating agent, 5:60 KHRR 296-299 AAAA, 2:85
drug, 4441
Joduron, 4541 KC 516 Kidneys
Joins, 1:390, 1:406 experimental hair growth and edema, 3:62-63
Joint ventures, 2:705 drug, 4441 hnctions, 3:56-57
JOM-13,470-71 Kefauver-Harris amendment, operation, 357-61
Josamycin, h763 2:686,4424 Kidney toxicity, 2:612-613
Journal content searching, 1:383 Kelatorphan, 1:650, 1:651, adaptive responses, 2:617-618
JTC-801 4219-220 Kidney transplantation, 5:487,
opioid analgesic, 6:447 opioid peptide metabolism in- 6:489
JTE-522,4:239,4240,4241 hibitor, 6:441, &442 1-year survival rate, 5:488
JTT-705,3:371,3:372 Kelthane, 2:555 Kieselguhr
Junctional rhythm, 3:9 Kemadrin resins for combinatorial li-
Jun protein, 5:22,5:25 anticholinergic, 6:132,6:135 brary synthesis, 2 2 9
Justicidin E, 4216 for Parkinson's disease, 6:731, KIN-802
Juxtamedullary nephrons, 3:57 6:732 radiosensitizer, 5:179
Kennard-Stone method, 1:65, KIN-804
Kaempferol, 1:865 1:66 radiosensitizer, 5:179
Kalihinol A Keratin, 2:221 Kinases
antimalarial, 5:993-994 and skin wrinkling, 4373 focused screening libraries
Kallikrein, 3:225 Kerlone, 6:5 targeting, 1250
Kallikrein-kinin system Ketanserin, 3:328,3:329, Kinase tumor-activated pro-
plasmid DNA-mediated gene 6:570-571 drugs, k 9 0
therapy study, 4654 Ketazolam, 6:551-552 Kinetoplastid parasitic diseases,
Kanamycin, 1:870, 1:871,2:207 Ketoamides residues 5:1035
antimycobacterial application, in pseudopeptide arrays, 2:12 antiprotozoal agents for,
5:811,5:842-844 Ketobemidone, 6:376 6:1035-1076
efficacy and dosage, 5:811, Ketoconazole, 1:717,3:724, King's Clover, drugs derived
5:863 5:893-897 from, 1:882
renal and hepatic toxicity, formulations and indications, Kininase 11, See Angiotensin-
2:615 5:890,5:891 converting enzyme
selective toxicity, 5:260-261 P-glycoprotein inhibitor, Kininogen, 3:225
side effects, 2:615,5:844 4631 Kit ligand, See Stem cell factor
Kanamycin A, 6:842-843 selective toxicity, 5268 Kitz-Wilson plots, 1:757
Kanamycin B, 2:184,5:842-843 Ketocyclazocine Klinefelter's syndrome, 3:698
Kanamycin C, 5:842-843 ligand to characterize kappa Klonopin, 6:529
Kantrex, 5811 receptor, 6:342 KMD-3213,6:33
Kaposi's sarcoma, 5299 8-Ketodeoxycoformycin, 1:751 KM231-DU257
Kappa opioid receptors, 6:331, Ketokanamycin A, 2:180-181 tumor-activated prodrug,
6:341-354,6:355-356 Ketol-en01tautomerization 5:83,5:94
and addiction, 6:336-337 NMR spectroscopy, 1:527-528 K-means clustering, 1:401,
ligands used to characterize, Ketolides, 1:876,6:776-781 1:406
6:342, 6:343-347, 6:451 structure, 2:193,2:194 K-medoids clustering, 1:406
Cumulative Index

K-Nearest Neighbors, 1:53, Kyoka (OTC license in Japan), L-792782


1:62-63 4:430 binding affinity with GABA,/
KNI-272, 1:562 Kyorin, 3:370,3:371 Bz, 6:795
Knockout mice Kyotorphin analogs L-793,422,5:908
for gene expression profiling molecular packaging, 2:591 L. major DHFR, QSAR inhibi-
studies, 4613 tion studies, 1:33
T
IL-1,4:173 L-35, 3:390 Label extenders, 2:623
IL-2,4:175 L-345,3:390 Labeling
IL-4,4176 L-1210 over-the-counter drugs,
IL-5,4177 growth inhibition, 1:37, 4:427-428 -
-
IL-6,4179 1:40-41 Labetalol
IL-12,4:180 inhibition of DHFR, 1:32, 1:34 alp-antagonist, 6:5
IL-13,4181 L-152,804,6:887 applications, 6:16
INF-y, 4183 L-162,313, 1:669 structure-activity relationship,
TNFa, 4182 L-364,286, 1:855 628, 6:32
Knowledge-based scoring, L-365,260, 1:856,6:544, LabMAP, 4:624
1:264-265,1:307, 6573574 Laboratory information manage-
1:310-312 L-370,518, 1:660 ment systems, 1:377
Knowledge-bases, 1:352, 1:379 L-375,378,3:314,3:316 Lachesine
Knowledge Discovery in Data- L-674,636,4217 relative anticholinergic activ-
bases (KDD), 1:394, 1:406 L-685,434 ity, 6:156
Koate structure-based design, 1:439 Lacidipine, 3:22
hemostatic preparation, 3992 L-685,458 bioavailability and half-life,
Koenigs-Knorr method, 2:228 for Alzheimer's disease, a 7 5 5 393
KogenateHeIixate L-687,306 cardiovascular effects, 3 2 6
hemostatic preparation, 3:292 for Alzheimer's disease, 6:763 Lacrimation, a110
Kohonen's Self-organizing Map L-689,660 p-Lactam antibiotics,
method, 1:65, 1:66 for Alzheimer's disease, 6:763 1:868-874,5608-610. See
Konyne L-696,256,5:703,6:706 also specific antibiotics and
hemostatic preparation, 2292 L-708,906 classes of antibiotics, such
Korundamine A anti-HIV drug, 5:473,5:474 as Cephalosporins or Peni-
antimalarial, 5:995,5:996 L-731,988 cillins
Kompensamines anti-HIV drug, 5:473,5:474 antibacterial broad-spectrum,
antimalarial, 5:995,5:996 L-732,747 5:705-709
Koshland-Nemethy-Filmerpal- structure-based design, 1:440, antimycobacterials, 5:858
ziel-Engek model, of al- 1:441 clinical application, 5:623-628
lostery, 2:301 L-733,060 combinations therapies, 5:625,
hemoglobin, 3:386 tachykinin antagonist, 3:224 56.26
KOWWIN, 1:389 L-733,692 current trends driving indus-
KP-736,5:643, 5:646 experimental hair growth try, 5:711-714
K-ras protein, 5:22,5:24 drug, 4438,4441 discovery, 2:39,5:628-637
and COX-2,5:34 L-735,525, 1:797 hydrolysis, 5:609, h619-621
Kriptin, 6214 L-740,093,6:581 mechanism of action,
KRM-1648,5:847, 5:852 L-741,462, 5:703, 5:706 5:610-613
KRP-297,3:370,3:371 L-742,694 mechanism of resistance to,
K-type allosteric effects, 2:296, preincubation, 2:73 5:613-623
2:303 L-742,728,5:703,5:706,5:707 mosaic gene formation,
KU-2285 L-745,337, 4242 5:616-618
radiosensitizer, 5:180 L-745,870,6:40,8:42 recent developments,
Kubinyi bilinear model, 1:3, L-746,072, 1:211 5:701-711
1:31 L-749,329 selective toxicity, $254, 5960
KW-2189 endothelin receptor antago- side effects and interactions,
alkylating agent, 5:54,5:61, nist, 3206 5:624-625
5:64 L-754,030, &581 p-Lactamase inhibitors, 1:718,
KW-3902,2122 L-761,000,4243 1:868-874
KW 6002 L-786,392,5:703,5:705,5:706, antimycobacterials, 5:858
for Parkinson's disease, 6:733 5:707 classification, 5:694-701
Cumulative Index

p-Lactamase inhibitors (Contin- Lanham Act, 2:757,2:759, Leave-some-out cross validation,


ued) 2:761,2:763-764 1:64
development of, 5:609 Lanosterol, 4:375 Ledins, 2:233,2:240-242,2:263
mutagenesis studies of antibi- Lansoprazole Leflunomide, 4:175,5:489
otic resistance, 2:90-91 CYP2C19 substrate, 4627 clinical use for organ trans-
recent developments, Lanthanide chelates plants, 5:522-523
5:710-711 radiopaque materials, 4490, side effects, 5523 -?
X-ray crystallographic studies, 4491 Left shifters, for hemoglobin,
1:483 Lantus, 4 7 3:386
p-Lactamase receptor cell line, Lanvis Legion, 1:387 -
2:50,2:52 antimetabolite, 5 7 6 Leishmaniasis
P-Lactamases, 5608- 609 Lapinone antiprotozoal agents for,
5:1035,5:1047-1052
classification and relevance in antimalarial, 5976
Lenampicillin, 5632
clinics, 5:618-621 Lapudrine, 5959
Lendormin, 6:207
evolution, 5:618 Large-scale synthesis, See Drug LennardJones potential, 1:285
extended-spectrum, 5619 synthesis Lenograstim, 3:263-264
molecular and phenotypic Lariam, 5934 Lentinan, 1:849
classification, $620 Larodopa, See L-Dopa Lentiviruses
p-Lactamase tumor-activated Lasix, 3 8 8 chemokine receptors,
prodrugs, 5:88 Lasofoxifene, 3:662,3:664-665, 4170-171
Lactase, 4 3 3 3:668 vectors for cancer gene ther-
Lactate dehydrogenase LASSO0 algorithm, 1:217 apy, 5 4 1
allostery, 2:306 Latamoxef, 5:652 Lentizol, a 4 8 5
Lactoylcholine, 6:150 Latanoprost, 4304 Lepirudin, 3:29, 3:285,3:316
dissociation constant, &I51 Latent inactivators, 1:756 ADME, 3:296
Lamarckian genetic algorithm, Latent semantic structure in- clinical trials, 3:293
1:299 dexing, 1:255 formula weight, mechanism of
Lamiazid, 5810 Laudexium, 1:857, 1:858 action, and route of admin-
Lamifiban, 3:29,3:319 Lawsone, 4:471-472 istration, 3:286
Laminin, 5:12,6:216 Lck tyrosine kinase, 5:22 structure, 3:288
inhibitor of amyloid p-peptide LD,,, 2:613 treatment regimen, 3:298
aggregation, 6:759 LDL, See Low density lipopro- Leprosy, 5809-813, 51035
interaction with sickled cells, teins pathogenesis and epidemiol-
3:459 LDL-receptor upregulators, ogy, 5:825-826
Lamisil, 5890, 5 8 9 1 3369 recent developments and
Lamivudine, 1:812-813, 1:816 LDR receptor, 3:11 present status of chemo-
anti-HIV drug, 5471,5472 Lead therapy, 5:865-866
drug resistance, $333-334 radiopaque material, 4486 Leptin, 6:872,6:873
for hepatitis B virus, Lead discovery anorectic agent, 6:883, a 8 8 5
5:327-329,5335-336 history of, 2:38-41 Lercanidipine, 3:22
selective toxicity, 5:267 process of, 2:41-62 bioavailability and half-life,
Lamotrigene receptor targets, 2:343-351 3:23
clinical trial using genotyping, Lead generation, 1:426 cardiovascular effects, 3:26
4643 Lead identification, 1:244. See fastest growing class of cal-
Lamotrigine also High-throughput cium channel blocker, 3:23
ADME, 6:285-286 screening Lergotrile
anticonvulsant, 6:265, 6:268, focused screening libraries for, for Parkinson's disease, 6:722,
6:269,6:298,6:319 1:250-252 a725
clinical efficacy, 6:273 virtual screening for novel, Lescol, a 3 4 3
development, 6:302 1:320-321 Lescopine, a117
dose, 6:270 Lead molecule fragment analogs, Lesopitron, 6:570,6:581
pediatric indications, 6:274 1:707-710 LESTR, 4166
side effects, a 2 7 9 LEADSeeker, 2:67 Letrozole, 3:632, 3:643
Lamprene, 5810 Leaf nodes, 1:377 Letter license, 2:723
Landiolol, 2:542-543 Leave-one-out cross validation, Leucine aminopeptidase inhibi-
Langerhans cells, 5224 1:57, 1:64 tors, 1:737-738
Cumulative Index

Leucovorin 5-lipoxygenase inhibitors, Levonordefrin


with irinotecan, 5:131 4211-216 a,-agonist, 6:3
Leu-enkephalin, 6:331, LTA4inhibitors, 4219-220 applications, 6:12
6:356-358 LTC, synthase, 4220 Levonorgestrel
Leu-enkephalin analogs Leukotriene C, applications, 3:631, 3:632
molecular packaging, biological actions of, 4210 Levophed, 6:3
2:587-589 biosynthesis, 4206,4207 Levopropoxyphene P
Leukemia discovery of, 4208,4209 selective toxicity, 5:269-270
cell characterization by gene Leukotriene C, synthase, 4206, Levormeloxifene, 3663
expression profiling, 4607, 4207,4:209,4:220 Levorphanol, 1:708,6:372 -

4608 Leukotriene D, dose, 6:334


Leukemia inhibitory factor, biological actions of, 4210 Levothroid, 3:576
3268-269 biosynthesis, 4206,4207 Levothyroxine, 3580-581,
discovery of, 4:208,4209 5:250-251
Leukeran
Leukotriene D, antagonists, Lewis y epitope, 2:226
alkylating agent, 5:54 4227-228 Lewry bodies, 6:712,6:716
Leukine, 3:260 Leukotriene E, Lexotan, 6:207,6:529
Leukocyte function-associated biological actions of, 4210 LF16-0687
antigen 1 (LFA-1) biosynthesis, 4206,4207 bradykinin antagonist, 3227
target of NMR screening stud- discovery of, 4208,4209 L-FMAU
ies using SAR-by-NMR, Leukotriene F,, 4:207 for hepatitis B virus, 5:327,
1:566-567 Leukotriene modulators, 5:329-330
Leukocytes, 4130 4204-205 LGD-1331
chemokine-induced transmi- Leukotriene pathway, 4206 experimental hair growth
gration, 4131 Leukotrienes drug, 4441
Leukotriene & biosynthesis, 4:205-208 LH-RH antagonist, 1:634
biosynthesis, 4:206-207 discovery, 4208 LH-RH peptidomimetic analog,
discovery of, 4208 radioprotective agent, 1:640
Leukotriene A, hydrolase, 4:206, 5:171-172 Liarazole, 3:725
4207 sources and actions of, LibEngine, 1:221
broad distribution of, 4:208-210 LiBrain, 1:220
4208-209 Levabuterol Libraries, 1:367, 1:400. See also
X-ray crystallographic studies, applications, 6:14 Combinatorial libraries; Li-
1:491 Levamisole gand libraries
Leukotriene & hydrolase inhibi- selective toxicity, 5:273 focused screening libraries for
tors, 4219-220 Levatol, 6:5 lead identification,
Leukotriene antagonists Leveling effect, 1:722 1:250-252
CysPTl antagonist clinical Levetiracetam for NMR screening, 1:574-576
studies, 4226-227 ADME, 6:291 phage display, 2:96
peptide-leukotriene antago- anticonvulsant, 6:265, 6:268, QSAR for rational design of,
nists, 4:220-226 6:269, a298 1:68-69
Leukotriene & synthase, 4:206 development, a 3 0 4 random peptide, 2:95
Leukotriene B, dose, 6:270 Librium, 6:529
biological actions of, 4209 pediatric indications, a 2 7 4 Licensing, 2:705, 2:723,
biosynthesis, 4206,4:207 side effects, 6:279 2:755-756
discovery of, 4:208 Levobetaxolol Licochalcone A
receptors, 4:209 P-antagonist, 6:5 antimalarial, kg99
Leukotriene B, antagonists applications, 6:16 Lidocaine, 3:32,3:34,3:167
derived from structure of LB,, Levobunolol ATP-sensitive potassium
4228-229 P-antagonist, 6:5 channel inhibition, 3178
related to HAP-type LTD, an- applications, 6:16 cardiovascular effects, 3:36
tagonists, 4227-228 Levobupivacaine multiple inhibitory mecha-
Leukotriene biosynthesis inhibi- selective toxicity, 5:273 nisms, 3:33
tors, 4:210-211 Levo-Dromoran, 6:334 uses and side effects, 3:35
5-lipoxygenase-activatingpro- Levofloxacin, 5:853 Lidorestat
tein (FLAP) inhibitors, Levomethadyl, a 3 3 3 structure-based design,
4216-219 dose, 6:334 1:448-449
Cumulative Index

Life-enhancing drugs, 4:431 siderophores (iron-specfic), Lipid colloidal systems, 2:672


Lifestyle drugs, 4422-423. See 3:483-488 Lipidic peptides, 2:509-510
also Over-the-counter drugs visually assisted design, 1:110 Lipid-membrane artificial red
current and future trends, Ligand strain energy, 1:308 blood cells, 3:420-421
4473-475 LIGSITE, 1:291 Lipid metabolism, 3358-362
defined, 4431 Limaprost, 4305 androgen effect on, 3:682
hair growth disorder drugs, Limbitrol thyroid hormone effect on, T
4433-440 dose for eating disorders, 3571
indications and drug exam- 6:851 Lipid oxidation, 2:617
ples, 4432 Lincomycin, 5787-788 Lipids. See also Antihyperlipi-
and self-medication, 4:423 Lincosamides, 5787-789 demic agents
sexual disorder drugs, Linear free energy relationship, formation, 2:459-460
4440-450 1:12, 1:14 lowering with thyromimetics,
smoking cessation agents, Linear interaction energy 3:575
4450-458 method, 1:120 protection from oxidation by
sunscreens, 4458-472 Linear notation, 1:368-369, vitamin E, 4383
Life-threatening diseases 1:406 role in artherogenesis, 3342
accelerated developmentlre- Linear QSAR models, 126-28 as targets for toxicity,
view, 2:687, 2:696-697 descriptor pharmacophores, 2~616-617
extensive first-pass effect not 1:61-62 Lipid suspensions/solutions
as great an issue in develop- Linear regression analysis for oral dosages, 2:671-672
ment, 2:646 in QSAR, 1:8-11, 1:50, 1:53, Lipid technologies
and Treatment IND, 2:690 1:67 and luminal degradation,
Ligand-based design Line-shape, in NMR, 1:512 2:677
NMR screening for, 1:564-577 and ligand dynamics, for oral dosages, 2:671-674
NMR spectroscopy for, 1:510, 1:528-531 Lipid transport, 3:358-362
1~517-532 Lineweaver-Burk plot, 1:727, Lipinski's "rule of 5"
Ligand-based virtual screening, 1:729, 1:731 and combinatorial library de-
1:188 and allostery, 2:296,2:304 sign, 1:214-215, 1:216
Ligand design, 1:110-118 iron transport in bacteria, in druglikeness screening,
LigandFit 3491 1:245
sampling/scoringmethods Linezolid, 2:195-196,5792-793 for molecular similarityldiver-
used, 1:261 combinatorial libraries, sity methods, 1:193, 1:208
Ligand flexibility, See Flexible 2:20-21 and NMR screening, 1:575
ligands systemic antibacterial, and passive diffusion, 2:256
Ligand-gated ion channels, 5:588-590 and peptide arrays, 2:6
2:333-334. See also Recep- Linkage disequilibrium, 4620 and permeability, 2:659
tors Link nodes, 1:381, 1:397 Lipiodol
Ligandin Linopirdine myelography application,
binding to contrast agents, acetylcholine-release modula- 4570
4557 tor, 6:97-98 radiopaque material, 4:493,
Ligand libraries cognition enhancer, 4494
diversity-based, a350 6:818-820 Lipitor, 3:343,3:609
pharmacophore-based, LINUS (Local Independent Nu- discovery, 3:362-363
2:345-350 cleating Units of Structure), Lipocortin I
Ligands. See also Allosteric ef- 1:124 X-ray crystallographic studies,
fectors; Protein-ligand in- Linux, 1:396, 1:406, 1:411 1:491
teractions Liothyronine, 3:580-581 Lipolysis
macromolecule-ligand interac- Lipantil, 3:343 insulin's role in regulating,
tions, NMR spectroscopy, Lipid arrays 42
1:510, 1:517, 1:535-562 multiple parallel synthesis, Lipolytic agents, 6:843,6:846
non-peptidic ligands for pep- 2:13-14 clinical applications, a857
tide receptors, 1:667-674 Lipid-based oral drug delivery, Lipophilic antifolates, 5 7 9
for opioid receptor character- 2252 Lipophilicity, 1:286
ization, 6:342, 6:343-347 Lipid-based vectors in CADD of soft drugs, 2:574
receptor-ligand interactions, for plasmid DNA-mediated and metabolism, 2:479-480
2:339-342 gene therapy, 4658-663 and partition coefficient, 2:656
Cumulative Index

and permeability, 2:659 Liquid chromatography Liver x-receptor agonists,


and prodrug design, 2:249 for enantiomer separation, 3:371-372
Lipoplex, 4658 1:787 LJC-084,5:709-710
for nonviral gene delivery, Liquid chromatography-mass LJC-11036, 5:709
5:42-43 spectrometry (LC-MS), Loading dose, 2:641
in vivo use, 4663-665 1:586-591 Lobeline, 4457
Lipopolyplex, 4658 affinity screening, 1:598-599 cholinergic, 6:56 P
for plasmid DNA-mediated fast, 1:596 Lobucivar
gene therapy, 4665-666 future developments, for hepatitis B virus, 5:333
Lipoprotein-associated phospho- 1:607-608 Local stereochemistry, 1:398 -
lipase A, inhibitors, 3:374 gel permeation chromatogra- Loceryl, 5:891
Lipoproteins phy screening, 1:599 Lock-and-key hypothesis, 1251,
and coronary artery disease, pulsed ultrafiltration screen-
1:252
310 ing, 1:603-606
deformable models, 1:5
metabolism, 3:358-362 for purification of combinato-
Liposome-based plasmid DNA- rial libraries, 1:592-594 Locus maps, 1:140
mediated gene therapy, structurelpurity confirmation Lodosyn
4658-663 of combinatorial libraries, for Parkinson's disease, 6:724
Lipoplex, 4:658, 4:663-665 1:594-596 Lofepramine
Lipopolyplex, 4658, Liquid chromatography-NMR- affinities for monoamine re-
4665-666 MS, 1:608 ceptors, 6:495
Liposomes, 2:672,2:673 Liquid dosage forms, 2:654 antidepressant, 6:485,6:486,
with gadolinium chelates as for low-melting compounds, 6:487
radiopaque, 4492 2:655 inhibition of serotonin, norepi-
hemoglobin encapsulation, Liquid-filled capsules, 2:654 nephrine, and dopamine
3:420,3:421 Liquids transporters, 6:500
with influenza antivirals, force field models for simple, pharmacokinetic parameters,
5:382 1:176 6:497
iodinated suspension ra- Liquid secondary ion mass spec- Log 1/C, 1:25, 1:27-29
diopaques, 4572575 trometry (LSIMS), 1:586, Log CR, 1 2 5
for toxicity reduction, 2:615 1587 Logic, in query features, 1:406
with vincristine, 5:142 Liquid-solid separation Logic and Heuristics Applied to
5-Lipoxygenase in large-scale drug synthesis, Synthetic Analysis
discovery of, 4208 2:416 (LHASA), 1:379
in leukotriene biosynthesis, Liquivent, 3:399 Log MW, 1 2 4
4205-207 Lisinopril, 1:650, 1:881 Log P
single nucleotide polymor- asymmetric synthesis, 1:807, chloroform-octanol, 1:17
phism~,4618 1:809 chromatographic determina-
structure and mechanism, impact of ACE polymorphisms tion, 1:17-18, 1:23
4211-212 on effectiveness, 4:634 estimation systems, 1:388,
12-Lipoxygenase, 4205 and snake venom peptides, 2:6 1:389
15-Lipoxygenase, 4205 Lissoclin disulfoxide, 4:163, for molecular similarityldiver-
5-Lipoxygenase-activating pro- 4164 sity methods, 1:193, 1:208
tein (FLAP) Lisuride and polarity index, 1:26
in leukotriene biosynthesis, for Parkinson's disease, 6:722, Log Perm, 1 9 5
4205,4206,4207 6:725 Log TA98,1:25-26
5-Lipoxygenase-activating pro- Literal patent infringement, Lomefloxacin, 6:853
tein (FLAP) inhibitors, 2:743-744 Lomerizine, 1:41, 1:42
4210,4216-219 Literature content searching, Lometrexol
5-Lipoxygenase inhibitors, 1:383 structure-based design,
4210-216 LitLink, 1:387 1:429-430
agents inhibiting both 5-LO Liver Lomotil, 6:334
and COX-2,4246-248 thyroid hormones effect on, Lomustine
15-Lipoxygenase inhibitors 3572 alkylating agent, 5:54,
high-throughput screening Liver toxicity, 2:613 5:64-65
for, 2:60,2:61,2:62 adaptive responses, 2:617-618 London forces, See van der
Lipstatin, 6:881 Liver transplantation, 5:487 Wads forces
Cumulative Index

Long QT syndrome, 2:76,2:619, gene expression profiling in molecular modeling, 1:112,


2:627-628 study, 4613 1: 113
anti-arrhythmic drugs, 3168 with niacin, 3:350 for novel lead identification,
Long term potentiation, a780 with Niaspan, 3:368 1:321
Loop (high ceiling) diuretics, Lovenox, a 2 8 6 Ludiomil, 6:485
3:88,3:89-111, 3:142 Low density lipoproteins (LDL), Lumefantrine
Loop of Henle, 3:57-58,3:60 2:616,3:340-341 antimalarial, 5:978-979 -7

Loperamide, 6:333 and coronary artery disease, dosage forms, 5:935


antidiarrheal, 6:338 3:lO-11 Luminal, a 2 0 4
dose, a334 current drugs to lower, Luminal degradation, 2:676,
P-glycoprotein substrate, 3:342-352 2:677
4631 new treatments for lowering, Lumisterol, 4374-375
Lopid, 3:343 3:368-370 LUMO (Lowest Unoccupied Mo-
lecular Orbital) energy,
Lopinavir, 1:648, 1:659 reduced by thyroid hormones,
l:ll, 1~14, 1:26, 1:54
anti-HIV drug, 5:476-477 3:571
Lunetron, 3:88
asymmetric synthesis, 1:807, transport, 3:358-359 Lung cancer
1:809 Lower osmolality intravascular cell characterization by gene
selective toxicity, 5:267 contrast agents, 4495, expression profiling, 4607,
Lopirazepam, 6:554 4:538 4608
Loprazolam, 6:207,6:553 Lowest obsemed effect level Lung transplantation, 5:487
Lopressor, 6:5 (LOEL), 2:620 Luret, 3:88
Loprox, 5:891 Low Mode Search, 1:292, 1:301 Lurotecan
Lora, 6:209 Low molecular weight heparin, antitumor natural product,
Loracarbef, 5:654 2:204,2:210,3:285 5:133
Loramet, 6:207,6:551 ADME, 3:295 Lustral, 6:485
Loratadine, 2:618 adverse effects, 3:294 Luteinizing hormone, 3:616
classification in various coun- clinical trials, 3292 and androgen synthesis,
tries, 4:430 mechanism and sites of action, 3:682- 683
selective toxicity, 5:275 3309-310 and estrogen synthesis, 3:642,
Lorazepam, 6:207,6:530,6:551 structure, 3:288 3:654-655
dose for anxiety, 6:529 treatment regimen, 3298 X-ray crystallographic studies,
polymorphic forms, 2:414 Lown-Ganonge-Levine syn- 1:491
Lorcainide, 3:32,3:34 drome, 3:19 Luteinizing hormone releasing
cardiovascular effects, 3:38 Loxapine factor, 3:616,3:683
uses and side effects, 3:35 dose, 6:601 Luvox, 0:485, a 5 2 9
Lorentz-Lorenz equation, 1:24 pharmacokinetics, biotrans- dose for eating disorders,
Lormetazepam, 6:207,6:551 formation, and drug interac- 6:850
Losartan, 3:198,3:199 tions, tk635-636 LuxS
CYP2C9 substrate, 4627 receptor binding and side ef- X-ray crystallographic struc-
P-glycoprotein substrate, fects, a606 ture elucidation, 1:494-495
4631 Loxitane, a 6 0 1 LW-50020, 1:849
Losigamone L1210 screening, for antitumor LY-117018
anticonvulsant, a 3 1 4 agents, 5:109 estrogen receptor affinity,
Losoxantrone L-selectin a659
topoisomerase I1 inhibitor, cloning, 2:106 LY-164929
6:68,5:72 L-seledin inhibitors, 2:223-224, analgesic, 6:411
Lost profits, patent infringe- 2:241 LY-170680,4222
ment, 2:746-747 L-type calcium channels, 3:7-8, LY-171883 (Tomelukast),
Loteprednol etabonate, 3:168 4221-222,4226
2:547-549 LU135252 LY-191704
Lotrafiban, 3319 endothelin receptor antago- experimental hair growth
Lotusate, 6:204 nist, 3:206 drug, 4437,4441
Lovastatin, 1:878-879, 3:343, Lubricants, 2:678 LY-227053
3:345,3:609 LUDI, 1:259, 1:295-296, 1:315 analgesic, 6:378
ADME, a356 combinatorial docking, 1:318 LY-246708
for angina treatment, 3:11 empirical scoring, 1:310 for Alzheimer's disease, 6:763
Cumulative Index

LY-246736 Lymphokines, 4130. See also Macromolecular prodrugs,


analgesic, 6:378 Cytokines 2:505-507
LY-253886 Lymphomas, 1:718 Macromolecular structure deter- -
analgesic, 6:378 cell characterization by gene mination, 1:334
LY-255283,4227 expression profiling, 4:606 NMR spectroscopy applica-
LY-255582 Lymphotadin, 4:132 tions, 1:533-535
analgesic, 6:378 Lysine Macromolecule-ligand interac- r
LY-293111,4:227-228 chemical modification re- tions, See Protein-ligand
LY-300164 agents, 1:755 interadions
anticonvulsant, 6:312 Lysolipids, 2:616 Macrophage colony-stimulating -
LY-303366, 1:877,5:902 Lysomal storage factor, 3252
LY-315920 carbohydrate-based therapeu- X-ray crystallographic studies,
structure-based design, 1:454
tics in development, 1:491
LY-338387
2:218-219 Macrophages, 3:252-254,3:259
picornavirus antiviral, 5407
LY-341495,6:654 Lysozyme, 5:224 and adaptive immunity, 5225,
LY-343814 LY171883 (Tomelukast), 5227
picornavirus antiviral, 4221-222 and innate immunity, 5:224
5409-410 role in atherosclerosis, 3342
LY-353349 M-14659,5643 MACROSEARCH, 1:94
picornavirus antiviral, 5409 M8506,5:953 Madar, 6:207
LY-353352 MACCS3D, 1:259, 1:363 Magace, 3:632
picornavirus antiviral, 5409 in molecular modeling, 1:111 Magnesium, 3160
LY-354740,6:581,6:654 MACCS (Molecular Access Sys- as antiarrhythmic agent,
experimental smoking cessa- tem), 1:254, 1:361-362 3171
tion agent, 4:459 Machine learning techniques Magnesium ferrite
LY-377604,6:884, 6:886 in molecular modeling, 1: 151 radiopaque material, 4489
LY-379268,6:654-655 in QSAR, 1:62 Magnesium supplements
LY-392098 Machines sickle hemoglobin hydration
for Alzheimer's disease, 6:765 patents on, 2:718 agent, 3:461
LY-404187 Macrocyclic mimetics, Magnetic resonance imaging,
for Alzheimer's disease, 6:765 1:635-636 See Nuclear Magnetic Reso-
LY-426965 Macrolide antibiotics, nance (NMR) imaging
experimental smoking cessa- 15474-876. See also Eryth- Magnetization transfer NMR,
tion agent, 4:459 romycins 1:568-570
LY-466700 antimycobacterials, 5:855-858 Ma huang, 1:884-885,6:10,
hepatitis C antiviral, 5:416 binding, 2:193-194 6:12,6:168, e l 7 2
LY-519818,3:370 biosynthesis, 5765-774 Major facilitator genetic super-
17,20-Lyaseinhibitors, 4"-carbamate, 5782 family, 2:267
3:724-726 clinical use and currently used Major histocompatibility com-
Lycopene drugs, 5758-761 plex proteins, 5:224-225,
positive ion APCI mass spec- discovery, 2:39 5:235
trum, 1:588 drug resistance, 5774-776 and organ transplant rejec-
tandem mass spectrum, 1:591 future developments, tion, 5487
Lymphadenography, 4567. See 5:784-785 and peptide immunogenicity,
also Radiopaques nonbacterial activity, 5238-239
Lymphadenopathy associated 5782-784 Major tranquilizers, 6:600. See
virus (LAVIHIV-21,5459 pharmacology and mode of also Antipsychotic agents
Lymphangiography, 4:567. See action, 5762-765 Malaoxan, 2:557
also Radiopaques recent developments, Malaria, 5:920-921,5:1035. See
Lymphatic filariasis, 51035 5:776-782 also Antimalarial agents
Lymphochip, 4606 selective toxicity, 5261-263 economic and political issues,
Lymphocytes, 3252-254 side effects, toxicity, and con- 5932-933
Lymphocyte trafficking, 2:106 traindications, 5:761-762 global incidence, 5926-928
Lymphography, 4567. See also structure-activity relation- immunity and prophylaxis,
Radiopaques ships, 5765-774 5930-932
Lymphoid progenitors, 3:253 MACROMODEL, 1:94 and sickle-cell anemia, 3:452
Cumulative Index

Malaria parasites, 5921-924 Malignant arrhythmias, Marijuana, 1:853,6:858


biochemistry and genetics, 3157-164 Marimastat, 5:217,5:218
5:924-926 Maloprim, 5:934 for Alzheimer's disease, 6:752 -
vector control, 5931-932 Maltase-glucoamylase, 4:3336 Marine source drugs
Malaridine, 59'79 Mandelate racemase inhibitors, antiasthma, 1:886
Malarone, 5935 1:762, 1:763 anticancer, 1:867-868
antimalarial, 5:976-978 Manerix, 6:485 Marinol, 6:854 T
Malate dehydrogenase for Parkinson's disease, 6:729, Marketing studies
allostery, 2:306-307 6:730 and delay of marketplace en-
Malathion, 2:556-558 Manhattan distance, 1:68 try of new drugs, 2:705
MALDI sequencing (of heparin), Manidipine, 3:22 Markup languages, 1:371-372,
2935-236 bioavailability and half-life, 1:405
(+ 1-Malekulatineantimalarial, 323 Markush feature, 1:381
5997 cardiovascular effects, 3 2 6 Markush structures, 1:367,
Male-pattern baldness, 4433,4435 ManLev, 2:226 1:368, 1:373, 1:406
Male pseudohermaphroditism, L-Mannaric acid MARPAT, 1:385
3:698 anti-HIV drug, 5476-47'7 Masoprocal, 1:849
Male sex hormones, 3:598, Mannich base prodrugs, 2:505 Mass spectrometry, 1:583-592
3679-681. See also Ana- Manning-binding lectins, affinity capillary electrophore-
bolic steroids; Androgens; 2:241-242 sis-mass spectrometry,
5a-Dihydrotestosterone Mannitol 1599-600
(DHT); Testosterone osmotic diuretic, 3:63-64 affinity chromatography-mass
absorption, distribution, and with xipamide, 3:105-106 spectrometry, 1:598-599
metabolism of anabolic ste- Mannosidohydroxystreptomycin, bioaffinity screening using
roids, 3:707-715 2: 172 electrospray FTICR MS,
absorption, distribution, and Mannosidostreptomycin, 5:840 1:601-603
metabolism of androgen an- Manufacture claims, 2:718 carbohydrate-based drugs,
tagonists, 3721 Manufacturing information 2:232
absorption, distribution, and submitting as part of IND pro- encoding and identification of
metabolism of endogenous, cess, 2:691 combinatorial compounds
3:685- 692 Manzamine A and natural product ex-
absorption, distribution, and antimalarial, 5:994 tracts, 1:596-597
metabolism of synthetic, MA0 inhibitors, See Monoamine frontal affinity chromatogra-
3:703-705 oxidase inhibitors phy-mass spectrometry,
biosynthesis, 3:616-618, Mappacine combinatorial li- 1:601
3682-685 brary, 2:27-28,2:30 future directions, 1:607-608
currently marketed anabolic Mappia foetida, 5:130 gel permeation chromatogra-
steroids, 3705 Maprotiline phy-mass spectrometry,
currently marketed synthetic affinities for monoamine re- 1:599
androgens, 3:697 ceptors, 6:495 LC-MS purification of combi-
endogenous, 3681- 697 antidepressant, 6:485,6:486, natorial libraries, 1:592-594
structure-activity relationship 6:487 MS-based screening,
for anabolic steroids, inhibition of serotonin, norepi- 1:597-598
3:707-715 nephrine, and dopamine pulsed ultrafiltration-mass
structure-activity relationship transporters, 6500 spectrometry, 1:603-606
for androgen antagonists, pharmacokinetic parameters, solid phase mass spectromet-
3718-721 6:497 ric screening, 1:606-607
structure-activity relationship side effects profile, 6:493 structurelpurity c o n h a t i o n
for synthetic, 3:699-703 Marboran of combinatorial com-
synthetic androgens, smallpox antiviral agent, pounds, 1:594-596
3:697-706 5435,5:437 types of mass spectrometers,
toxicities of anabolic steroids, Marcaine 1:585
3715-716 classical resolution, 1:795 use in solid phase organic syn-
toxicities of androgen antago- Marcellomycin thesis, 2:7,2:30
nists, 3'721-722 antitumor natural product, Mast cell growth factor, See
toxicities of synthetic andro- 5:124,5:126 Stem cell factor
gens, 3705 Margin of safety, 2:613 Mast cell mediators, 3267
Cumulative Index

Mast-cell proteases, 2:238 MC-02363,5703,5704 Mechlorethamine


Material Safety Data Sheets da- MC-02479,5:703, 5704 alkylating agent, 553, 554,
tabase, 1:386 MC-510,027,5:909, 5910 555
Material Safety Data Sheet MCDOCK Mecillinam, 5633-634
searching, 1:384 Monte Carlo simulated an- prodrugs, 2:510
Maternal IgG transport, nealing, 1:297 in vitro antibacterial activity,
2:261-262 M-cells, 2:261 5635 ?
Matrilysin, 5:13,5:14 McN-A-343 Medazepam, 6:549
Matriptase cholinergic, 6:77 Medicinal product, 2:502
virtual screening of inhibitors, MCP-1 ligand Medomin, 6:205 -
1:269-271, 1:272 and CCR1,4:137-138 Medrogesterone, 3:721-722
Matrix-assisted laser desorption
and CCR2,4143-147 Medroxyprogesterone, 3:641,
ionization (MALDI), 1:586,
MCP-3 ligand 3:654
k596, k606-607
and CCR1,4138 applications, 3:631, 3:632
Matrix metalloproteinase inhibi-
tors, 1:227, 1:555-557 and CCR3,4148-149 with estrone, 3650
antiangiogenic agents, MCP-4 ligand interactions with steroid re-
5216-217 and CCR3,4148 ceptors, 3:633
for cancer, 5:45-46 MCP-5 ligand Medrysone, 3:750,3:753,
for cancer treatment, 537-38, and CCR2,4:144 3:827-828
5:45 MCP-1R02 monoclonal antibody, Mefloquine, 1:889-890
chemical-shift mapping of 4: 144 antimalarial, 5943-946
binding to, 1:545 MCP-1RO5 monoclonal antibody, artemisinin potentiates,
target of NMR screening stud- 4: 144 1:887-888
ies using SARby-NMR, MDCK cell systems dosage forms, 5:934
1:566 permeability studies, 2:659 Mefruside, 372-73,382
target of structure-based drug MDC ligand Megace, 6:854
design, 1:443-445 and CCR4,4153 Megakarocyte growth and devel-
transition state analog inhibi- MD Docking (MDD) algorithm, opment factor, 3270
tors, 1:651-652 1:298 Megakarocytes, 3253,3254,
virtual screening, 1:315 MDL 18,962,3:728 3:256
Matrix metalloproteinases MDL28170 Megestrol, 3632
and angiogenesis, 5216 dose, 6:854
for Alzheimer's disease, 6:755
and carcinogenesis, 512-14 interactions with steroid re-
MDL Information Systems, Inc.
Matrix Placemate, 2:67 ceptors, 3:633
databases, 1:386-387
Maxair, 6:4 metabolism, 6:866
Maximal electroshock seizure, Mdm2 gene
for wasting, 6:858
6:292 and p53 gene, 5:29 Meglitinide, 4 2 0
Maximum Auto-Cross Correla- Mean residence time in the Meglumine, 1:796-797
tion (MACC), 1:202 body, 2:644 contrast media salts, 4541
Maximum likelihood estimation Mean residence time in the cen- for leishmaniasis,
of nicotinic receptor rate con- tral compartment, 2:644 51049-1051
stants, 2:372-373 Measles virus, 5:390 Melagatran, 3:314, 3:315
Maximum tolerated dose (MTD), antiviral agents, 5:390-396 structure-based design, 1:442,
2:620,5154 Meat Inspection Act of 1906, 1:444
Maxmin approach, 1:208 2:685 Melamine, 3123
May apple, drugs derived from, Mebaral, 6:204 Melanin
1:865,5:134 Mebendazole and skin tanning, 4464-465
Maybridge catalog, 1:385 antihelmintic, 5:1090-1091, Melanin-concentrating hormone,
Mazapertine, 6:567-568, 6:569 51091 6:870
Mazindol, 6:856 Mecarnylamine Melanocortin, a870
absorption and metabolism, experimental smoking cessa- Melanocortin receptors, 4 6 0
6:866 tion agent, 4459 a-Melanocyte stimulating hor-
dose, 6:845 nicotinic receptor antagonist, mone, 4:59-60
structure-activity relation- 2:390,2:397 and appetite regulation, 6:870
ships of analogs, 6:880-881 Mechanism-based enzyme inhib- constrained cyclic lactam ana-
MC-02331, 5703,5704 itors, 1:759-760, 1:764-771 logs of agonists, 464-65
Cumulative Index

a-Melanocyte stimulating hor- MEM 1003 Mepartrican, 1:849


mone (Continued) cognition enhancer, 6:820 Mepenzolate
minimum active sequence, Memantine anticholinergic, 6:137
460-61 for Parkinson's disease, 6:733, relative anticholinergic activ-
P-Melanocyte stimulating hor- a734 ity, a156
mone, 459-60 Memapsin 2, 6:753 Mepergan Fortis, 6:335
y-Melanocyte stimulating hor- Members, of Rgroups, 1:368,1:406 Meperidine, 1:708, 1:851,6:332
mone, 459-60 Membrane-associated toxicity, cytochrome P,,, isozyme sub-
Melanogenesis, 4464 2:613-615 strate, 6:339
Melanoma, 4458,4465-466 Membrane-bound drug targets, dose, a334
cell characterization by gene 1:351 rigid analog, 1:696
expression profiling, 4607, Membrane-bound proteins Mephaquine, 5:934
4608 molecular modeling, 1:154 Mephentermine
Melanotan 11,4450 NMR structural determina- applications, 6:12
a-Melanotropin tion, 1:535 general adrenergic agonist,
conformationally restricted Membrane-bound receptors, 1:5 6:3
peptidomimetics, 1:637 Membrane-depressant agents Mephenytoin
Melanotropins (Class I antiarrhythmics), ADME, 6:273
antagonists, 465-67 3:31, 3:32,3:34-38,3:167, anticonvulsant, a266
constrained cyclic lactam ana- 3:168 dose, 6:270
logs of a-MSH agonists, Membrane insertion scanning, Mephenytoin hydroxylase, 4627
464-65 2:270-271 Mephobarbital, a204
minimum active sequence of Membrane permeability, See Mephohexital, a204
MSH, 460- Permeability Mepiperphenidol, 6:123,6:139
~ - P h of
e ~MT-11: importance Membrane transport proteins, relative anticholinergic activ-
to binding and biological 2:249-251.2:265-267 ity, 6:157
activity, 461-62 absorption enhancement by Mepron, 5:935
ring-expanded analogs of MT- targeting, 2:254-255 Meptazinol, 6:379
11,463-64 apical sodium-dependent bile Mepyramine, a214
structure-activity relationship, acid transporter, 2:277-285 Meralluride, 3:67
459-60 ATP-binding cassette genetic Merbaphen, 3:65
P-substituent effects, 462-63 superfamily, 2:267 2-Mercaptoethylamine (MEA)
Melarsoprol integral membrane protein radioprotective agent, 5:152,
for African trypanosomiasis, structure, 2:270 5:155-160,5:169-170,
5:1041-1043 intestinal peptide transporter 5:172
Melatonergic agents, 6:251-254 case study, 2:274-275 2-Mercaptoethylguanidine
Melatonin, 6:214,6:215 P-glycoprotein case study, (MEG)
for Alzheimer's disease, 6:758, 2~272-274 radioprotective agent,
6:768 solute carrier genetic super- 5:158-160,5:161
analogs, 1:693 family, 2:267 2-Mercaptopropylguanidine
antagonists, 1:211-212 structural models of, (MPG)
Melfiat-105 Unicelles, a 1 7 1 2~269-270 radioprotective agent, 5:158,
Melidorm, a205 substrate design, 2:269-270 5:161
Melilotus officinalis(ribbed mel- therapeutic implications, 6-Mercaptopurine, 1:717,5:513
ilot), 1:882 2:267-269 antimetabolite, 575, 6:76,
Melittin Menadione, 4385-386,4387 5:81
molecular modeling, 1: 124 MEN1 gene, 6:27 resistance to, 6:290
Mellaril, a 6 0 1 Meningeal vascular amyloid, 2-Mercaptothiolazine
Mellein 6:744 radioprotective agent, 6:160
hepatitis C antiviral, 5:422, Menoctone Mercuhydrin, 3 6 7
5:424 antimalarial, 6:976 Mercurial diuretics, 3:64-66
Meloxicam, 4243 Menoquinone-4,4386 animal studies, 3:62
Melphalan Mentax, 5:891 Mercurophylline NF XII, 3:67
alkylating agent, 6:53,5:54 Menthyl anthranilate Mercuropurin, 3:67
Melting point structure-activity relationship, Mercury compounds
characterization, 2:655 4469 topical antibacterials,
salts, 2:651 sunscreen, 4460 52552-553
Cumulative Index

Mercury search program, 1:387 carbon oxidation and reduc- sulfur oxidation and reduc-
Merged Markush Service, 1:386 tion, 2:441-445 tion, 2:447-448
Meridia, 6:844 and chirality, 2:478-479 3D quantitative structure-
Merimepodip conjugation reactions, metabolism relationship
structure-based design, 1:447 2:450-475 (3D-QSMRs),2:481-483
MERLIN, 1:39, 1:386 conjugation with CoA, thyroid hormones, 3569-570
Meropenem 2:459-461 Metabolism databases, 1:385,1:386 r
antimycobacterial application, and disease, 2:474-475 Metabolism screening, 1:591
5:858 electronic factors, 2:480-481 pulsed ultrafiltration applica-
discovery, 5:668-669, enantiomers, 1:786-787 tion, 1:605 -
5:680-681 enzyme induction, 2:476-478 Metabolite database, 1:386
pharmacokinetics, 5:623-624 enzyme inhibition, 2:475-476 Metabolite toxicity, 2:621-624
side effects and interactions, Metabonome, 2:621
ethnic differences, 2:472-473
5:625 Metabonomics
functionalization reaction en-
use recommendations, 5:626 toxicology implications, 2:623
in vitro activity, 5:692 zymes, 2:437-441
Metadata, 1:375, 1:376, 1:406
Merozoites, 5:920,5:922 functionalization reactions, Metadate ER, 6:170
Merrifield resin, 2:30 2:431-4352~437-465 Meta-layer searching, 1:395
Mersalyl, 3 6 5 gender differences, 2:472-473 Metal chelates
Mersoben, 3:66 genetic factors, 2:467-472 radiopaque, 4:489-490
Mesna global expert systems to pre- Metal ion complexes
radioprotective agent, &I72 dict biotransformation, radioprotective agents, 5963
Mesopin, a117 2:481-483 radiosensitizers, 5:196
Mesoridazine glucuronidation and glucosi- Metalloelastase, 5:13
dose, a 6 0 1 dation, 2:453-456 Metallopeptidase inhibitors
receptor binding and side ef- glutathione conjugation and transition state analogs,
fects, a606 redox reactions, 2:461-464 1:649-652
Mespirenone, 3:118, 3119 hydration/hydrolysis, Metarnitron, 1:42
Messenger RNA, See mRNA 2:449-450 Metaprel, 6:4
Mesterolone, 3:709 interindivual factors, Metaproterenol
Mestranol, 3:634,3:635 2:466-473 p-agonist, 6:4
applications, 3631, 3:632 intraindivual factors, applications, 6:14
oxidative metabolism, 3:636 2:473-478 structure-activity relationship,
Metabolic assays inversion of arylpropionic ac- 6:29
high-content, 2:72-79 ids, 2:460 Metaproterenol sulfate inhaler
Metabolic inhibitors and lipophilicity, 2:479-480 reversed from OTC back to
radioprotective agents, methylation, 2:450-452 prescription status, 4426
5:162-163 modulation by structural vari- Metaraminol
radiosensitizers, 5:193-196 ations, 2:483-490 a,-agonist, 6:3
Metabolic profile molecular modeling, applications, 6:12
in vivo toxicity testing, 2:619 2:48l- 483 structure-activity relationship,
Metabolic rate nitrogen oxidation and reduc- 6:30
thyroid hormone effect, tion, 2:445-447 Metastable forms, 2:669
3:570-571 @oxidationand 2-carbon Metastasis, 5:12
Metabolism, 2:431-435. See also chain elongation, 2:460-461 Metazocine, 1:708, &375
Absorption, distribution, oxidative cleavage, 2:448-449 Met-chemokine P-7,4150
metabolism, and excretion presystemic elimination, Metconazole, 1:41, 1:42
(ADME);Retrometabolic 2:677-678 Met-enkephalin, 6:331,
drug design; Toxicophores; and prodrug design, 6:356-358
Xenobiotic metabolism 2:484-487,2:499-526 Metformin, 421-23
acetylation and acylation, questions related to answered a-Methadol, 6:385
2:456-459 in lead discovery and opti- p-Methadol, a 3 8 5
and age, 2:474 mization, 2:435 Methadone, 1:708,6:332, &333
antidepressants, 6510-516 questions related to answered analogs, 6:385-387
biological factors influencing, in preclinical and clinical cytochrome P4S0isozyme sub-
2:466-478 phases, 2:435 stratelinhibitor, 6:339
and biological rhythms, 2:474 sulfation, 2:452-453 dose, &334
Cumulative Index

Methadriol, 3699 with infliximab, 4182-183, Methyldopa


Methahydrin, 3:77 5:234 a,-agonist, 6:3
Methamphetamine, 6:171, interaction with dihydrofolate applications, 6:14
6:177,6:185 reductase, 1:120 structure-activity relationship,
ring substitution analogs, P-glycoprotein substrate, 6:29
1:704 4631 a-Methyldopa, 1:785
R-Methanandamide, 1:852, recombinant DNA studies of prodrug, 2:502 P
1:853 interaction with DHFR, Methylene bis-benzotriazolyl
Methandrostenolone, 3:708 2:97 tetramethylbutylphenol
anabolic activity, 3:716 selective toxicity, 5:264 (MBBT), 4472 -
Methanol soft analogs of, 2:567 Methylene blue
force field models for, 1:176 structure-based design, 1:425 antimalarial, 5:988
Methantheline Methoxamine Methyleneketone residues
anticholinergic, &I37
a,-agonist, 6:3 in pseudopeptide arrays, 2:12
relative anticholinergic activ-
applications, 6:12 5,lO-Methylene-tetrahydrofo-
ity, 6:156
structure-activity relationship, late, 1:426, 1:427
Metharbital, 6:205
Methazolamide, 3 6 9 , 3 7 0 6:30 5,lO-Methylene tetrahydrofor-
Methemoglobin, 3404 Methoxsalen mate polyglutamate, 4406
Methenamine experimental smoking cessa- a-Methylfentanyl, 6:383
systemic antibacterial, 5:596 tion agent, 4459 N-Methylglucamine, 4:541
Methenolone, 3:709,3:714, Methoxychlor, 3:651-652 Methyl group roulette, 1:700
3715 2-0-(2-Methoxyethyl)chimeras, Methylhomatropine
Methicillin, 1:869, 1:870, 1:871, 2:153-155 relative anticholinergic activ-
5631 Methscopolamine, 6:124 ity, 6:156
in vitro antibacterial activity, relative anticholinergic activ- Methylhyoscyamine
5:635 ity, 6:156 relative anticholinergic activ-
Methicillin-resistant staphylo- therapeutic use, a117 ity, 6:156
cocci, 5:617-618 Methsuximide stereoisomerism, 6:148, 6:149
Methiodal sodium, 4497 ADME, 6:282 Methylin, 6:170
Methionine:adenosyl trans- anticonvulsant, a267 Methylleucatropine
ferase, 1:148 dose, 6:270 relative anticholinergic activ-
Methionine hydrochloride Methyclothiazide, 3:77 ity, e l 5 6
nonclassical resolution, 1:803 a-Methylacawiosin, 4 3 6 Methyllycaconitine
Methisazone N-Methyl-acetemide
ligand for nicotinic receptors,
activity against orthopoxvi- force field models for, 1:176
2:358,2:391,2:394,2:395
ruses, 5:439 N-Methyl-D-aspartate receptor
antagonists, See NMDA re- 1-Methyl-3-nitro-1-nitrosourea
smallpox antiviral agent,
5:435,5:437 ceptor antagonists alkylating agent, 5:64
Methitural, 6:205 Methylating agents, 5:54 Methylphenidate (Ritalin)
Methixene Methylation. See also DNA hy- classical resolution, 1:793-794
relative anticholinergic activ- permethylation; DNA meth- dose, 6:170
ity, 6:157 ylation metabolism, a177
Methoctramine in metabolism, 2:450-452 nonclassical resolution, 1:801
anticholinergic, 6:131 Methylatropine, 2:58, a124 physiology and pharmacology,
Methods in Organic Synthesis relative anticholinergic activ- 6:179,6:181-182
database, 1:385 ity, 6:156 side effects, adverse effects,
Method validation, 2:419 therapeutic use, a117 and drug interactions,
Methonium compounds 2-Methyl-1,4-benzenediol 6:174
nicotinic receptor antagonist, allergenicity prediction, 1:833 structure-activity relation-
2:396-397 lp-Methylcarbapenems, ships, 6:187-199
Methotrexate, 1:717, 1:718, 5:675-683 N-Methyl-4-phenyl-l,2,3,6-tetra-
1:749 Methyl-CpG-binding domain- hydropyridine (MPTP; de-
antimetabolite, 5:75,5:76, containing proteins, 5:8 signer drug), 6:380
5:77,5:78-79 p-Methylcrotonyl CoA carbox- and Parkinsonism, 6:717-721
flavivirus antiviral, 5:428 ylase Methylphosphonates, 2:118,
folic acid with, 4:407, 4411 biotin dependent, 4404 2:120,2:126
Cumulative Index

2-Methylpiperazinedithiofor- properties, 4508 Mibefradil, 3:17,3:160,


mate protein binding, 4557 3:171-173
radioprotective agent, red blood cell effects, 4548 ATP-sensitive potassium
5:160-161 structure-activity relationship, channel inhibition, a178
6a-Methylprednisolone,3750, 4517 bioavailability and half-life,
3:753,3:758,3:768,3:770, Metrizoate, 4497 3:18
3:772, 3:797, 3:800 adverse reactions, 4544 cardiovascular effects, a 1 9 7
half life, 3:776 angiography application, removedlrestricted by FDA,
N-Methyl-4-propionoxy-4-phe- 4569 4642
nylpiperidine (MPPP; de- cations used with, 4541, Micafungin, 5888,5901, 5903 -
signer heroin) 4542 Micatin, 5:891
and Parkinsonism, a718 excretion, 4563 Micelle solubilization,
4-Methylpyrogallol, 4:31 hyperosmolality, 4542,4543
2:671-672
N-Methylscopalamine, 2:58 neurotoxicity, 4554
and luminal degradation,
Methyltestosterone, a697 particulate, 4576
17a-Methyltestosterone,3681 pharmacokinetics, 4561 2:677
5-Methyltetrahydrofolatepoly- properties, 4504 Michaelis-Menten constants,
glutamate, 4405,4407, red blood cell effects, 4548 1:725-728
4414 urography application, 4:571 use in QSAR, 1:7,1:8
Methyltrienolone, 3:708 Metronidzole Michaelis-Menten kinetics,
Meticillin, 5:609 peptide ester, 2:508 1:725-728
Metipranolol radiosensitizer, 5:178 and drug clearance, 2:638
0-antagonist, 6:5 Metropine, 6:117 Miconazole, 55393-897
applications, 6:16 Metropolis algorithm, 1:94, 1:98 formulations and indications,
membrane function disrup- Met-SDF-10 ligand, 4155 5:891
tion, 2:614 and CXCM, 4167 selective toxicity, 5:268
Metoclopramide Metyrapone, 3:120 Microarray chips, 1:334,
dose for eating disorders, Metyrosine 1:344-345. See also DNA
6:852 antiadrenergic, 6:4 microarrays
for eating disorders, &858 applications, 6:15 Microbial secondary metabolites,
Metocurine, 1:856, 1:857 Mevacor, 3:343,3:609 1:848
Metolazone, 3:83, 3:86 D,L-Mevalonate, 1:745 Microelectroporation, 4657
Metoprolol, 3:28, 3:179 Mevastatin, 1:744-745, Microemulsified perfluorochemi-
0-antagonist, 6:5 3:342-343 cal blood substitutes,
applications, 6:16 discovery, 3:362 3~428-429
cardiovascular effects, 3:39, Mexico Microemulsions, 2:672-673
3:40 trade secret protection, 2:769 and luminal degradation,
CYP2D6 substrate, 4627 Mexiletine, 3:32, 3:34 2:677
as high permeability guide, cardiovascular effects, 3:36 Micronase, 4 1 3
2:666 CYP2D6 substrate, 4627 Micronizing mill, 2:674
metabolism, 6:21 increased mortality from, 3:45 Microorganisms
renal clearance, 1:38 multiple inhibitory mecha- and Budapest Treaty, 2:723
uses and side effects, 3 3 8 nisms, 3:33 patentability, 2:718
Met-RANTES ligand uses and side effects, 3:35 Micropatent, 1:386
and CCR1,4139 Mexrenone, 3:120 Microsatellite nucleotide re-
and CCR3,4149-150 Mezlocillin, 5:633 peats, 4620
and CCR5,4155 indications, 5:625 Microsoft Access, 1:373
Metrizamide, 4497, 4531 pharmacokinetics, 5624 Microsomal triglyceride transfer
development of, 4495 MGSA ligand protein (MTP) inhibitors,
histamine release, 4559 and CCR1,4137-138 3:368-369
liposome encapsulated, 4573 MGV vaccine, 2:217,2:220 Microtiter plates, 2:66-67
myelography application, 4571 MHC I receptor Microtubules, 5136
nephrotoxicity, 4551,4552 homology modeling, 1:123 Microwave acceleration
neurotoxicity, 4554, 4555, molecular modeling, 1:117 of multiple parallel synthesis,
4556 MH166 monoclonal antibody, 2:30
osmolality, 4539 4179 Mictine, 3:124
pharmacology, 4540 Mianserin, 6:576:570-571 Micturation, e l 1 0
Cumulative Index

Midazolam, 6:207, a 5 5 3 structure-activity relationship, Mitomycin A


CYP3A41517 substrate, 4627 4437 antitumor natural product,
Middle tier, 1:392, 1:406-407 Minpress, 6:4 5:120, 5:121
Midecamycin, 5:763 Miokamycin, 5:763 Mitomycin C
Midodrine Miosis, e l 1 0 antitumor natural product,
a,-agonist, 6:3 MIP-la ligand, 4138-143 5:120-122
applications, 6:12-13 antibodies to CCR1, 4139 hypoxic selectivity, 5:84-85
Mifepristone, 3:651 and CCR2,4:144 prodrugs, 2:505
interactions with steroid re- and CCR5,4153-155 radiosensitizer, 5:182
ceptors, 3:633 MIP-1P ligand Mitomycins
MIG ligand and CCR5,4153-155 antitumor natural product,
and CXCR3,4165,4166 MIP-3a ligand 5:110,5:120-122
Miglitol, 1:849,2:206,2:212, and CCR6,4159 tumor-activated prodrug, 5:87
Mitosis promoting factor, 5:193
431,432,433-34,435, MIP-3P ligand
Mitoxantrone, 5:85
436-37 and CCR7,4160-161
P-glycoprotein substrate,
Milameline Mirapex 4631
for Alzheimer's disease, 6:763 for Parkinson's disease, 6:722, topoisomerase I1 inhibitor,
Milbemycins, 1:891, 1:892 a725 5:68,5:69,5:70-71
Milling Mircette, 3:632 Mitozolomide
in large-scale synthesis, 2:414, Mirisetron alkylating agent, 5:54,6:65,
2:417 cognition enhancer, 6:816 566-67
for particle size reduction, Mirtazapine Mitrizamide
2:674 antidepressant, 6:485,6:486, excretion, 4565
and solid state structure, a489 pharmacokinetics, 4562,
2:669 inhibition of serotonin, norepi- 4:563
MIL program, 2:372-373 nephrine, and dopamine Mivacron, 2:539
Miltefosine transporters, a500 Mivacurium, 1:857, 1:859, 2:539
for leishmaniasis, pharmacokinetic parameters, Mixed disulfide hypothesis, of
5:1051-1052 6:497 radioprotective agents,
L-Mimosine side effects profile, 6:493 5:168-169
analogs, 1:690 Mismatch repair genes, 5:8 Mixed dyslipidemia, 3:342,3:344
MIMUMBA, 1:255 and cancer heritable syn- Mixtures, 1:367-368
Mineralcorticoid receptor, 3:120 dromes, 5:32 Mizoribine, 1:849, 5489
Mineralcorticoids, 3612 Misonidazole, 5:84 clinical use for organ trans-
Mineral oil radiosensitizer, 5:177 plant~,5~521-522
in lipid formulations, 2:671 Misoprostol, 4:303-304 side effects, 5:522
Mini-fingerprints, 1:255 Mitarnycin MK-1,464-65
Mini-Mental State Examination, reaction with nucleosides, MK-2, 466, 4:67
a781 2:616 MK-3,466,4:67
Minimum effective concentra- Mitemcinal, 2:211-212,2:220 MK-4,466,4:67
tion, 2:641 Mithixene MK-196,3:92-93
Minimum topological difference anticholinergic, a 1 3 5 MK-329, 1:855
(MTD) method, 1:4, 1:147 Mithracin MK-383, 1:213
Minimum toxic concentration, antitumor natural product, MK-434
2:641 5:122-124 experimental hair growth
Mining minima algorithm, Mithramycin drug, 4441
1:292, 1:299-300 antitumor natural product, MK-447,3108-109
Minocin, 5:740 5:110,5:122-124 MK-473,393
Minocycline, 2:185,2:186,5:740, Mitochondria MK-0476,4:223-224,4226
5:742 adaptive toxic response, 2:617, MK-499, 1:814-815, 1~818
Minoxidil, 4433 2:618 MK-0571,4223,4226
adverse effects, 4433 Mitogen-activated protein ki- MK-0591,4217,4:218
approval in Japan, 4430 nases MK-0663,4237
development of, 4438-439 and carcinogenesis, 5:24 MK-0677, 1:671, 1:674
mechanism of action, target of structure-based drug MK-678, 1:657
4435-436 design, 1:456-459 MK-0679,4223,4:224,4226
Cumulative Index

MK-0787,5:668-669 Molecular biology and electrostatic interactions,


MK-801 for facilitating high-through- 1:81-85
anticonvulsant, 6:306 put screening, 2:74 and force fields, 1:79-81
MK-826,5:682,5:684,5:708 receptors, 2:35-336 known receptors, 1:103-127
MK-869 Molecular Biology Database Col- ligand design, 1:110-118
antidepressant, a517 lection, 1:345 metabolism, 2:481-483
MK-0886 Molecular comparisons, molecular comparisons, ?'
FLAP inhibitor, 4207, 1:138-142 1:138-142
4216-217 Molecular connectivity, 1: 192, and molecular mechanics,
MK-966,4235 1:407 1:79-100
ML-236B, 1:879 estimation systems, 1:388 pharmacophore-based ligand -
in QSAR, 1:26, 1:55, 1:56, libraries, 2:346
MLPHARE, 1:478
1:61 pharmacophore versus binding
MM-25,3:390
Molecular docking methods, See site models, 1:127-135
structure-based design, 1:423,
Docking methods potential surfaces, 1:85-89
1:424
Molecular dynamic simulations. protein structure prediction,
MM-30 See also Monte Carlo simu- 1:122-127
structure-based design, 1:423, lations and QSAR, 1:5
1:424 barrier crossing, 1:98 and quantum mechanics,
MM-4550,5:670 with docking methods, 1:292, 1:lOO-103
activity, $690 1:298 similarity searching,
MM-13902, $670 and force field-based scoring, 1:135-138
activity, 5:690 1:308 site characterization,
in vitro activity, 5:692 hydrogen bonds, 1:107 1:105-110
MM-17880,5:670 in molecular modeling, 1:85, and statistical mechanics,
MM-22380,5:670 1:93,1:95-100,1:116-117, 1:94-95
MM-22381,5:670,5:675 1:142 in structure-based design,
MM-22382, $670 and non-Boltzmann sampling, 1:419, 1:420
MM-22383, $670, $674 1:lOO systematic search, 1:89-94,
MM2 force field, 1:80, 1:307 protein flexibility, 1:301302 1:116
MM3 force field, 1:80, 1:118 statistical mechanical, 1:94, unknown receptors, 1:127-153
Mh4-PBSA method, 1:315 1:95 and virtual screening, 1:244
MoAb 7E3,3:462 of temperature, pressure, and Molecular multiple moments,
MoAb LM609,3:462 volume, 1:96 1:54
Moban, 6:601 thermodynamic cycle integra- Molecular packagmg
Mob genes, $614 tion, 1:99 for chemical delivery systems,
Moclobemide in virtual screening, 1:263 2:587-591
antidepressant, 6:485,6:486, water's role in docking, Molecular property visualiza-
6:488 1:302-303 tion, 1:137-138
for Parkinson's disease, 6:729, Molecular eigenvalues, 1:54 Molecular recognition, 1:283
a730 Molecular electrostatic potential, and hydrophobic interactions,
pharmacokinetic parameters, 1:102 1:15
6:497 Molecular extensions, 1:130-131 physical basis of, 1:284-289
side effects profile, 6:493 Molecular field descriptors, 1:54, Molecular replacement, 1:477
Modafinil, 6: l7O,6: 193 1:55-57 Molecular sequence alignment,
Modeccin, 2:263 Molecular Graphics and Model- 1:353
Modeling, See Molecular model- ing Society, 1:360 Molecular sequence analysis
ing Molecular holograms, 1:54 bioinformatics for, 1:335-336
Model mining, 1:3 Molecular mechanics, 1:79-100 Molecular shape analysis, 1:53
Model receptor sites, 1:149-150 force fields, 1:174-177 Molecular shape descriptors,
Mofetil, 4175 Molecular modeling, 1:77-79, 1:54
Mogadon, 6:207 1:153-154,1:358 Molecular similarity/diversity
Moisture sorption isotherms, affinity calculation, 1:118-122 methods, 154, 1:188-190
2:662-664 and bioinformatics, 1:351 analysis and selection meth-
Molar refraction, 1:24, 1:54 common patterns, 1:142-150 ods, 1:203-209
MOLCONN-Z, 1:55, 1:192, conformational analysis, 1:87, combinatorial library design,
1:389 1:93-94 1:190, 1:214-228
Cumulative Index

Molecular similarityldiversity Monoclate and non-Boltzmann sampling,


methods (Continued) hemostatic preparation, 3292 1:lOO
descriptors for, 1:191-203 Monoclonal antibodies, 2:88. See statistical mechanical, 1:94,
example applications, also Humanized antibodies 1:95
1:228-237 anti-HIV drug, 5:475-476 thermodynamic cycle integra- -
future directions, 1:237 carbohydrate-based, 2:239 tion, 1:99
and molecular modeling, clinical use for organ trans- in virtual screening, 1:263
1:135-138 plants, 5:489,5:509-513, Montelukast sodium (MK-0476),
virtual screening by, 1:188, 5:525-526 4223-224,4226
1:190, 1:209-214 pharmacokinetics, 5510 selective toxicity, 5:252 -
Molecular structure descriptors pharmacology, 5:510-513 Moore's Law, 1:393
in QSAR, 1:26 selective toxicity, 5:257 Morgan algorithm, 1:378, 1:407
Molecular targets, See Drug targets side effects, 5513 Moricizine, 3:32
Molecular weight Monocolin K, 1:879 cardiovascular effects, 3 3 8
for molecular similaritykliver- Monocytes, 3:252-254 increased mortality from, 3:45
sity methods, 1:193, 1:208 Monodral, 6:137 multiple inhibitory mecha-
and QSAR, 1:24-25 Monod-Wyman-Changeaux nisms, 3:33
MOLGEO, 1:255 model uses and side effects, 3:35
Molgramostim, 3:260,3:261 and allostery, 2:300-301, Morphazinamide, 5:836
Molindone 2:313 Morphiceptin, 1:144, 1:145
dose. 6:601 and binding-gating problem in Morphinan analgesics, 1:850,
pharmacokinetics, biotrans- nicotinic receptor family, a334
formation, and drug interac- 2:370 structure-activity relation-
tions, 6:640 and hemoglobin allostery, ships, 6:372-373
receptor binding and side ef- 3:386 Morphine, 1:634, e331-332,
fects, 6:606 Monograph status, over-the- a333
Molinspiration, 1:390 counter drugs, 4425 cytochrome P,,, isozyme sub-
Molipaxan, a 4 8 5 Monokines, 4130. See also Che- strate, 6:339
Molluscum contagiosum virus mokines dose, 6:334
chemokine receptors, 4:171 Monoliganded receptors ecological function, 1:848
MOLPAT, 1:110-111 nicotinic acetylcholine recep- fragment analogs, 1:707-708
Mometasone furoate, 3:750, tors, 2:374-375 heroin as "accidental" prodrug
3:753,3:767 Monoliganded receptors nico- of, 2:500
Monasus ruber, 1:879 tinic acetylcholine receptors history of use, 6:358-360
Monistat, 5:891 (muscle-type), 2:374-375 ligand to charaderize mu re-
Monoamine oxidase Monomer Toolkit, 1:377-378 ceptor, a342
and depression, 6:507 Mononine nonpeptide affinity labels used
and Parkinson's disease, a716 hemostatic preparation, 3:292 to study, 6:403-405
Monoamine oxidase inhibitors, Monte Carlo simulated anneal- for pain relief after myocardial
1:718,6:485,6:486 ing infarction, a165
for anxiety disorders, 6:528 and combinatorial library de- structure-activity relationship,
for eating disorders, 6:851, sign, 1:218 6:361-362
6:858, a859 with docking methods, 1:292, structure-activity relation-
efficacy relative placebo, 6:489 1:297 ships of derivatives,
for Parkinson's disease, with virtual screening, 1:263 6:362-364
6:729-731 Monte Carlo simulations. See Morphine alkaloids, 1:849-851
pharmacokinetics, 6:497-498 also Molecular dynamic sim- Morpholine antifungal agents,
side effects, 6:491-492 ulations 5:903
structure-activity relationship, barrier crossing, 1:98 Mortl, 5:17
6512-513 and combinatorial library de- Mosaic genes, 5:616-618
Monoaminergic antidepressants, sign, 1:217 Mosflm/CCP4, 1:478
a516 de novo design, 1:113 Mos protein kinase, 5 2 2
Monoamine transporters, with docking methods, 1:292, Most descriptive compound
6:498-502 1:297-298 (MDC) method, 1:207-208
Monobactams, 1:873,5:664-668 in molecular modeling, 1:85, Motofen, 6:334
brief description, 5:609 1:86, 1:93, 1:96-99, Mouse stem cells
use recommendations, 5:626 1:116-117, 1:142 for toxicity testing, 2:626-627
Cumulative Index

Moxalactam, 5:652-653 Multilevel chemical compatibil- Murine leukemia virus


Moxestrol, 3634, 3:635, 3658 ity, 1:249 vectors for cancer gene ther-
Moxisylyte, 4:442 Multiple-copy simultaneous apy, 6:41
Mozenavir search methods (MCSS), Muromonab CD3, 5:490
anti-HIV drug, 5:476-477 1298 Muscarine, 6:41
MPS I disease, 2:218-219 Multiple isomorphous replace- as cholinergic, 6:57-61
MPTP (designer drug), a380 ment (MIR) phasing, 1:477 Muscarinic acetylcholine recep- r
and Parkinsonism, 6:717-721 Multiple parallel synthesis, tor agonists
Mr2034,6:375 2:l-5 for Alzheimers' disease,
Mr2266,6:375 infonnetrics, 2:30 6:762-764 -
MR contrast agents, 4567 lipid arrays, 2:13-14 miscellaneous structurally
MRL-1237 microwave acceleration, 2:30 unique cholinergics,
picornavirus antiviral, 5:413 nucleoside arrays, 2:13,2:14 6:78-80
Muscarinic acetylcholine recep-
MRNA, 2:169,2:621 oligosaccharide arrays, 2:13,
tor antagonists
and antisense technology, 2:14
for Alzheimers' disease,
2:116 patent issues, 2:30-31 6:762-764
bacterial, 5:738 peptide arrays, 2:6-13 Muscarinic acetylcholine recep-
and Branched DNA technique, product purity, 2:28-29 tors, 6:41-43
2:623-624 resins and solid supports for, distance range matrices, 1:136
and expression profiling, 2:29-30 interaction of anticholinergics
1:340341 solid and solution phase li- with, 6:151-153
and ribosome function, braries of small, druggable recombinant DNA studies,
2:169-170 molecules, 2:14-30 2:lOl-102
MRS2279,3:321 solid phase synthesis of infor- stereoisomer analogs,
MSDRLICSIS, 1:361 mational macromolecules, 1:705-706
MS drugs, 6:675 2:5-14 Muscarinic MI acetylcholine re-
MS-MS, See Tandem mass spec- synthetic success, 2:28-29 ceptors, 6:41-42
trometry (MS-MS) Multiple regression analysis agonists and antagonists,
MT-11, 461-64, 4 6 6 in QSAR, 1:8-11, 1:50, 1:52, 6:115-116
Mucor, 5:883 1:53 Muscarinic M, acetylcholine re-
Mucormycosis, 5:883 Multiple sclerosis, 6:674-675 ceptors, 6:41-42
Mulliken population analysis, Multistep prodrugs, 2:487-490 agonists and antagonists,
1:lOl-102 Multisubstrate analog enzyme 6:115-116
MULTICASE SAR method, inhibitors, 1:720, 1:741-748 Muscarinic M, acetylcholine re-
2:621 Multi-tier architecture, 1:392, ceptors, 6:41-42
for studying P-glycoprotein, 1:407 agonists and antagonists,
2:621 Multivalency 6:115-116
toxicity prediction application, in carbohydrate-based drugs, Muscarinic M, acetylcholine re-
1~828-843 2233-235 ceptors, 6:41-42
Multidimensional databases, Multiwavelength anomalous dif- agonists and antagonists,
1:390, 1:407 fraction (MAD) phasing, 6:115-116
Multidimensional NMR spec- 1:474, 1:477-478 Muscarinic M, acetylcholine re-
troscopy, 1:512-514 Munich Information Center for ceptors, 6:41-42
Multidimensional scaling, 1:201 Protein Sequences (MIPS), agonists and antagonists,
Multidimensional scoring, 1:291 1:335 6:115-116
Multidrop automated screening Mu opioid receptors, 6:331, Muscarone
robot, 2:65 6:341-354 cholinergic, 6:57-61, 6:80
Multidrug resistance gene prod- and addiction, 6:336-337 Muscle-type nicotinic acetylcho-
ucts, 2267 ligands used to characterize, line receptors, See Nicotinic
Multidrug resistance proteins, 6:342,6:343-347 acetylcholine receptors,
5:285-286 signal transduction, muscle-type
Multidrug resistance-related 6:342-343 Muse, 4442
protein, 5285-286 structure and molecular biol- Mu-selective enkephalin ana-
Multi-endpoint analysis ogy, 6:350-354 logs, 6:410-412
in toxicity testing, 2:624-626 Murel, a138 Mu-selective opioid receptor ago-
Multi-infarct dementia, a 7 8 0 Murine IL-4 mutants, 4176 nists, 6:333, a 3 4 8
Cumulative Index

Mu-selective opioid receptor an- Mycobacterium chelonae, 5:815 Myeloid progenitors, 3:253,
tagonists, 6:333,6:348 Mycobacterium fortuitum, 5:815 3254
somatostatin derived, regimen for treatment, k867 Mylotarg, 5:228,5:231
6:437-438 Mycobacterium haemophilum, tumor-activated prodrug,
Musettamycin 5:815 5:83,5:92
antitumor natural product, Mycobacterium kansasii, 5:815 Myocardial cells, 3:3-4
5:124,5:126 regimen for treatment, 5866 Myocardial diseases T
Mustards, See Nitrogen mus- Mycobacterium leprae, 5:809, plasmid DNA-mediated gene
tards 5:825-826 therapy, 4655-656
Mustargen susceptibility testing, k827 Myocardial infarction, 3:3,3:289
alkylating agent, 5:54 Mycobacterium malmoense, 5:815 coronary occlusion, 3156-157 -
Mutarnycin regimen for treatment, 5:866 and lipids, 3:340
Mycobacterium marinum, 55315 malignant arrhythmias,
antitumor natural product,
regimen for treatment, 5:866 3157-164
5:120-122
Mycobacterium microti, 5:814 pathophysiology, 3:156-164
Mutated in multiple advanced
Mycobacterium scrofilaceum, preconditioning, 3:157
cancers (MMAC) tumor sup- 5:815 AT, receptor expression in,
pressor gene, 5:30 regimen for treatment, 5:866 3:197
Mutation Mycobacterium simiae in stroke patients, 6:675-676
in genetic algorithms, 1:87, regimen for treatment, 5:866 treatment regimens, 3298
1:88 Mycobacterium tuberculosis, ventricular remodeling, 3:164
ionizing radiation, 5:153-154 5:809,5:813-825 Myocardial infarction agents,
in nicotinic acetylcholine re- susceptibility testing, 5826-829 3:155-156. See also Antiar-
ceptors (muscle-type), Mycobacterium ulcerans, 55315 rhythmic agents
2:375-382 Mycobacterium xenopi, 5815 for pain relief, 3:164-165
and tumorigenesis, 5:2 Mycobadin M, 5:818 for remodeling prevention,
Mutation hot spots, 5:5 Mycobadin P, 5:818 3:180-181
Mutual Recognition Procedure Mycobactin S, 3:486,3:487, for treatment of arrhythmias,
(European over-the-counter 3:493,5:818 3167-180
drugs), 4428-429 synthesis, 3:524 for treatment of thrombolysis,
Muzolimine, 3:108 Mycobutin, 5:811 3:165-167
MVIIA (Ziconotide) Mycolic acid, 5:816 Myocardial ischemia, 3:3,3:157,
NMR spectroscopy, Mycophenolate mofetil, 1:849, 3:289,6:675-676
5:489, 5:490 extracellular potassium accu-
1:518-523, 1:526, 1:534
clinical use for organ trans- mulation during, 3:162-163
MVT-101, 1~103-104,1:105,
plants, 5:518-521 and oxygen supply, 3:8,3:9
1:117
for herpes, 5:321-322 plasmid DNA-mediated gene
Myambutol, 5:810 with leflunomide, 5:523 therapy study, 4655
Myasthenia gravis side effects, 5:521 treatment of arrhythmias in-
cholinergics for, 6:41 structure-activity relationship, duced by, 3:167-180
Mycobacteria, 5:813-821. See 5:520-521 Myocardial oxygen demand, 3:9
also Antimycobacterial Mycophenolic acid, 5:518 Myocardial oxygen supply, 3:8-9
agents flavivirus antiviral, 5:428 Myocardial pacemaker cells, 3 4 ,
pathogenesis and epidemiol- for herpes virus, k321 329
ogy, 5821-826 structure-based design, Myocardium, 3:3,3:4
Mycobacteria other than tuber- 1:446-447 Myoglobin, 1:419
culosis, 5:814, 5:824 Myc protein, 5:22,5:25-26 N-Myristoyl transferase inhibi-
Mycobacterium, 5:813-814 Mydriacyl, a 1 3 8 tors, 5:908-909,5:910
Mycobacterium abscessus, 5:815 Mydriasine, a117 M I zinc finger peptides
regimen for treatment, 5867 Mydriatics influenza antiviral agents,
Mycobacterium africanum, 5:814 anticholinergic activity assay, 5:387
Mycobacterium avium, 5:809, 6:119-120,6:153
5:814,5:815 anticholinergics, 6:114-115 Nabilone, 1:853
regimen for treatment, 5:866 Myelography, 4:567. See also Nabi-NicVax
Mycobacterium bovis, 5:813, Radiopaques experimental smoking cessa-
5:814,5:815,5:820-821, radiopaques applications, tion agent, 4459
56323 4:570-571 Nacton, a138
Cumulative Index

NAD, 4394,4:395,4396 classical resolution, 1:794-795 Natriuretic peptide receptors,


precursors and cellular ener- enzyme-mediated asymmetric 3217
getics, 6:687-690 synthesis, 1:805 Natural killer cells, 5225
substrate for PAW, prodrugs, 2505 Natural product mimetics,
6~677-679 Napsagatran, 2:311, 3:314, 1:636
synthesis pathway, 6:689 3315 Natural products. See also Anti- 7
NAD glycohydrolase inhibitors, Naqua, 3:77 tumor natural products
6:686-687 Narcobarbital, 6:205 antiasthma drug leads,
Nadolol Narcolepsy 1:883-886 -
P-antagonist, 6:5 CNS stimulant for, 6:173, antibiotics drug leads,
applications, 6:16 6:193 1:868-878
cardiovascular effects, 3:39, Narcotal, 6:205 anticancer drug leads,
3:40 Narcotic agonists, 6335 1:858-868
renal clearance, 1:38 opioid receptor affinities, antimalarial agents,
uses and side effects, 3:38 6:348 5:993-999
NADP, 4394 Narcotic analgesics. See also antiparasitic drug leads,
NADPH Opioid analgesics; Opioid 1:886-891
nitric oxide synthase binding receptors cardiovascular drug leads,
site, 6698 future developments, 1:878-883
Nadroparine, 2:210,2:212 6448-450 CNS drug leads, 1:849-856
Nafadotride, 6:643 history, 6:358-360 CNS stimulants, 6:168
Nafcillin, 5:631 recent developments, in compound deck for HTS,
biliary excretion, 6:623 6:443-448 2:37
pharmacokinetics, 5624 Web resources, 6:450-452 drugs derived from, 1990-
Nafoxidine, 3:662, 3664 Narcotic antagonists, 6:335 2000, 1:849
Naftifine, 1:717,5:899-900 opioid receptor affinities, extract encoding and identifi-
formulations and indications, 6:348 cation, 1596-597
k891 Nardil, a 4 8 5 isolation for carbohydrate-
Naftin, k891 dose for eating disorders, based drug development,
Naja naja a-toxin, 2:377 6:851 2:232-233
Naked plasmid DNA for Parkinson's disease, 6:729, leads for new drugs,
for cancer therapy, 5:39 6:730 1:847-894, 2:84
for plasmid DNA-mediated Narwedine, 15302, 12303 neuromuscular blocking drug
gene therapy, 4:652-656 Natamycin leads, 1:856-858
Nalbuphine, 6:335,6:363 polymorphic forms, 2:414 NMR structure elucidation,
prodrugs, 2502 Nateglinide, 411,4:14,4:15, 1~517-518
Nalmefene, 6:363 416, 417,419,4:20 nonpatentability, 2:718
Nalorphine, 1:850 binding parameters, 4 1 8 for receptor target lead discov-
Naloxone, 1:850,6:333 National Cancer Institute data- ery, 2345
Naltrexone, 6:333 base, 1:222, 1:254, Natural products databases,
nonpeptide affinity labels used 1:385-386, 1:387 1:387, 1597
to study, 6:403-405 antitumor natural products, Natural soft drugs, 2571
Nandrolone, 3:707,3:714 5:llO Naturetin, 3:76
Nannochelin, 3486, a487 National Center for Biotechnol- Navane, 6:601
synthesis, 3524 ogy Information (NCBI), Navelbine
NAPAP, 3314 1:335 antitumor natural product,
Naphazoline sequence databases, 1:387 5142-143
a,-agonist, 6:2, 6:3 National Center for Toxicologi- Navidrix, 3:76
applications, 6:13 cal Research, 2688 NCI 60 cells
structure-activity relationship, National Toxicology Program, characterization by gene ex-
6:30-31 1:246, 1:829 pression profiling,
NAP-2 ligand Natrilix, 3:83 4:607-608
and CCR1,4:137-138 Natriuretic peptide family drug response screening by
and CXCR2,4161,4:162 biological actions, 3:217-218 gene expression profiling,
NAPRALERT, 1597 biosynthesis, metabolism, and 4:609
Naproxen structure, 3:214-217 NE-0080,2:214,2:220
for Alzheimer's disease, 6767 therapeutic potential, 3:218 NE-1530,2:214,2:220
Cumulative Index

Nearest neighbors methods, Neomycin B, 2:176-177 Neuromedin L, 3:221


1:53, 1:62-63, 1:67 Neonal, 6205 Neuromuscular drugs
Necrosis, 2:77 Neonatal IgG transport, natural products as leads,
apoptosis contrasted, after 2261-262 1~856-858
myocardial infarction, 3:157 Neonicotinoids Nemnal nicotinic acetylcholine
in stroke, 6:676-677 selective toxicity, 5278 receptors,See Nicotinic acetyl-
Neem, 5:996 Neoral, 5:491,5:492 choline receptors, neuronal r
Nefazodone, 6:496 Neosporin, 5748 Neuronal nitric oxide synthase,
affinities for monoamine re- Nephrons, 3:57-58 6:695-708
ceptors, 6:495 Neprilysin Neuropeptide receptor-acting -
antidepressant, 6:485,6:486, for Alzheimer's disease, 6:760 drugs
6:489 Neptazane, 3:70 antidepressants, 6:517-518
inhibition of serotonin, norepi- Neravil, 65405 Neuropeptide Y
nephrine, and dopamine Nerve gases, 6:90-93 and anxiety, 6:546
transporters, 6:500 Netilmicin, 5748 and appetite, 6:870
pharmacokinetic parameters, Netropsin biological actions, 3:210-212
a497 binding perturbations, 1:544 biosynthesis and metabolism,
side effects profile, 6:493 Neu5Ac2en 3908-209
Neflinavir structure-based design, 1:451 structure, 3208
anti-HIV drug, 5475-476 Neumega, 3:266 X-ray crystallographic studies,
Nefrolan, 3:83 Neupogen, 3263 1:492
Negative-contrast radiocontrast Neural networks, See Artificial Neuropeptide Y antagonists,
agents, 4484 neural networks 3:212
Negative cooperativity, Neuraminidase inhibitors, Neuropeptide Y inhibitors,
2:296-297,2:304-305 1:717,2:208,2:240 1:671, 1:673, 1:674
Negative monographs, over-the- flexible docking studies, 1:265 Neuropeptide Y receptors,
counter drugs, 4425,4:426 PMF function application, 3:209-210
Negative symptoms, of schizo- 1:314 Neurophysin, 3:199,3:200
phrenia, 6:602 Screenscore application, 1:319 Neuroreceptors
Neighborhood behavior, 1:211 target of structure-based drug allosteric protein target,
Neisseria design, 1:450-452 2:314,2:315
penicillin-binding protein, X-ray crystallographic studies Neurotensin, 3:229,3:230
5:614,6:616,5:617 [int B virus], 1:491 Neurotransmitter binding pro-
Nelfinavir, 1:648 Neurodegenerative conditions, teins, 2:335
asymmetric synthesis, 6:674-676 Neurotransmitters. See also spe-
1:817-818 and cellular energetics, cific neurotransmitters,
and CXCFU, 4:167 6:679-689 such as Dopamine
CYP3A41517. . substrate. 4627 DNA damage and repair, bioactivation, 2:500
P-glycoprotein substrate, 6:677-679 and sleep, 6:225,6:227-228
4631 necrosis and apoptosis, Neurotransmitter transporters,
selective toxicity, 5267 6:676-677 6:498-499
structure-based design, 1:440, nitric oxide synthase inhibi- Neutralase, 2:215-216,2:220
1:442 tors, 6:695-706 Neutral endopeptidase (NEP),
Nembutal, 6204 NMDA receptor antagonists, 1:650-651,3:134
Nemonapride, a 6 4 1 6:689-695 Neutral endopeptidase inhibi-
Neodorphins, 6:357, a 3 5 8 Neurofibrillary tangles, 6:744 tors, 3:134-138
NEOGENESIS, 2:52 Neurogenic inflammation, 3:223 natriuretic peptides, a218
Neohesperidin Neurokinin A, 3:221 Neutral protamine Hagedorn,
rotavirus antiviral, 5431 Neurokinin A receptor, 3:222 46,47
Neohydrin, 3:67,3:70 Neurokinin B, 3:221 Neutral red
Neomycin, 1:870, 1:871, Neurokinin B receptor, 3:222 hepatitis C antiviral, 5:417
2:176-177,5:748 Neuroleptic malignant syn- NeuTrexin
selective toxicity, 5260-261 drome, 6:607-608 antimetabolite, 5:76
structure-activity relationship Neuroleptics, 6:600. See also Neutrophilic granulocytes,
of rings I and I of both sub- Antipsychotic agents 3252, 3:253
classes, 2:177-183 molecular modeling, 1:150 and granulocyte-colony stimu-
toxicity, 2:184-185, 2:615 Neuromedin-B, 3:229 lating factor, 3:262-264
Cumulative Index

and granulocyte-macrophage Nicorandil, 3:13,3:15, 3178 activation mechanism,


colony stimulating factor, Nicorette, 4452 2:366-368
3:259 Nicospan, 3:368 agonists, 2:393
Neutrophils Nicostatin, 3:350,3:368 agonists for Alzheimer's dis-
and adaptive immunity, 5:225, Nicotinamide (vitamin B,) ease, 6:764-765
5227 analogs tested in pellagra,&690 antagonists, 2:382-384,
chemokinelcytokine receptors, and cellular energetics, 2:394-397 7
4133 6:687-689 and autosomal-dominant noc-
and innate immunity, 5:224 complexation with aromatic turnal frontal lobe epilepsy,
Neutrophil trafficking, 2:106 drugs, 2:670 2:392-393 -
Nevirapine NAD glycohydrolase inhibitor, calcium effects on, 2:386-387
allosteric effector, 2:314,2:315 a686
cation-selective, 2:360
anti-HIV drug, 5472 PARP inhibitor, 6:680, a686
and cognition enhancement,
large scale synthesis, 2:408, radiosensitizer, 5184
6:797-811
2:412,2:420-429 Nicotine, 6:41
selective toxicity, 5:267 and Alzheimer's disease, a764 genes, 2:358
New chemical entities, 2:38 analogs and congeners as cho- M2-M3 loops, 2:367-368
stagnation of growth in, 2:534 linergics, 6:49-57 and smoking cessation agents,
New Drug Application, 2:688, derivatives as cognition en- 4455-457
2:698-700 hancers, 6:797-806 structure and topology,
Abbreviated, 2:742 inhibitor of amyloid P-peptide 2:358-368
Accelerated Approval, 2:700 aggregation, 6:758 subunit genes in man, 2:359
and in-process controls, 2:418 peripheral pharmacological Nicotinic acetylcholine recep-
over-the-counter drugs, 4424 actions, 4455 tors, muscle-type, 6:42
percentage passing phase I of pharmacological action, 4454 acetylcholine binding region,
IND, 2:695 possible protective effect in 2:364
Priority Review, 2:698,2:700 Parkinson's, 6:717, antagonists, 2:382-384
process flow chart, 2:699 6:718-719 binding-gating problem,
solid-state physical require- structure-activity relationship, 2:368370
ments of drugs, 2:414 4455 calcium effects on, 2:386-387
Standard Review, 2:698,2:700 Nicotine addiction, 2:358 channel blocker antagonists,
New Jersey Genetic Privacy Act, Nicotine dependence, 4450 2:383
4644 neurological basis of, competitive blocker antago-
NF1 gene, 5:27 4454-455 nists, 2:383
NGD91-3,6:580 Nicotine (gum), 4451,4452 conotoxin antagonists,
NGD 94-1, 6:40,6:41 adverse effects, 4451 2:395-396
Niacinamide, 4:394, 4396 classification in various coun- desensitization, 2:371
Niacin equivalents, 4361 tries, 4430 diliganded receptors,
Niacin (vitamin B,), 3:343, development of, 4457 2:373-374
3349-350,3:366, pharmacokinetics, 4453 epsilon subunit mutations,
4392-394 Nicotine (patch), 4451,4452 2:377-379
deficiency, 4 3 9 4 3 9 5 adverse effects, 4451 extracellular part, wooden
Dietary Reference Intakes, classification in various coun- model of, 2:364
4397 tries, 4430 function and structure,
and folic acid, 4405 pharmacokinetics, 4:453 2:368-384
hypervitaminosis niacin, Nicotine replacement therapy, function measurement meth-
4395-397 4:451 ods, 2:370-371
metabolism, 3:357-358 Nicotinic acetylcholine receptor macroscopic currents, 2:379
side effects, 3355 agonists membrane-spanning pore,
uptake and metabolism, 4394 for Alzheimer's disease, 2:362
vitamin status assays, 4:366 65'64-765 molecular architecture,
Niaprazine, 6:213, 6:214 Nicotinic acetylcholine receptor 2:360-361
Niaspan, 3:343,3:350 antagonists, 2:394-397 monoliganded receptors,
Nicardipine, 3:22 Nicotinic acetylcholine recep- 2:374-375
bioavailability and half-life, tors, 6:41-43 mutations, 2:375-382
3:23 acetylcholine binding region, rate constant fitting,
cardiovascular effects, 3:26 2:364366 2:371-373
Cumulative Index

Nicotinic acetylcholine recep- Niftifine Nitric oxide


tors, muscle-type (Continued) selective toxicity, 5268 binding to hemoglobin, 3386,
single-channel conductance, Nifurtimox 3:387
2:387 for American trypanosomiasis cardioprotection role, 3:46
snail ACh-binding protein, (Chagas' disease), hyperglycemia effect on, 4 4 -
2:362-364 5:1046-1047 from nitratelnitrite vasodila-
structure, 2:358-362, Nigericin tors, 311-12 P
22368384 antimalarial, 5991 reduction in hyperglycemia,
vestibules, 2:361-362 Night-eating syndrome, 6:840 44
wild-type, 2:373 Nigrin b, 2:263 role in contrast media toxic -
Nicotinic acetylcholine recep- NIH 10498 effects, 4:549
tors, neuronal, 2:358, experimental smoking cessa- role in erections, 4:445,4:449
2:384-386,6:42 tion agent, 4459 scavenging by hemoglobin,
acetylcholine binding region, Nikkomycins, 5:906 3:401-402
2:364 Nilandron, 3:720 and sickle-cell anemia,
agonists, 2:393394 Nilutamide, 3:717,3:720 3:462-463
and autonomic ganglia, 2:385, Nilvadipine, 3 2 2 Nitric oxide NMI-870,4450
2:388 bioavailability and half-life, Nitric oxide synthase, 1:736,
biophysical properties, 3:23 3779, a695
2:386-388 cardiovascular effects, and erection, 4445
calcium effects on, 2:386-387 326-27 Nitric oxide synthase I1
and central nervous system, Nimesulide, 4241 plasmid DNA-mediated gene
2:389392 Nimetazepam, a207 therapy study, 4653
and cochlea, 2:385,2:387, Nimodipine, 3:22 Nitric oxide synthase inhibitors,
2:389 bioavailability and half-life, 1:738-739,3:420,
conotoxin antagonists, 2:396 3:23 6:695-706
inward rectification, 2:388 cardiovascular effects, 3:27 Nitriles
membrane-spanning pore, Nimorazole radioprotective agent,
2:362 radiosensitizer, 5:178-179 5:162-163
and peripheral nervous sys- Nipecotic acid analog anticon- residues in pseudopeptide ar-
tem, 2:388 vulsants rays, 2:12,2:13
physiological role, 2:388-392 ADME, 6:286-291 Nitrilotriacetate
single-channel conductance, Niravoline radioprotective agent, 5163
2:387-388 analgesic, 6:389 Nitrites
Nicotinic acid antihyperlipi- Nisoldipine, 3 2 2 antispasmodic, 6:111
demic agents bioavailabilityand half-life, 323 as vasodilators, 3:ll-15
ADME, 3357-358 cardiovascular effects, 3:27 Nitrobenzamide
clinical applications, Nitidine anti-HIV drug, 5469, 5470
3:349350 dual topoisomerase IlII inhibi- 9-Nitrocamptothecin
marketed agents, 3:343 tor, 5 7 3 antitumor natural product,
side effects, adverse effects, Nitracine 5133
drug interactions, and con- radiosensitizer, 5179-180 6-Nitrodopamine
traindications, 3:355 Nitracine N-oxide, 5:84,5:85- nitric oxide synthase inhibi-
structure-activity relationship, Nitrate reductase, 3 1 5 tors, 6:705
3:366-367 Nitrates Nitrofurans
Nicotinic acid prodrugs, 2:505 pharmacokinetics and toler- systemic antibacterial,
Nicotinic receptor family, 2:360 ance of organic, 3:15 5594-596
Nicotrol, 4452 as vasodilators, 3:ll-15 Nitrogen mustards
Nicotrol inhaler, 4452 Nitrazepam, a207 alkylating agents, 552,
Nicotrol NS, 4452 ADME, 6:282 5:53-57
Nifedipine, 3:22, 3:160,3:170 anticonvulsant, 6:266, 6:267, minor groove targeting,
bioavailability and half-life, 6:307 557-59
323 side effects, a277 sickle hemoglobin modifiers,
cardiovascular effects, 3:26 Nitrendipine, 3:22 3:461
CYP3A41517 substrate, 4627 bioavailability and half-life, Nitrogen oxidation and reduc-
vascular-to-cardiac selectivity 3:23 tion
ratio, 3172 cardiovascular effects, 3:27 in metabolism, 2:445-447
Cumulative Index

Nitroglycerine Nocardicin C, 5:660,5:661, Non-peptide peptidomimetics,


for pain relief after myocardial 5663 1:636, 1:657-674,4:72
infarction, a165 Nocardicin D, 5661, 5663 Nonpolar interactions, See van '
pharmacokinetics, 3:15 Nocardicin E, 5661, 5:663 der Wads forces
Nitroimidazoles Nocardicin F, 5:661,5:663 Non-prescription drugs, 4423,
binding to hypoxic cells, Nocardicin G, 5:663 4424
5:180-182 Nocardicins Nonreceptor tyrosine kinases,
radiosensitizers, 5177 biological activity, 5663-664 524-25
Nitroimidazopyrans synthesis, 5660-663 Nonsolid oral dosage forms,
antimycobacterial application, Nocistatin, 6:357 2:654 -
5:858-859 Noctal, 6:205 Nonsteroidal anti-inflammatory
NitroMed, 4450 Noctamid, 6:207 drugs
6-Nitronorepinephrine Noctec, 6:209 for Alzheimer's disease, a767
NoDoz, e l 7 0 COX-2-selective, 2636-87,
nitric oxide synthase inhibi-
NOE, See Nuclear Overhauser 4:242-244
tors, 6:705
effects (NOE), in NMR and decreased cancer risk,
N-Nitroso-N-phenylhydroxy- Nolatrexed, 1:428 5:34
larnine antimetabolite, 576, 5:79 development of, 4:230
radioprotective agent, 5163 Nolvadex, 3:343,3:632 first tier of cancer pain treat-
Nitrosureas selective toxicity, 5276 ment, 6:332333
alkylating agents, 554, Nomegestrol, 3:654 lesions caused by, 2510
564-65 in contraceptives, 3:654 and ulcers, 4:91-92
S-Nitrosylated PEG-hemoglobin Non-Boltzmann sampling, 1:100 Nonstructural chemical data,
@NO-PEG-Hb),3:419 Nonclassical bioisosteres, 1:373
5-Nitrouracil 1:690-694 Nonsynonymous single nucleo-
PARP inhibitor, 6:681 Nonclassical resolution, of chiral tide polymorphisms, 4620
Nitroxides molecules, 1:799-804 Nontuberculosis mycobacteria,
radioprotective agent, 5171 Non-clathrin coated endocytosis, 5:814,5:824
Nivalin, 1:892 2:260 N-Nonyl deoxynojirimycin,
Nivaquin, 5934 Noncompetitive inhibitors, 2:222-223,2:226
Nizoral, 5890,5891 1:730-731 No observed adverse effect level
NK 109 Noncovalent bonds, 1:6,1:170 (NOAEL), 2:613,2:620
dual topoisomerase ID1 inhibi- energy components for inter- Nopron, 6:214
tor, 5:73 molecular drug-target bind- 8-(Noradamantan-3-y1)-1,3-
NK receptor antagonists, ing, 1:171-174 dipropylxanthine, 3:122
1:669-670, 1:672 Noncovalently binding enzyme Noradrenaline,See Norepineph-
NLP-1 inhibitors, 1:720-754 rine
radiosensitizer, 5:179 Non-GPCR-linked cytokine re- Noradrenergic-selective re-
NMDA receptor antagonists, ceptors, 2:334 uptake inhibitors, 6:486.
6:689-695 Non-insulin dependent diabetes See also Norepinephrine-
analgesics, 6:449 mellitus, See Diabetes melli- selective reuptake inhibitors
antidepressants, 6516 tus, type 2 Norapomorphine
NMDA receptors, 2:386-387 Nonisosteric bioanalogs, alkyl chain homologation ana-
and anxiety, 6546 12689-694 logs, 1:701
and schizophrenia, 6:604 Nonlinear QSAR models, Norbolethone, a710
NMR, See Nuclear Magnetic 1:28-29 Nordazepam, 6:207
Resonance (NMR) spectros- descriptor pharmacophores, Norepinephrine, 6:2
COPY 1:62-63 and anxiety, 6x543444
NMR timescale, 1537 Nonlinear regression, 1:67 applications, 6:9
NMSO3,5:394 Non-melanoma skin cancer, biosynthesis, storage, and re-
NN-703, 1:671, 1:675 4465 lease, 6:22-25
Nocardamine, 3:483,3:486, Non-monograph status, over- and body weight, 6:855
3524 the-counter drugs, 4425 general adrenergic agonist,
synthesis, 3527-528 Nonnucleoside HIV reverse 6:3
Nocardicin A, 5:660,5:661, transcriptase inhibitors, inhibition by depressants,
5663-664 5472-473 6500
Nocardicin B, 5:661, 5663 Non-overlapping mapping, 1:398 metabolism, 6:16-17
Cumulative Index

Norepinephrine (Continued) 19-Nortestosterone, 3:702-703 NS-2359


physiological significance, anabolic activity, 3:716 experimental smoking cessa-
621-22 North American Free Trade tion agent, 4:459
role in CNS stimulant action, Agreement (NAFTA), 2:780 NS-2710,6:580
6:183-184 and patent interference, NS-3623
role in CNS stimulant effects, 2:736-737 sickle hemoglobin hydration
6:181,6:183-184 and trade secrets disclosure, agent, 3:461 P
Norepinephrine-selective re- 2:768 NSC-65106,4155
uptake inhibitors, 6:486, Northern blot, 2:621 NSC-356894, 6:490
6:494,6:496 hybridization with DNA mi- N-type calcium channels, 3:7
combined with dopamine re- croarrays, 4603-604 Nubain, a335
uptake inhibitors, 6:885 Nortriptyline Nuclear factor-erythroid 2 (NF-
serotonin-selected contrasted, affmities for monoamine re- E2)
a501 ceptors, 6:495 and sickle-cell anemia, 346'7
structure-activity relationship, antidepressant, 6:485,6:486, Nuclear hormone receptors
6:510,6:511-512 6:487 focused screening libraries
Norepinephrine transporter, CYP2D6 substrate, 4627 targeting, 1:250
6:498-499 dose for eating disorders, transcription regulation by
inhibition by antidepressants, 6:851 thyroid hormones, 3:567
6:500 for eating disorders, a 8 5 8 Nuclear Magnetic Resonance
Norethandrolone, 3:707 inhibition of serotonin, norepi- (NMR) imaging, 1:510
anabolic activity, 3716 nephrine, and dopamine radiopaques for, 4487,
Norethindrone, 3:632,3:650, transporters, 6:500 4:490-492
3:666 pharmacokinetic parameters, Nuclear Magnetic Resonance
biotransformation, 3:641 6:497 (NMR) screening methods,
in contraceptives, 3:654 side effects profile, 6:493 1~510,1:562-577
interactions with steroid re- Norvir capacity issues, 1:190
ceptors, 3:633 structure-based design, 1:438, Nuclear Magnetic Resonance
reactions of, 3604-605 1:440 (NMR)spectroscopy, 1:351,
Norethisterone, See Norethin- Nostructure, 1:410 1:507-514, 1:592. See also
drone NOT logical operator, 1:406 SAR-by-NMR approach
Norethynodrel, 3:632,3:666 Novaltropine, 6:117 applications, 1:516-517
interactions with steroid re- carbohydrate-based drugs,
Novantrone
ceptors, 3:633 2232
topoisomerase I1 inhibitor,
Norfloxacin, 1:41, 1:42 chemical shift mapping,
antimalarial, 5:936,5:983 6:68
1:543-545
Norgestimate, 3:632,3:667 Novastan, 3:29,3:286 instrumentation, 1:514-516
interactions with steroid re- Novobiocin with LC-MS, 1:608
ceptors, 3:633 NAD glycohydrolase inhibitor, ligand-based design, 1:510,
Norgestrel, 3:632, 3666-667 6:686 1:517-532
biotransformation, 3:641 Novoderm, 2:550 macromolecule-ligand interac-
interactions with steroid re- Novolin, 4 7 tions, 1:510, 1:517,
ceptors, 3:633 Novolog, 4 7 1:535-562
Norinyl, 3:632 NovoSeven metabolic, 1:510
Normethandrone, 3707 hemostatic preparation, 3:292 metabonomics application,
anabolic activity, 3716 Novrad 2:623
Normison, 6:207 selective toxicity, 5269-270 and molecular modeling, 1:78
Normodyne, 3:28,6:5 Novurit, 3:67 multidimensional, 1:512-514
Nornicotine, 6:49 Noyes-Whitney equation, 2:658 for pharmacophore modeling,
Noroxyphenonium, a 1 2 3 NP-27,5:891 1:531-532
Norplant, 3:632 NPS-1407, 1:812, 1:815 receptor-based design, 1:510,
Norpramin, a485 NPS-1776 1:532-562
dose for eating disorders, anticonvulsant, 6:312 recombinant DNA applica-
6:850 N-ras protein, 5:22,6:24 tions, 2:96
Norstatine, 1:652 NREM sleep, 6224-225 in structure-based drug de-
18-Nortestosterone, 3:707 NS-398, 4241, 4242 sign, 1:419, 1:516-517
Cumulative Index

and structure-based library Nucleoside reverse transcriptase structure-activity relationship,


design, 1:225 inhibitors 4469
structure determination of nevirapine synthesis, 2:408, sunscreen, 4:460
bioactive peptides, 2:420-429 Octyl salicylate
1:517-518 Nucleotide-excision repair, 6:677 absorption and disposition,
structure elucidation of natu- Nucleotide intercalation, 1:183 4463
ral products, 1:517-518 Nucleus factor of activated T- structure-activity relationship?
use in solid phase organic syn- cells (NFAT), 4173 4468
thesis, 2:7, 2:30 Nucleus tractus solitark, 6:873 sunscreen, 4460
and virtual screening, 1:244 Numorphan, 6:334 Oculoselectivity, 2:520 -
Nuclear Magnetic Resonance Nuvance, 4176 Ocupress, 6:5
(NMR) titrations, 1:545 NW-1015 Off-label use
anticonvulsant, 6:312 lifestyle drugs, 4431
Nuclear Overhauser effect
Nydrazid, 5:810 Ofloxacin, 6:853-855
(NOE) pumping, 1:573
Nystatin, 6:889,5:893 Ogen, 3:632
Nuclear Overhauser effects OGT-918,2:218,2:220,2:240
formulations and indications,
(NOE),in NMR, 1:511, 5:891 4-OHA, 3:727
1:512 Ohmfentanyl, 6:383,6:384
for conformational analysis, 0 (graphics program), 1:478 OiVwater partitioning system
1:525 Obe-Nix 30-P, a 1 7 1 partition coefficient character-
and distance range matrix, Obesity, 6:838,6:839-840. See ization, 2:655-656
1:136 also Anti-obesity drugs OKT3,2:239
for macromolecular structure CNS stimulants for, 6:173, Olanzepine
determination, 1:533 &I93 dose, 6:601
and NMR screening, comorbidities associated with, for Parkinson's disease, a 7 2 5
1:571-573 6:840 receptor binding and side ef-
NOE docking, 1:545-546 guidelines for treatment, fects, 6:606
transferred NOE technique, a842 OLAP (OnLine Analytical Pro-
1:532 and insulin resistance, 4 3 cessing), 1:390, 1:408
Nuclear pore complex, 4662 Object-oriented language, 1:407 Old tuberculin, 6:818-819
Nuclear receptor boxes, 4 2 7 Object relational database, 1:407 Oleamide, 6:254-255
Nuclear receptor corepressor, Obsessive-compulsive disorder, Oleandomycin, 1:870, 1:871
3:567 6:527 Oligomycin
Nuclease-resistant ribozyme OC 144-093,2:21-22,2:24 renal and hepatic toxicity,
drugs, 2:119-120, OCA-983,5:709 2:615
2:147-148 Occular absorption Oligonucleotide conjugates,
Nucleases prodrugs, 2:519-521 2~147-150
and antisense technology, Occupancy theory, receptors, Oligonucleotide ligation assay,
2:116 2~323-326 4625-626
Nucleic acid receptors, 1:5 Ocreotide, 1:657 Oligonucleotide microarrays,
Nucleic acids. See also DNA, Octamethylpyrophosphoramide 4601-606
RNA (OMPA), 6:91,6:92 Oligonucleotide therapeutics,
biochemical force fields, OctanoVwater partitioning sys- 2:115-120. See also Anti-
1:175-176 tem, 1:16-17 sense oligonucleotides;
effects of oligonucleotide ther- partition coefficient character- Phosphorothioate oligonu-
apeutics on, See Oligonucle- ization, 2:655,2:656 cleotides
otide therapeutics predictor of aqueous solubil- backbone modifications,
NMR structural determina- ity, 2:657 2:150-152
tion, 1:535 predictor of permeability, binding and effects of binding
as targets for toxicity, 2:616 2:659 to nonnucleic acid targets,
Nucleic acid vaccines, 4657 Octocrylene 2:121-122
Nucleoside arrays, 2:6 absorption and disposition, combinatorial approaches,
multiple parallel synthesis, 4:463 2:120
2:13,2:14 sunscreen, 4460 "control oligonucleotides,"
Nucleoside HIV reverse tran- Octyl methoxycinnamate 2:122
scriptase inhibitors, absorption and disposition, heterocycle modifications,
5:470-472 4462,4:463 2:144-147
Cumulative Index

Oligonucleotide therapeutics Ondansetron, 6:573 Opioid antagonists, 6:333


(Continued) cognition enhancer, 6:813, delta-receptor selective,
kinetics of effects, 2:122 6:815-816 a367370
medicinal chemistry, 2:120, nonclassical resolution, 1:802 kappa-receptor selective,
2:143-153 ON0 1078,4224-225,4226 6:365-367
proof of mechanism, ON0 4057,4228,4229 opioid receptor affinities,
2:120-123 ON0 RS-411,4224,4226 6:348 P
purity, 2:120-121 OP2000,2:216,2:220 structure-activity relation-
and ribozymes, 2:119-120 OPC-4392,6:650 ships, 6:364-370
and RNA structure, 2:121 OPC-14597, 6:650 Opioid bowel dysfunction, a337 _
RSV antiviral agents, OPC-21268,3:201 Opioid peptide analogs,
Ek396-397 OpenBabel, 1:372 6:407-409
strategies to induce transcrip- Open Molecule Foundation, from amphibian skin,
tional arrest, 2:118-119 1:360 6:409-410
structure, 2:121 Open reading frames P-casomorphin analogs,
sugar modifications, housing in DNA databases, 6:422-425
2:150-152 1:338 deltorphin analogs, 6:432-437
terminating mechanisms, Opioid agonists, 6:333 dermorphin analogs,
2:122 delta-receptor selective, 6:428-432
variations in in vitro cellular 6:395-400 dynorphin analogs, 6:418-422
uptake and distribution, kappa-receptor selective, endomorphin analogs,
2:121,2:132-133 e387-395 6:422-425
Oligosaccharide arrays, 2:6 opioid receptor affinities, enkephalin analogs,
multiple parallel synthesis, a348 6:410-418
2:13,2:14 Opioid analgesics, 6:331-333 other peptides with high affin-
Olivomycin, 2:221,2:226 ADME, 6:339-341 ity for opioid receptors,
OLTP (OnLine Transaction Pro- central nervous system, 6:341 6:437-440
cessing), 1:390, 1:408 currently used drugs, 6:333, peptidase inhibitors,
OM991 e334-335 6:440-443
for Alzheimer's disease, 6:754 cytochrome P,,, substrates peptide affinity label deriva-
OM992 and inhibitors, a 3 3 9 tives, 6:440
for Alzheimer's disease, 6:754 endogenous opioid peptides, TIPP and related peptides,
Omaciclovir 6:341-354 6:425-428
for herpes virus, 5310 future developments, with Tyr-D-aa-Phe sequence,
6:448-450 6:428-437
Omapatrilat, 1:651
history, 6:358-360 Opioid-receptor-like 1 (ORL1)
OMEGA, 1:255
miscellaneous nonpeptide opi- receptor, 6:341-342,6:358,
Omeprazole, 2:516 ates, 6:407 6:444
antimalarial, 5:989 radioligand binding assays, nonpeptide ligands for,
CYP2C19 substrate, 4627 6:344-347 6:447-448
with quinine, Ek936 recent developments, Web resources dealing with,
Onapristone, 3:651 6:443-448 a451
Onchidal receptor types, 6:341-354 Opioid receptors, 6:331. See also
anticholinesterase, 6:94 side effects, adverse effects, Delta opioid receptors;
Onchocerciasis, 5:1035 and drug interactions, Kappa opioid receptors; Mu
Oncogenes, 6:3,5:21-26 6:333-339 opioid receptors
targeting loss of function, signal transduction mecha- characterization, 6:343-350
Ek44-45 nisms, e342-343 cloning, 6:341-342,6:350
transcription factors as, soft drugs, 2:544-547 computational models, 6:352
Ek25-26 structure-activity relation- dimerization, 6:354,
types of, 5:22 ships of nonpeptide ligands, 6:443-444
Oncologic, 2:621 6:360-407 mutagenesis studies,
Oncostatin M, 3:269 in vitro efficacy assays, 6:351-352
Oncovin 6:347-349 nomenclature, a 3 4 1 3 4 2
antitumor natural product, in vivo evaluation, 6:349-350 nonpeptide affinity labels used
5:142 Web resources, 6:450-452 to study, 6:400-407
Cumulative Index

signal transduction mecha- Organmercurial diuretics, Orphenadrine


nisms, tk342-343 3:64-66 for Parkinson's disease, 6:731,
splice variants, 6:352-354 Organoarsenical agents, 1:717 6:732
structure and molecular biol- Organ transplantation, Orpisin, 3:124
ogy, a 3 5 0 3 5 4 5~486-487 Ortho-Cept, a632
subtypes, 6:331,6:352-354 recent developments, Ortho Cyclen-21, 3:632
Opium, 1:848, 1:849, 6:331, 5523626 Orthogonality, 2:14 P
6:358-359 trends in management of, Ortho-Novum, 3:632
OPTCOL method, 5:381 5:487-489 Orthopoxviruses, 5:435-437
Optimization approaches Organ transplant drugs antiviral agents, 5:435-440
for combinatorial library de- agents blocking nucleotide Orthovisc, 2:211
sign, 1917-220 synthesis, 5:513-523 Oseltarnivir, 1:452, 1:717,
OptiPranolol, 6:5 agents blocking T-cell func- 2:208-209, 2:212, 2240,
OptiSim method, 1:207 tion, 5:489613 5:361
and combinatorial library de- clinical use, 5:489 for influenza, 5:368-372
sign, 1:220 recent developments, selective toxicity, 5266, 5:267
Optro, 3:398,3:400, 3:408-412 k523-526 Osmitrol
clinical trials, a399 Organ transplant rejection, osmotic diuretic, 3:64
Oracle, 1:373 5:486-487 Osmoglyn
Oral dosage form t-cell's role in, 5:487-488 osmotic diuretic, 3:64
Biopharmaceutics Classifica- Orgaran, 3:29,3:286 Osmotic balance, 2:613
tion System, 2:665-666 Orientation map (OMAP), Osmotic diuretics, 3:63-64
Class I: high solubility high 1:131, 1:144, 1:146 OSPPREYS (Oriented-substitu-
permeability, 23665-667 Oriented-substituent pharma- ent Pharmacophore PRop-
Class 11:low solubility high cophores, 1:224 ErtY Space), 1:199, 1:224
permeability, 2:667-671 Orinase, 4:12 Osteoarthritis
Class 111: high solubility low Orlaam, a 3 3 4 COX-2 inhibitors for,
permeability, 2:674-676 Orlistat, 1:848, 1:849 4248-249
Class IV:low solubility low absorption and metabolism, Osteoblasts, 4376,4377
permeability, 2:667,2:676 6:860 Osteoclasts, 4376,4:377
Class V: metabolically or dose, 6:844 Osteomalacia, 4376
chemically unstable com- side effects, 1:859 Osteoporosis, 4376-377,5273
pounds, 2:667,2:676-678 structure-activity relation- Ouabain
development strategies, ships of analogs, 6:880-881 suppression of arrhythmias
22665-679 OR logical operator, 1:406 caused by, 3:174
excipient and process selec- use in molecular similarity1 Outward-rectifying Kf current,
tion, 2:678-679 diversity methods, 1:194 3:7
lipid technologies, 2:671-674 Ormaplatin Overexpression, 2:74
nonsolid form selection, 2:654 alkylating agent, 5:54,5:59 Overlapping mapping, 1:398
physicochemical property Ornidyl, 4440 Over-the-counter Drug Fads
evaluation, 2:654-665 Ornipressin, 3:200 label, 4428, 4:429
solid form selection, Ornithine decarboxylase Over-the-counter Drug Review,
22650-654 genetic variability in expres- 2:687,4424-426
Orap, 6:601 sion, 5:7 classification after, 4426-427
Oratrol, 3 7 0 Ornithine decarboxylase inhibi- reclassification criteria for Rx-
Orexin A, 6:872 tors, 1:717, 1:766, 1:768, OTC, 4427-428
ORF 74,4171 1:769 Over-the-counter drugs,
ORG-2058, a666 for hair growth inhibition, 4422-423. See also Life-
interactions with steroid re- 4436-437 style drugs
ceptors, 3:633 Orphan Drug Act, 2:687,2:771 classification in Europe,
ORG-5020 Orphanin FQ/Nociceptin, 6:342, 4428-430
interactions with steroid re- 6:357,6:358,6:444-445 classification in Japan,
ceptors, 3633 structure-activity relationship, 4430-431
ORG-12962,6:572,6:581,6:886 6:446-447 classification in US.,
Organ clearance, 2:636-637 Web resources dealing with, 4424-428
Organic structure databases, 6:451 current and future trends,
1:385 Orphan receptors, 2:334-335 4473-475
Cumulative Index

Over-the-counter drugs (Contin- Oxcarbazepine oxygen


ued) ADME, 6:275, 6:286 binding to hemoglobin A,
hair growth disorder drugs, anticonvulsant, 6:265,6:268, 3:386,3:446
4433-440 6:269,6:298,6:306 binding to sickle hemoglobin,
and self-medication, 4423 clinical efficacy, a 2 7 3 3:445-446
sexual disorder drugs, development, 6:302-303 Oxygen extraction, 38-9
4440-450 dose, 6:270 Oxygen sensors P
smoking cessation agents, pediatric indications, a274 for cellular proliferation as-
4450 - 458 side effects, 6:279 says, 2:50
sunscreens, 4458-472 Oxendolone, 3719 Oxygen supply -
Ovral, 3632 Oxiconazole, 5:904 and hemoglobin, 3386
Ovulation formulations and indications, myocardial, 3:8-9
modulation of, 3:654-655 $891 Oxygent, 3:422-423
OWFEG (one window free en- Oxidase tumor-activated pro- clinical trials, 3427
ergy grid) method, 1:308, drugs, 5:91 pharmacokinetics, 3423
1:315 Oxidation pharmacology, 3425- 426
Oxacephalosporins, 5:652-654 carbon in metabolism, Oxyglobin
1-Ox-acephalothin,$652 2~441-445 clinical trials, 3:399
Oxacephems, $652-654 enzyme-mediated asymmetric, Oxyhemoglobin, 3:387
brief description, $609 1:806 in sickle-cell anemia,
Oxacillin, $631 nitrogen in metabolism, 3:447-448
biliary excretion, $623 2:445-447 Oxymesterone, 3:710
p-lactarnase classification sulfur in metabolism, Oxymetazoline
based on activity, 5:619, 2:447-448 a,-agonist, 6:3
5:620,6:621 P-Oxidation applications, 6:13
pharmacokinetics, 5:624 in metabolism, 2:460-461 structure-activity relationship,
1-Oxadethiacephems,5:652-654 Oxidative cleavage 6:30-31
Oxaliplatin in metabolism. 2:448-449 Oxymetholone, 3710
alkylating agent, 5:54, Oxidizing agents anabolic activity, 3:716
$59-60,5:61 topical antibacterials, Oxymorphone, 6:363
Oxamic acid thyromimetics, 5:551-552 dose, 6:334
3582-583 Oxidoreductases Oxyphencyclimine
Oxamniquine and drug metabolism, 2:439 anticholinergic, 6:136
antihelmintic, $1091, $1095 target of structure-based drug relative anticholinergic activ-
Oxandrin, a 8 5 4 design, 1:445-449 ity, 6:157
Oxandrolone, 3:706,3:711, Oximonam, 6:666,5:668 Oxyphenonium
3714 in vitro activity, $667 anticholinergic, e l 3 7
anabolic activity, 3:716 Oxistat, 5:891 mydriatic and cycloplegic ac-
dose, 6:854 8-Oxodeoxygenase, 2:616 tivity, 6:153
metabolism, 6:867 3-(3-0~0-17p-hydroxy-4-andro- relative anticholinergic activ-
for wasting, 6:858, 6:860 sten-17-a-y1)-propanoicacid ity, 6:156
Oxapenams, 5:609 lactone, 3114 Oxytetracycline, 1:870,2:185,
Oxazepam, 2:618,6:530 1-Oxoisoindolines,3544-85 2:186,5:740,$742
dose for anxiety, 6:529 Oxotremorine analog cholin- Oxytocin, 4 6 7
Oxazolam, 6:551-552 ergics, 6:71-78 structure activity relationship,
Oxazole residues Oxotremorine-M 467-68
in pseudopeptide arrays, 2:12 cholinergic, 6:75 Oxytocin antagonists, 466-69
Oxazolidinedione anticonvul- Oxprenolol Ozolinone, 3110
sants, 6:271 renal clearance, 1:38
ADME, 6:282-284 Oxybenzone P-1075
Oxazolidinones, $792-793 absorption and disposition, experimental hair growth
antimycobacterial application, 4:462 drug, 4 4 4 1
$859 sunscreen, 4:460 P53 gene, 5:27-29
combinatorial libraries, Oxycodone, 6:332,6:363 allosteric protein target,
2:20-21,2:22 dose, 6:334 2:314,2:315
systemic antibacterials, OxyContin, a 3 3 4 and drug resistance,
$587-594 Oxyfluor, 3422, 3423 5:287-289
Cumulative Index

gene therapy target, 5:44-45 Pancuronium Paramethasone, 3:750,3:797,


and prostaglandin synthesis, nicotinic receptor antagonist, 3:802
4232 2:384 Paramyxovirus fusion proteins
role in cell cycle, 5 1 6 Panic disorder, 6:527 antiviral agents, 5390-396
P509 Panipenem, 5:677,5:693 Paraoxon, 6:91,6:93
radiopaque material, 4:578 Pantoprazole Paraplatin
P. carinii DHFR, QSAR inhibi- CYP2C19 substrate, 4627 alkylating agent, 5:54 7
tion studies, 1:32-33 Pantothenic acid, 4400-401, Parasitic infections, 5:1035,
PA-505 4:403 51090. See also Malaria
antimycobacterial, 5859 Dietary Reference Intakes, Parasympathomimetics, See -
PA-824 4400 Cholinergics
antimycobacterial, 5859 hypervitaminosis pantothenic Parathion, 1:774,2:558,6:91,
Pacemaker cells, 3:4, 3:29 acid, 4401 6:93
uptake and metabolism, 4401 Parathyroid hormone
Pacific yew, paclitaxel from,
vitamin status assays, 4367 Alal and Val2 in signal trans-
1:861-862,5136
Pantothenol, 4401,4402 duction, 4 5 5
Paclitaxel, 1:843, 1:848,
1:861-863
Pantretin, 4320, 4:374 At-8' and w5 in receptor-
Papain ligand interactions, 4 5 5
antitumor natural product, QSAR studies, 1:5 and calcium reabsorption in
5:110,5:136-138 transition state analog inhibi- kidneys, 3:59
OC 144-033 enhances activity tors, 1:654 conformationally constrained
of, 2:22 Papaverine, 4:442,4:448,6:361 cyclic analogs of hPTH(1-
P-glycoprotein substrate, 4631 antispasmodic, 6:111 31)Amide, 458-59
with RSR13,5:190 Papaver somniferum (opium Gly12in receptor-receptor in-
selective toxicity of antibody poppy), 1:848, 1:849 teractions, 455-56
conjugate, 5258 Paper New Drug Application, structure-activity relationship,
with tirapazamine, 5:85 2:742 453-55
Pactamycin, 2:195,2:196 Papillomaviruses, 5:297, truncated analogs: minimum
Padimate A, 4468 5:301302 sequence requirements,
Padimate 0 antiviral agents, 5337-339 45658
structure-activity reiationship, D-Parabactin,3488, 3489 and vitamin D, 4:376
4468 L-Parabactin, 3:483, 3:485, X-ray crystallographic studies,
sunscreen, 4460 3~488-495 1:492
Pagoclone, 6:558-559 pM values, 3484 Parathyroid hormone-related
Pain, 6:331-333. See also Nar- synthesis, 3:522 protein, 453-54
cotic analgesics; Opioid an- D-ParabactinA, 3:489,3:492 Parecoxib sodium, 4241
algesics L-Parabactin A, 3:489,3:492 Paregoric, 6:337-338
cholinergics for, 6:41 Paracellular transport, 2:250, Parenteral administration
Pairwise interactions, 1:79-80 2:658 prodrugs, 2:514-515
Palivizumab, 5227,5395 Paracetamol Parent structure, 1:368, 1:404
PALLAS System, 1:389 peptide ester, 2:508 Pareto optimality, 1:220
Paludrine, 5934 Paracoccidioides brasiliensis, Paricalcitol, 4377, 4378
Paluther, 1:887,5:935 5:883 Paris Convention, 2:707, 2:711,
Pamaquine, 1:888-889,5950 Paracoccidioidomycosis, 5883 2:729,2:751-752
Pamelor Paracoccus denitrificans Parkin
dose for eating disorders, a851 iron uptake by, 3:488-495 and Parkinson's disease, 6:716
Pamine, 6:117 Parainfluenza virus, 5:390 Parkinsonian dementia, 6:78(1
Panadiplon, 6:564-565 antiviral agents, 5 3 9 0 3 9 8 Parkinsonism, (3712, 6:716
Pancreas transplantation, 5487 Parallel chemistry, 1:283 in Alzheimer's disease, 6:745
1-year survival rate, 5:488 Parallel library, 1:214 and MPTP (designer heroin),
Pancreatic P-cells, 4:2. See also Parallel processing, 1:408 6:717-721
Insulin and hypoglycemic Parallel track, in Investigational Parkinson's disease, 6:674,
agents New Drugs Application Pro- 6:712-713
Pancreatic polypeptides, cess, 2:689-690 cholinergics for, 6:41
3~208-209 Parallel track policy, of Investi- diagnostic agents for,
molecular modeling of avian, gational New Drugs Appli- 6:734-736
1:124 cation Process, 2:689-690 etiology, 6:715-721
Cumulative Index

Parkinson's disease (Continued) Parsidol Patent databases, 1:386


pathophysiology, 6:713-715 for Parkinson's disease, 6:731, Patent infringement, 2:709,
role of iron, 3504, 3505 65'32 2~740-743
role of manganese, 6:716,6:717 Partial agonists, 2:40 defenses to, 2:743-746
Parkinson's disease therapeu- Partial charge, 1:366, 1:373 discovery and trial process,
tics. See also L-Dopa Particle size reduction, 2:674 2:748-751
adenosine antagonists, 6:733 and dissolution rate, 2:658 remedies for, 2:746-748 'Z
anticholinergic agents, Particulates "reset" patents, 2:714
6:731-733 iodinated suspension ra- Patent interference, 2:735-738
catechol-0-methyltransferase diopaques, 4575-576 Patents, 2:704-710. See also -
(COMT)inhibitors, 6:731 Partition coefficients, 1:16-17, Prior art
dopamine D, receptor ago-
1:54 absolute novelty, 2:707,2:710,
nists, 6:726-728
characterization, 2:655-656 2:711-712
dopamine D, receptor ago-
Partition function, 1:94-95 best mode requirement,
nists, 6:725-726
dopamine potentiating agents, Partitioning algorithms, 1:67 2:723-724,2:727
6:729-731 Parvoviruses, 5:304-305 correction, 2:738-740
future directions, 6:736 antiviral agents, 5341-342 design patents, 2:770-771
L' enabling" requirement,
glutamate antagonists, Paser, 5:810
6:733-734 PASS, 1:291, 1:390 2:707-708,2:722-723,
monoamine oxidase inhibitors, Passerini reaction 2:727-728
6:729-731 use in solid phase organic syn- enforcement, 2:740 -751
serotonin agonists, a734 thesis, 2:15 first to invent us. first to file,
Parlodel Passive difhsion, 2255-256, 2:706,2:710-711
for Parkinson's disease, 6:722 2:658-659,2:665 geographic limitation, 2:708
Parnate, 6:485 in kidneys, 357-60 improvements of patented in-
for Parkinson's disease, 6:730 kinetics, 2256-257 ventions, 2:710,2:716
Paromomycin, 2:195,2:196 Patch-clamp method, 2:76 international agreements,
for leishmaniasis, 5:1051 Patentable subject matter 2:751-753
Parovirus B19,3:295 United States, 2:718-720 and multiple parallel synthe-
Paroxetine. 6530 worldwide, 2:720-721 sis, 2:30-31
affinities for monoamine re- Patent and Trademark Office no requirement for use of in-
ceptors, 6:495 (U.S.), 2:706
vention in US., 2:753
antidepressant, 6:485,6:486, delays in patents caused by,
novelty, 2:706,2:730
6:488 and term extension,
CYP2D6 substrate, 4:627 obviousness, 2:706,
2~714-715
dose for anxiety, 6:529 obviousness rejections, 2:731 2:730-732
dose for eating disorders, and patent interference, prosecution, 2:715-717
6:849 2:737-738 provisional applications,
for eating disorders, 6:857 patent term extension, 2:708 2:724-729
inhibition of serotonin, norepi- procedure for obtaining pat- reduction to practice, 2:711
nephrine, and dopamine ents, 2:733-735 requirements for, 2:718-740
transporters, 6:500 "special" application status, "reset," 2:714
pharmacokinetic parameters, 2:716 strategy, 2:709-710
6:497 Patent appeals, 2:717 term, 2:709,2:712-718
for premature ejaculation, 4443 Patent applications term extension, 2:714-715
side effects profile, 6:493 grace period, 2:707 and trade secrets, 2:766-767
PARP-1,6:679 publishing, 2:717-718 U.S. Patent Office procedure,
PARP-2,6:679 strategy, 2:709-710 22733-735
P U P - 3 , a679 Patent Citations Index, 1:386 worldwide, 2:751-754
PARP inhibitors, 6:680-686 Patent claims, 2:724 Patent searching, 1:383-384
P U P (poly(adenosine5'-diphos- interpreting, 2:743 Patent specification, 2:721-724
phateribose)polymerase), not required in provisional Pathilon, 6:139
a674 applications, 2:728 Pathways, 1:495-496
and cellular energetics, Patent Cooperation Treaty, X-ray crystallographic analy-
6:679-680 2:752-754 sis, 1:495-496
and DNA repair, 6:677-679 contracting states, 2:753 Patient package inserts, 2:687
Cumulative Index

Pattern recognition, 1:408 Pemoline, &I70 pharmacokinetics, 5623


and cluster analysis, 1:401 side effects, adverse effects, preventing bacterial degrada-
with QSAR, 1:53 and drug interactions, tion, 1:718
Pavatrine, a134 6:174-175 selective toxicity, 5:253-254,
Paxil, 6:485,6:529 Penarns 5260
dose for eating disorders, brief description, 5609 side effects and interactions,
6:849 P-lactamase inhibitors, 52624-625 T
Pazinoclone, 6:558-559 5:698-699 synthesis, 5629-630
PC 1358 Penbutolol Penicillin sulfoxide-cephalos-
experimental hair growth P-antagonist, 6:5 porin conversion,
drug, 4441 applications, 6:16 5646-649
PC cluster computing, Penciclovir Penicillin T, 5:629
1:283-284 for hepatitis B virus, Penicillin V, 5608,5609,5:629,
PCModels, 1:386 5:330331,5:334 5631
PD-117302 for herpes virus, 5307-308 Penicillin X, 5629
analgesic, 6:389,6:390 peptide ester, 2:508 Penicillipepsin inhibitors
PD-119229 Penems molecular modeling, 1:116
structure-based design, brief description, 5609 Penicillium, 5608
1~460-461 P-lactamase inhibitors, Penicillium brevicompactum,
PD-128763 5:698-699 1:879
PARP inhibitor, a 6 8 1 synthesis, 5654-659 Penicillium chrysogenum, 15369,
PD-138387,4246-247 Penetration enhancers, 5:609,5:628
PD-142893 2:251-252 Penicillium citrinium, 1:879
endothelin receptor antago- Penicillin Amendment of 1945, Penicillium notatum, 5628
nist, 3206 2:686 Pentaerythritol tetranitrate,
PD-145065 Penicillinase-resistant penicil- 3:13,3:14
endothelin receptor antago- lins Pentafuside
nist, 3:206 use recommendations, 5626 anti-HIV drug, 5468-469
PDB file format, 1:369 Penicillin-binding proteins, Pentamidine
PDGF beta 5:613 for African trypanosomiasis,
X-ray crystallographic studies, evolution, 5:618 5:1037-1039
1:492 modification of native, for leishmaniasis,
Peak intensities, in NMR, 1:512 5:616-618 5:1051-1052
Pedi-pred, 3:770 and resistance to P-lactams, Pentazocine, 6:333,6:335,6:375
Pefloxacin 5613-616 Penthienate
antimalarial, 5983 Penicillin dihydro F, 5:629 anticholinergic, 6:137
Pegasys, 5363 Penicillin F, 5:629 relative anticholinergic activ-
PEG-hemoglobin, 3:400, Penicillin G, 5608,5609, 5:631. ity, a156
3417-419 See also Benzylpenicillin Pentobarbital, a 2 0 4
clinical trials, 3:399 pharmacokinetics, 5624 Pentostatin, 1:717, 1:750-751,
immunogenicity, 3:406 structure, 5628,5629 1:849
Pegylated agents, See Polyethyl- use recommendations, 5626 antimetabolite, 5:76,5:81
ene glycol (PEG) in vitro antibacterial activity, Pentothal, 6:204
Peipheral vascular disease, 5:635,5:667 Pentoxifylline
3340 Penicillin K, 5629 IL-12 inhibition, 4180
Peldesine Penicillin N, 5629 radiosensitizer, 5:184
structure-based design, 1:460 Penicillin iso-N, 5629 Pepleomycins
Pellagra, 4392,4394,4395, Penicillin 0, 5629 antitumor natural products,
6:687 Penicillins, 1:717, 1:868-870 5:115
nicotinamide analogs tested, antimycobacterial application, Pepsin inhibitors
6:690 5:858 antiulcer application, a158
Pelviagraphy, 4567. See also brief description, 5:609 Pepsinogens, 6:111-112
Radiopaques discovery of, 2:39,5:628-637 Pepstatin
PernADD, 6:170 ester prodrugs, 2:504 renin inhibitor, 2:98
Pemetrexed P-lactamase classification residues in pseudopeptide ar-
structure-based design, based on activity, 5:620, rays, 2:12-13
1:429-430 5:621 PeptiCLEC-TR, 19304
Cumulative Index

Peptic ulcer, 6:113-114 Peptidomimetics, 1:128-129, Permax


Peptidase inhibitors, 6:440-443 1:633-634,4:72 for Parkinson's disease, 6:722,
Peptidase tumor-activated pro- classification, 1:634-636 6:725
drugs, 587-88 conformationally restricted Permeability
Peptide affinity label derivatives, peptides, 1:636-643 and aqueous solubility of
6:440 future directions, 1:674-677, drugs, 2:656-657
P
Peptide arrays, 2:6 475-76 and Biopharmaceutics Classi-
multiple parallel synthesis, with high afiinity for opioid fication System, 2:665-666
2:6-13 receptors, 6:438-440 characterization, 2:658-660
peptide surrogates employed, molecular modeling, 1:154 Class 5 drugs: high solubility
2:12-13 non-peptide, 1:636, 1:657-674 high permeability,
Peptide backbone mimetics, peptide bond isosteres, 2:665-667
12636, 1~644-645 1:644-646 Class I1 drugs: low solubility
Peptide bond isosteres, protease inhibitors, high permeability,
1:644-646 2:667-671
1:646-655
Peptide esters prodrugs, 2:508 Class I11 drugs: high solubility
speeding up research,
low permeability,
Peptide hormones, 446-48. See 1:655-657 2:674-676
also Melanotropins; Oxyto- template mimetics, 1:643-644 Class I Ydrugs: low solubility
cin; Parathyroid hormone; Peptoids low permeability, 2:676
Vasopressin residues in pseudopeptide ar- improving with prodrugs,
bioassays, 4 5 2 rays, 2:12 2:674-675
commonly held beliefs about, Peramivir, 2:214,2:220, lipid-based oral drug delivery,
447 5:374376 2:252
conformation, 448-51 structure-based design, 1:452 and partition coefficient, 2:656
future directions, 4:75-76 Percocet, 6:335 penetration enhancers,
synthesis, 4:48 Percodan, 6:335 2:251-252
topographical and conforma- Percutaneous intervention, prodrugs, 2:252-254
tional constraints, 452 3:156 strategies to enhance,
topography, 451-52 Perflubron-based fluorocarbon 2:251-255
Peptide-leukotrieneantagonists, emulsion Permeation enhancers, 2:675
4220-221 for sickle-cell therapy, 3:462 Permetrexed
diversified structures, antimetabolite, 576, 5 7 8
Perfluorochemicals, 3:396,
4224-226 Pernicious anemia, 4:407, 4415
3:421-429
FPL-55712-derived com- Pernoston, 6:205
clinical use, 3:398-399
pounds, 4:221-222 Peroxisome proliferator-acti-
leukotriene analog antago- currently used, 3:421-424
vated receptor a, 4 2 6 , 4 2 7
nists, 4222-224 pharmacokinetics, 3:424-425
Peroxisome proliferator-acti-
Peptide nucleic acids, 2: 119 Perfluoroctyl bromide
vated receptor 6,426,427
Peptides, 1:634 radiopaque material, Peroxisome proliferator-acti-
biochemical force fields, 4571-572 vated receptor y, 426-27
1:175-176 Perftoran, 3:422 Peroxisome proliferator-acti-
biological function, 2:5-6 emulsion stability, 3:428 vated receptor y agonists,
endogenous vasoactive, pharmacology, 3:425 4:26-28
3193-195 Pergolide Peroxisome proliferator-acti-
NMR structural determina- for Parkinson's disease, 6:722, vated receptor (PPAR) ago-
tion of bioactive, 1:517-518 6:725 nists, 3:370-371
non-Boltzmann sampling of Perhexiline analogs, 2:566-567 thiazolidinediones, 424,
helical transitions, 1:100 Pericytes, 5:216 4:2631
prodrug derivatives, Peripheral adiposity signals, Peroxisomes
2:507-508 6:872-873 adaptive toxic response, 2:617,
RSV antiviral agents, Peripheral nervous system 2:618
5:395-396 nicotinic acetylcholine recep- Perphenazine
Peptide W, 3208-210 tors, 2:388 dose, 6:601
Peptidoglycan, 5610-612 Peripheral satiety signals, 6:873 receptor binding and side ef-
Peptidoglycan transglycosylases, Peripheral vasodilators, 3:12 fects, a606
5:610 Permatil, 6:601 Persantine, 3:287
Cumulative Index

Personal chemical databases, polymerase chain reaction- PharmPrint method, 1:223


1:387-388 restriction fragment length Phase I, of Investigational New
Personnel training polymorphism genotyping, Drugs Application Process, .
for large-scale synthesis, 2:419 4:622- 623 2:691-693
Perutz stereochemical mecha- polymorphisms in drug metab- Phase I clinical trials
nism olizing enzymes, 4626-631 pharmacokinetics applica-
hemoglobin allostery, 3386 polymorphisms in drug target tions, 2:645-646 T
Pesticides genes, 4632-636 toxicity testing, 2:611
soft drugs, 2:555-558 polymorphisms in drug trans- Phase 11,of Investigational New
Pestivirus, 5:427 porter genes, 4631-632 Drugs Application Process, -
Petabyte, 1:408 pyrosequencing, 4624 2:693-695
single base primer extension Phase I1 clinical trials
Pethidine, 1:851
genotyping, 4623-624 pharmacokinetics applica-
Petichloral, 6:208,6:209
single gene studies in genes
PETRA, 1:390 tions, 2:646
influencing disease progres-
Petrin, 6209 toxicity testing, 2:611
sion, 4636-641
Petrolatum, 4470 SNP discovery, 4621-626 Phase 111,of Investigational
Petrosia contignata, 1:886 Pharmacokinetics New Drugs Application Pro-
Pfam, 1:349 applications in areas other cess, 2:695
P-Glycoprotein efflux pump, than drug discovery, 2:647 Phase I11 clinical trials
2:79,2:252 applications in development pharmacokinetics applica-
case study of transport, process, 2:645-647 tions, 2:646
2:272-274 parameters in drug disposi- toxicity testing, 2:611
and drug metabolism in intes- tion, 2:635-641 Phase IV,of Investigational New
tine, 2:676,2:678 parameters in therapeutics, Drugs Application Process,
efflux mechanism, 2:678 2:641-645 2:695
OC 144-103 effect on, 2:21-22 phosphorothioate oligonucleo- Phase IV clinical trials
and permeability, 2:658 tides, 2:132 pharmacokinetics applica-
polymorphisms in, 4631-632 prodrugs, 2:521-522 tions, 2:646-647
Phage display, 2 9 4 in vivo toxicity testing, 2:619 Phase problem
cell-specific targeting, 2:95-96 Pharmacophore-based ligand in X-ray crystallography,
selections against purified pro- libraries, 2:345-350 1:476-478
teins, 2:94 Pharmacophore keys, 1:376, Phenampromide
in vivo, 2:96 1:408-409 analgesic, 6:385, a387
Phage display libraries, 2:96 Pharmacophore mapping, 1:255 Phencyclidine
Phage M13,2:95 Pharmacophore point filters, rigid analogs, 1:696-697
Phanodorm, 6:205 1:196, 1249-250 Phendimetrazine, 6:171,6:187,
Pharmaceutical Affairs Law (Ja- Pharmacophores, 1:368 6:856
pan), 4430 with BCUT descriptors, absorption and metabolism,
Pharmacodynamics, 2:634 1:223-224 6:863
Pharmacogenetics, 2:85, binding site models con- dose, a846
4619-620 trasted, 1:127-135 structure-activity relationship,
Pharmacogenomics defined, 1:252-253, 1:408 6:185
combined enzymatichybrid- descriptor, for QSAR, 1:60-63 Phenelzine
ization genotyping, 3D searching, 1:366-367 antidepressant, 6:485,6:486,
4625-626 in molecular modeling, 1:110 6:488
enzyme-based genotyping for molecular similarityldiver- dose for eating disorders,
technologies, 4:622-624 sity methods, 1:194-201, a851
genotyping technologies, 1904-206 for eating disorders, a858
4622-625 NMR-based modeling, for Parkinson's disease, 6:729,
hybridization-based genotyp- 1:531-532 6:730
ing, 4624-625 NMR spectroscopy-based mod- pharmacokinetic parameters,
influence on clinical trials, eling, 1:531-532 a497
4641-644 oriented-substituent, 1:224 side effects profile, 6:493
obstacles facing, 4644-646 site-based, 1:235-237 Phenergan, 6214
as paradigm shift in health thyroid hormone, 3578 Phenethicillin, 5:631
care, 4645-646 virtual screening, 15252-260 P-Phenethylamines, 1:697-698
Cumulative Index

2-Phenethylamines applications, 6:15 Philadelphia chromosome, 5:19


appetite suppressants, structure-activity relationship, Phlebography, 4567. See also
6:855-856 6:31 Radiopaques
structure-activity relation- N-Phenylacetamidines CT application, 4568
ships, 6:875-881 nitric oxide synthase inhibi- Phleomycins
Phenformin, 421,4:23 tors, 6:698,6:700-701 antitumor natural products,
Phenidone, 4212 Phenylacetic acids 5:115,5:117
Phenmetrazine ionization of substituted, Phobias, 6526-527
structure-activity relationship, 1212-14 Phorate, 2558
6:185 Phenyl-2-aminopyridines Phosphatase and tensin homo-
Phenobarbital nitric oxide synthase inhibi- logue (PTEN) tumor sup-
ADME, 6:282-283 tors, 6:702-704 pressor gene, 5 3 0
anticonvulsant, 6:265, 6:267, Phenylbenzimidazole sulfonic Phosphatase tumor-activated
6:298 acid prodrugs, 5:87
clinical efficacy, 6:273 structure-activity relationship, Phosphate right shifters, for he-
dose, 6:270 4467 moglobin, 3:389
interaction with vitamin D, sunscreen, 4460 Phosphatidic acid, 2:616
4379-380 Phenylbutazone, 3:140 Phosphatidylcholine monolayers
P-glycoprotein inducer, 4631 Phenylephrine penetration by ROH,1:27
pretreatment effect on ra- a,-agonist, 6:3 Phosphatidylserine
diopaques, 4563 applications, 6:13 interaction with sickled cells,
rat toxicity, 2:617-618 structure-activity relationship, 3458
side effects, 6:278 6:30 Phosphocholine
Phenobarbital-like inducers, Phenylethanolamine N-methyl- docking to antibody McPC603,
2:79,2:618 transferase (PNMT) inhibi- 1:298
Phenols tors, 1:733-734, 1:740 Phosphodiesterase inhibitors
DNA synthesis inhibition by, Phenylethylamines, 6:3,6:4,6:5 selective toxicity, 5:277
1:40 metabolism, 6:16-18 Phosphodiesterases
growth inhibition by, 1:38, structure-activity relationship, alignment of catalytic domains
1:40-41 6:28-30 in gene family, 1:349
topical antibacterials, (R,S)-a-Phenylglycidate, 1:762 D-3-Phosphoglycerate dehydro-
6x548-550 (S)-a-Phenylglycidate, 1:762 genase
Phenothiazines, 2:144 Phenylpiperidine analgesics, allostery, 2:306
antipsychotics: pharmacoki- a334 3-Phosphoglycerate dehydroge-
netics, biotransformation, structure-activity relation- nase
and drug interactions, ships with carbon substitu- allostery, 2:306-307,2:310
6~633-635 ent at C,, 6:377-380 Phosphoglycerides
Phenoxazine, 2:144, 2:145 structure-activity relation- target of toxicity, 2:616,2:617
Phenoxybenzamine ships with oxygen substitu- Phosphoinositol3-kinase, 5:24
a-antagonist, 6:4 ent at C,, 6:380-381 Phosphoinositol3 kinase y
applications, 6:15 Phenylpropanolamine, a843 chemokine interaction, 4134,
Phenoxyethylamine, 6:33 dose, 6:848 4135
Phenprocoumon, 2:310,3:311 N'-(R-Pheny1)sulfanilamides Phospholipase A2
Phenserine antibacterial activity, 1:10 homology modeling, 1:123
anticholinesterases related to, Phenytoin, 3:32 target of structure-based drug
6:89 ADME, 6:273 design, 1:453-454
Phensuximide, 6:267 anticonvulsant, 6:265-267, X-ray crystallographic studies,
dose, 6:270 6:298 1:492
Phentermine, 6:171,6:185, with bleomycin, 5:116 Phospholipase C
6:186,6:855-856 cardiovascular effects, role in chemokine modulation,
absorption and metabolism, 3:36-37 4:134
6:861 clinical efficacy, a 2 7 3 role in clotting, 3:305-306
dose, 6:844,6:848 CYP2C9 substrate, 4627 role in prostaglandin synthe-
side effects, 1:859 dose, 6:270 sis, 4233
Phentolamine, 4442,4446, P-glycoprotein inducer, 4631 Phospholipids, 3:340-341
4448 side effects, 3:35, 6:276 in lipid formulations, 2:671
a-antagonist, 6:4 Phialophora, 5:883 targets of toxicity, 2:616-617
Cumulative Index

Phosphonate residues Phthalocyanines Picropodophyllotoxin


in pseudopeptide m y s , 2:12, radiosensitizers, 5175 antitumor natural product,
2:13 Phthisis, 5:809-810 5134
Phosphonoacetate, 1:740 Phthivazid, 5834 Pifithrin-a!
N-Phosphonoacetyl-L-aspartate Phylogenomics, 1:347-349 allosteric effector, 2:314,
(PALA), 1:743-744 Physical dependence 2:315
Phosphonoformate, 1:740 narcotic analgesics, 6:336 Pigeon liver DHFR, QSAR inhi- 'T
2-(Phosphonomethoxy)eth- Physical (particulate) sun- bition studies, 1:31-32
ylguanidines screens Pikromycin, 2:188
chain branching analogs, structure-activity relationship, Pilocarpic acid, 2:519 -
1:702 4470 Pilocarpine, 2:519-520
(R)-9-[2-(Phosphonome- Physicochemical characteriza- as cholinergic, 6:61-62
thoxy)propyl]adenine(R- tion, 2:654-655
Pilot plant studies
PMPA), 1:818-819 aqueous solubility, 2:656-658
and delay of marketplace en-
dissolution rate, 2:658
Phosphoroamidon try of new drugs, 2:705
hygroscopicity, 2:662-664
diuretic effects, 3134-135, for large-scale drug synthesis,
ionization constant,
3:137 2~660-662 2:409,2:414-417
Phosphorothioate oligonucleo- melting point, 2:655 nevirapine synthesis example,
tides, 2:118,2:120 partition coefficient, 2:424-427
aerosol administration, 2:134 2~655-656 Pimonidazole
binding and effects of binding permeability, 2:658-660 radiosensitizer, 5:179, 5180
to nonnucleic acid targets, solid state stability, 2:665 Pimozide
2:121-122 solution stability, 2:664 - 665 cardiotoxicity, 2:76
clinical activities, 2:138-139 Physicochemical descriptors, dose, 6:601
human safety, 2:142-143 1:54 pharmacokinetics, biotrans-
hybridization, 2:129 estimation systems, 1:389 formation, and drug interac-
nuclease stability, 2:132 for molecular similarity/diver- tions, 6:639-640
pharmacokinetic properties, sity methods, 1:193 receptor binding and side ef-
2:132 for virtual screening, 1:255 fects, 6:606
pharmacological properties, Physicochemical properties, Pinacidil, 3:177-178
2:135-138 1:373, 1:409 and extracellular potassium,
protein interactions, key properties of interest, 3:163
2:129-132 2:654 Pindolol, 6:4
topical administration, 2:134 Physostigmine, 1:774 applications, 6:16
toxicology, 2:139-142 anticholinesterases related to, Pioglitazone, 424,4:25, 4 2 8
in vitro cellular uptake, 6:88-90 binding affinities, 4 2 7
2~132-133 Phytoestrogens, 3:652 Pioneer drugs, 2:742
in vitro toxicology, 2:139 Phytohemagglutinins, and doctrine of equivalents,
in vivo pharmacokinetics, 2:263-264 2:744
2~133-135 Phytonadione, 4386,4387 Pipecolic acid, 1:805
in vivo pharmacological activi- Phytoprogestins, 3:652 Pipenzolate
ties, 2:136-138 PI-88,2:217-218,2:220 anticholinergic, 6:138
in vivo toxicology, 2:139-142 Picomaviral protein 2C inhibi- relative anticholinergic activ-
Phosphorus-derived cholin- tors, 5413 ity, a156
ergics, 6:90-93 Picornaviruses, 5398 Piperacillin, 5609, 5633
Phosphoryl-Leu-Phe, 3137 antiviral agents, 5:398-415 antimycobacterial application,
Phosphoryl transferases target of structure-based drug 5858
target of structure-based drug design, 1:454-456 indications, 5:625
design, 1:456-4561 Picornavirus protease inhibitors pharmacokinetics, 5624
Photoaging, 4465 nonpeptidic, 5:409-411 use recommendations, 5:626
Photodynamic therapy, peptidic, 5404-409 in vitro antibacterial activity,
5174-175 Picovir 5635
Photofrin, 5174-175 picornavirus antiviral, Piperaquine
PHP, See Pyridoxalated hemo- 5:399-400 antimalarial, 5990
globin-polyoxyethylene con- structure-based design, Piperazine
jugate 1~455-456 antihelmintic, 51091,51095
Cumulative Index

Piperidolate side effects, adverse effects, Plasmodium fragile, 5921


anticholinergic, e l 3 6 drug interactions, and con- Plasmodium knowlesi, 5:923
relative anticholinergic activ- traindications, a 3 5 5 Plasmodium malariae, 5920 -
ity, 6:157 structure-activity relationship, life cycle, k921-924
Pipethanate a367 Plasmodium ovule, 5920
anticholinergic, a136 Plant toxins, 2:263 life cycle, 5:921-924
Piprozoline, 3:109 Plant Variety Protection Act of Plasmodium simiovale, kg21 r
Piptal, 6:138 1970,2:848 Plasmodium vinckei, 5923
Piracetam, a304 Plaquenil, kg34 Plasmodium vivax, 5920
for Alzheimer's disease, 6:764 Plasma cells, 3:253 biochemistry and genetics, -
Pirbuterol Plasma-DNA mediated gene 5:924
P-agonist, 6:4 therapy, 4651-652 drug resistance, 5928-930
applications, 6:14 Plasma volume expanders, global distribution, 5:927
Pirenzepine 32429-432 life cycle, 5:921-924
anticholinergic, 6:128-129 Plasmid DNA-mediated gene Plasmodium yoelii, 5923
Piretanide, 3:88,3:103-104 therapy Plasmotrim, 5935
Piribedil for cancer, 5:39-40 Platelet-activating factor, a304
for Parkinson's disease, 6:723, direct delivery with naked Platelet ADP receptor antago-
6:726 plasmid DNA, 4652-656 nists
Piritrexim electroporation, 4656-657 mechanism and sites of action,
antimetabolite, 5 7 6 , 5 7 9 emulsion-mediated gene a320321
Pirlindole transfer, 4666-667 Platelet-derived growth factor,
chromatographic separation, entry of DNA into cells, k217-218
1:788-789, 1:790 4660-662 Platelet-derived growth factor
Pirodavir entry of DNA into nucleus, inhibitors
picornavirus antiviral, 4662-663 antiangiogenic agents,
5400-401 gene gun, 4657-658 5218-219
Piroxantrone lipid-based vectors, 4:658-663 Platelet endothelial cell adhe-
topoisomerase I1 inhibitor, Lipoplex, 4:658,4:663-665 sion molecule
5:68,5:72 Lipopolyplex, 4:658, plasmid DNA-mediated gene
Pitavastatin, 3:343,3:345, 4665-666 therapy study, 4669
3:353-354,3:368 non-viral vector related cyto- Platelet glycoprotein IIbIIIIa
ADME, 3356 toxicity, 4669-670 receptor, 3:285
enzyme activity, a 3 6 4 Polyplex, 4658,4667-669 in clotting, 3:303304
Pituitary adenylate cyclase-acti- Plasmids, 4652,4653 Platelet glycoprotein IIbDIIa
vating peptide, 3:226-228 and p-lactam resistance, receptor antagonists, 3:29,
Pit viper, drugs derived from, 5:614-616 3:318-320
1:881 patentability, 2:718 adverse effects, a294
Pivampicillin, 2:504, 2:510, Plasmin, 3:166,3:284,3:285 Platelet PAR-1 receptor,
5632 in clotting, 3:304,3:307 3:304-305
Pivmecillinam, 2:5 10 Plasminogen, 3:166,3:307 Platelet PAR-4 receptor,
Pivoting data, 1:409 Plasminogen activator inhibi- 3:304-305
PMY321,3:271-272 tor-1, $166 Platelet PAR-1 receptor antago-
PK,, 2:660-662 for angiogenesis control, 5 4 5 nists, a326
Placebo effect role in clotting, 3:307-308 Platelet PAR-4 receptor antago-
depressants, 6:488-489 Plasminogen activators, nists, 3:326-327
Placidyl, a 2 0 9 3:165-166 Platelets, 3:284-285
Plaintiffs, in patent cases, 2:741 Plasmodium berghei, 5:923 in clotting, 3:299308
Plant natural products, 1:848, Plasmodium brasilianum, kg21 exosome secretion, 5:241
1:893, 2:39 Plasmodium cynomolgi, 5923 PlateMate Plus automated
Plant patents, 2:708 Plasmodium falciparum, 3:452, screening robot, 2:65
Plant secondary metabolites, 5:920 Platinum complex alkylating
1:848 biochemistry and genetics, agents, 5:54,559-61. See
Plant sterols 5924-926 also Cisplatin
ADME, 3:358 drug resistance, 5:928-930 Platomycins
antihyperlipidemic agents, global distribution, 5927 antitumor natural products,
3~351-352 life cycle, 5921-924 &I17
Cumulative Index

Plavix, 3:29,3:287 antitumor natural product, Polymerase chain reaction-re-


Pleconaril 5:134 striction fragment length
picomavirus antiviral, Podophyllum emodi, 1:865 polymorphism genotyping,
$399-400 Podophyllum peltatum (May ap- 4622-623
structure-based design, ple), 1:865, 5:134 Polymeric IgA transport,
1:455-456 Point mutations, 4620 2:261-262
Plegine, 6:171, a 8 4 6 7
Poisson-Boltzmann equation, Polymeric IgM transport, 2:262
Plicamycin 1:83, 1:84 Polymeric radioprotective
antitumor natural product, Polarity index, 1:26 agents, 5:166-167
5:110,5:122-124 -
Polarizability, 1:85 Polymerized hemoglobins,
PLOGP, 1:389 Polarizability index, 1:11 3:397,3:412-417
PLP function, 1:266, 1:309 Polarization energy, 1:173 Polymethylene tetramine anti-
consensus scoring, 1:320
Polar surface area cholinergics, 6:131
hydrophobic interactions,
in druglikeness screening, Polymorphs, 2:651,2:652-653
1:319
performance in structure pre- 1:245 melting point, 2:653, 2:655
diction, l:314 Poldine metastable, 2:669
seeding experiments, 1:319 anticholinergic, a 1 3 8 Polynucleotides, 2:117
PLUMS, 1:225 relative anticholinergic activ- Polyomaviruses, 5:302-303
Pluracidomycin A, 5:670,5:671 ity, a 1 5 6 antiviral agents, 5:339-340
in vitro activity, 5:692 Policosanol, 1:849 Polyoxins, 5:906
Plymecillin, 5:609 Poloxamers Polyoxometalates
P38 MAP kinase for precipitation inhibition, broad spectrum antiviral
consensus scoring study, 2:669 agents, 5:435
1:266 Polyacrylamide resins Polyplex, 4:658,4:667-669
seeding experiments, for combinatorial library syn- for nonviral gene delivery,
1:318-319 thesis, 2:29 5:42
PMF function, 1:265, 1:311, Polyamidoamine dendrimers Polyribosine:polyribonocytidine,
1:312 for polyplexes, 4668 2:117
performance in structure pre- Polycarbamate Polyribosyl ribitol phosphate,
diction, l:314 residues in pseudopeptide ar- 2:209
seeding experiments, 1:319 rays, 2:12 Polysialic acid, 2:226
PMML (Predictive Model Polycyclic carbapenems, Polystyrene resins
Markup Language), 1:405 5:683-688
for combinatorial library syn-
Pneumococcal heptavalent virus Polyene antifungal agents,
thesis, 2:29
vaccine, 2:209,2:212 5:889-893,5:890,5:891
Pneumocystis carinii, 5:460, Polyethylene glycol (PEG) Poly-N-succinyl-p-1-6-glu-
5883 with interferon-a for hepatitis cosamine, 2:221-222,2:226
Pneumocystosis, k883 C, 5 3 6 3 3 6 4 Polythiazide, 3:77
PNU-107859 for precipitation inhibition, Polyvinyl alcohol (PVA)
NMR binding studies, 1:555 2:668 for precipitation inhibition,
PNU-140690, 1:659, 1:812, resins for combinatorial li- 2:668
1:813 brary synthesis, 2:29 for solid dispersions, 2:670
PNU-142372 for solid dispersions, 2:670 Polyvinyl alcohol sulfate
NMR binding studies, Polyethyleneimines anti-HIV drug, 5:466
1:555-556 for polyplexes, 4668 Polyvinylpyrrolidone (PVP)
PNU-95666-E PolyHeme, 3:397, 3:400,3:412, for precipitation inhibition,
for Parkinson's disease, 6:723, 3:414-415 2:668,2:669
a726 Polyiodinated triglycerides, for solid dispersions, 2:670
Pobilukast (SKF 104353),4222 4575-576 Pomona College Medchem,
POCmT, 1:259 Polymerase chain reaction, 2:92, 1:385
Podophyllin 4621 Population pharmacokinetic
drugs derived from, 1:865-867 with mycobacteria, 5:826 model, 2:646
for papillomavirus, 5:338 reverse transcriptaselpolymer- Porfimer sodium, 5:174-175
Podophyllotoxins, 1:849, ase chain reaction (RT- Porfiromycin
1:865-866 PCR), 2:128 tumor-activated prodrug,
alkylating agents, 5:52 in toxicity testing, 2:621 5:83,5:85, 5:86
Cumulative Index

Porous beads Potassium-sparing diuretics, pharmacokinetics applications


use for solid phase organic 3:125-133,3:142 in late phase, 2:646
synthesis, 2:6-13 Potato, solanaceous alkaloids Precose, 4 3 2
Porphiromycin from, 6:120-126 Predictable metabolism, 2:539 -
antitumor natural product, Potentially lethal damage repair, Prednisolone, 3:750,3:753,
5:120 5191-192 3:756,3:758,3:770,3:772,
Posaconazole, 5:898-899 Potential smoothing, 1:86 3:797,3:800,3:802-803,
Positional scanning, in solid Potential surfaces, 1:85-89 3:820-821,3:835-836,
phase organic synthesis, Potocytosis, receptor-mediated, a845
2:8,2:9,2:10 2259 half-life, 3:776 -
Positive-contrast radiocontrast Pott's disease, 5809 Prednisone, 3:750,3:753,3:758,
agents, 4484 Poxviruses, 5305 3:797
antiviral agents, 5:340-341 half-life, 3:776
Positive cooperativity,
chemokine receptors, side effects, a756
2:296-297,2:304305
4170-171 Pregabalin, 6:580
Positive symptoms, of schizo- dendritic cell transduction by, anticonvulsant, 6:312-313
phrenia, 6:602 5242-243 Pregnancy test kits, 4:424
Positron emission tomography PPAR y Pregnanes, 3:597,3:598,3:749
(PET) X-ray crystallographic studies, Pregnenolone
for Parkinson's disease diag- 1:492 formation, 3:609-612
nosis, 6:734-736 Practical grade compounds, 2:28 precursor for adrenal steroids,
serotonergic activity in anxi- Pradimicins, 5:908 3:612,3:615
ety, a579 Pralnacasan precursor for androgens,
Postoperative atony of gut/uri- structure-based design, 1:443, 3616
nary bladder 1:446 Preincubation effect, radiosensi-
cholinergics for, 6:40 Pramipexole, 6:650 tizers, 5180
Posttraumatic stress disorder, for Parkinson's disease, 6:721, Preinfarction angina, 3:10
a527 6:722,6:725-726 Preliminary screening,
Potassium Prandin, 4:14 1:111-112
accumulation of extracellular Pranlukast (ON01078), Preload, 3:9
during myocardial ischemia, 4224-225,4226 Prelu-2, a 1 7 1
3:162-163 Prantal, 6:136 Preludin, a185
extracellular-intracellular pro- Pravachol, 3:343,3:609 Premarin, a632
portion, 3:125 Pravastatin, 1:879, 1:880,3:343, dose for eating disorders,
for prevention of ventricular 3:345, a609 a853
remodeling, 3:181 ADME, 3356 Premature atrial contractions,
role in heartbeat, 3 : 4 5 for Alzheimer's disease, 6:757 3:9
role in kidneys, 3 5 9 for angina treatment, 311 Premature ejaculation, 4:440,
role of extracellular in ar- enzyme activity, 3364 4441,4443
rhythmias, 3:163-164 single nucleotide polymor- Premature ventricular contrac-
Potassium canrenoate, phism~influencing response tions, 3:9, 3:31
3:117-118 to, 4639-641,4644 Prenylamine, 3:17
Potassium channel, ATP-sensi- Praziquantel bioavailability and half-life,
tive, See ATP-sensitive po- antihelmintic, 51091, 3:18
tassium channel 5:1093-1094 cardiovascular effects, 3:19
Potassium channel antagonists, Prazosin Prescription Drug Marketing
ATP-sensitive, 3:175-176 applications, 6:15-16 Act of 1988,2:687
Potassium channel blockers, 3:6 selective a,-antagonist, 6:4 Prescription drugs, 4423,4424
Potassium channels, 3:7 structure-activity relationship, direct-to-consumer advertis-
and cognition enhancement, 6:31 ing, 4422
6:817-820 P60 receptor, 4:182 reclassification to over-the-
Potassium channel shaker P80 receptor, 4182 counter status, 4427-428
X-ray crystallographic studies, Precipitation inhibition, Prescription Drug User Fee,
1:492 2:668 - 669 2:688
Potassium mexrenoate, 3118 Preclinical development Presenilins
Potassium prorenoate, 3:117, pharmacokinetics applications and Alzheimer's disease,
3:118 in initial phase, 2:645 6:745-746
Cumulative Index

Pressure template mimetics, 1:644 for Parkinson's disease, 6:731,


molecular dynamic simula- in virtual screening, 6:732
tion, 1:96 1~251-252 relative anticholinergic activ-
Presystemic elimination, 2:676, PRO440 ity, 6:157
22677-678 anti-HIV drug, 5:468 stereoisomerism, a149
Pretz-D 0.25% spray, e l 7 1 ProAmatine, 6:3 Prodine, 6:376 P
Preventive maintenance pro- Probanthine ProDock
grams anticholinergic, 6:128, 6:138 affinity grids, 1:293
for large-scale synthesis, 2:419 Probarbital, 6:204 Monte Carlo minimization, -
Prevnar, 2:209,2:212 Probasin, 3:696 1:298
Primaquine, 1:889 PROBE, 1:126
ProDom, 1:349
antimalarial, 5949-954 Probe Designer, 2:623
Prodorm, a209
dosage forms, 5:934 Probenecid, 3:139-140
Prodrug design, 2:499-500
Primary hypothyroidism, a574 with bumetanide, a103
with cephalosporins, 5623 biopharmaceutical point of
Primaxin, 5693 view, 2:501=502
with hydrochlorothiazide, 3:78
Primidone pharmacokinetic point of
with metolazone, 3:86
ADME, 6:283 view, 2:501
Probucol, 3343
anticonvulsant, 6:265, ADME, 3:358 regulatory point of view,
6:267-268,6:298 clinical applications, 3:350 2:501-502
clinical efficacy, 6:273 side effects, adverse effects, Prodrugs. See also Tumor-acti-
dose, 6:270 drug interactions, and con- vated prodrugs
side effects, 6:278 traindications, 3:355 activation at site of action,
Principal components analysis structure-activity relationship, 2:515-516
with molecular similarityldi- 3:367 activation enzymes in cancer
versity methods, 1:192, Procainamide, 3:32,3:34,3:167 gene therapy or gene-di-
1:201 cardiovascular effects, 335-36 rected enzyme prodrug
in QSAR, 1:15 multiple inhibitory mecha- therapy, 2:517-518
Principal components regres- nisms, 3:33 amine prodrugs, 2:508-509
sion, 1:53 prodrugs, 2:505 antibody-directed enzyme pro-
Prindolol uses and side effects, 3:35 drug therapy, 2:518
renal clearance, 1:38 Procaine
Prinomastat antitumor prodrug by use of
radioprotective agent, 5:166
structure-based design, 1:444, CYP450 mediated activa-
Procaspase-8
1:446 and apoptosis, 5 1 7 tion, 2:518
PRINTS, 1:335, 1:349 Procaspase-9 bioavailability assessment,
Prinzmetal's angina, 3:9 and apoptosis, 5:18-19 2:522-523
Prions, 2:219-220, 4:46 Process claims, 2:718 chemical bonds, 2:503-510
Prior art, 2:716,2:721 and prior art, 2:732-733 chemical delivery system con-
anticipating patent claims, Process controls trasted, 2:537
2:745 in large-scale synthesis, 2:412, chemical hydrolysis, 2:510
and newness/novelty require- 2:418 Class 111, 2:674-675
ments, 2:729-730 Process development, 2:409 clearance approach, 2:522
and patent claims, 2:724 nevirapine synthesis, compartmental approach,
and provisional applications, 2~424-427 2:521-522
2:725,2:729 Process flow diagrams, 2:418 distribution, 2:515-518
Priority Review, in New Drug Process hazard review, 2:417 double prodrug concept, 2:517
Approval, 2:698,2:700 Process Risk Analysis, 2:411 esters, 2:504-505
Priscoline. 6:4 Process validation, 2:419 gastrointestinal absorption,
Privacy concerns PROCHECK program, 1:478 2:510-514
genotyping, 4644 Prochlorperazine kinetic studies in humans,
Privileged pharmacophores, dose, 6:601 2:522
2:346-350 receptor binding and side ef- lipidic peptides, 2:509-510
Privileged structures fects, a606 and luminal degradation,
centroids, 2:16 PROCRIT, 3:258 25377
in molecular similarityldiver- Procyclidine macromolecular prodrugs,
sity methods, 1:209 anticholinergic, a 1 3 5 2:505-507
Cumulative Index

Prodrugs (Continued) X-ray crystallographic studies, Propallyllonal, 6205


Mannich bases, 2:505 1:492 Propantheline
metabolic considerations, Progestins, 3:595,3:650-651. anticholinergic, 6:138
2:499-526 See also Estrogen-progestin relative anticholinergic activ-
metabolism, 2:484-487 combinations ity, 6:156
multistep, 2:487-490 binding to glucocorticoid re- Propargylglycine, 1:719-720
occular absorption, 2:519-521 ceptors, 3841 Propavan, a214 P
parenteral administration, currently marketed, 3:632 Propecia, 3:717,4:433
2:514-515 environmental and dietary, Property-based design,
peptide derivatives, 2:507-508 3:651-652 12234-235 -
peptide esters, 2:508 first antiandrogens, 3:718 Property-encoded nomenclature1
permeability, 2952-254 side effects, 3:631-633 MALDI sequencing (of hep-
pharmacokinetics, 2:521-522 tissue-selective, 3:652-654 arin), 2935-236
radiation-activated, 2:518 PROGOL, 1:67 Propicillin, 5:609,5:631
rationale of design, 2:524-525 Prograf, 5:495
Propine, 6:3
reversiblelirreversible conver- Progression, in carcinogenesis,
Propiomazine, 6:213,6:214
sion, 2:516-517 5:3-5
Progressive multifocal leukoen- Propionyl CoA carboxylase
soft drugs contrasted,
2:536-537 cephalopathy, 5:302-303 biotin dependent, 4404
sustained-release, 2:512-513 Proguanil Propivane
taste improvement, 2:513 antimalarial, 5:936, relative anticholinergic activ-
tissue targeting, 2:515 5:954-956 ity, 6:157
transdermal absorption, with dapsone, 5:959 Proplex
2:518-519 dosage forms, 5:934 hemostatic preparation, a292
virus-directed enzyme prodrug Project Library, 1:387 Propofel, 6:214,6:215
therapy, 2:518 Prokinetic agents Propoxyphene, 6:332
Proenkephalin peptides, 6:357, for eating disorders, 6:852, cytochrome P,,, isozyrne sub-
6:358 a858 stratelinhibitor, a339
Profibrinolytics, 3:3 Prolactin, 2:618-619 dose, 6:334
Proflavin Prolactin receptor selective toxicity, 5269-270
thermodynamics of binding to X-ray crystallographic studies, Propranolol, 1:881-882,328,
DNA, 1:183 1:492 3:32,3:179
Proflavine, 5:67 PRO-LEADS, 1299 applications, 6:16
Progesterone, 3:594,3:598, assessment, 1:303, 1:304 cardiovascular effects,
3:750,3:756,3:759, flexible ligands, 1263 3:39-40
3:842-844 PRO-LIGAND CYP2D6 substrate, 4627
binding, 3:771 genetic algorithm with, 1:89 enantiomers, 1:786
biosynthesis, 3:615,3:616, Prolixin, a 6 0 1 enzyme-mediated asymmetric
3:642-645 Promazine synthesis, 1:805-806
biotransformation, 3:640-642 dose, a 6 0 1 history, 6 2 7
CYP3A41517 substrate, 4627 receptor binding and side ef- membrane function disrup-
functions of, 3:645 fects, 6:606 tion, 2:614
interactions with steroid re- Promegestrone, 3:666,3:725 metabolism, &19-21
ceptors, 3:633 Promethazine, 6:213,6:214 multiple inhibitory mecha-
metabolism, a620 antiulcer application, 6:158 nisms, 3:33
microbial transformation, Promoter region, 4619 renal clearance, 1:38
2:602-603 Promotion, in carcinogenesis, resin-assisted synthesis, 2:27
nonsteroidal analogs of, 5:3-5 structure-activity relationship,
3:667-668 Pronethalol, 1:881 6:32-33
receptor affinity, 3780-786 history, 6:27 uses and side effects, 3:38
steroidal analogs of, Propafenone, 3:32 Propriety medicinal product,
3:666-667 cardiovascular effects, 3:38 2:502
Progesterone antagonists, 3:651 CYP2D6 substrate, 4627 R(-)N-n-Propyl-11-hy-
Progesterone receptors, increased mortality from, 3:45 droxynoraporphine
3:649-650 multiple inhibitory mecha- for Parkinson's disease, 6:723
activity assessment, 3:650 nisms, 3:33 Propyliodone, 4497
antibody FAB fragment, 1:128 uses and side effects, 3:35 properties, 4511
Cumulative Index

N-10-Propynyl-5,8-dideazafo- Prostaglandins structural genomics, 1:353


late, 1:426, 1:427 antiulcer application, 6:158 target of structure-based drug
Prorenone, 3120 biosynthesis, 4:232-233 design, 1:432-445
Proresid, 1:866-867 broad spectrum antiviral transition state analogs,
Proscar, 3:717,3:722 agents, 5:432-435 1:646-655
Prosecution history estoppel, discovery and connection to Proteases
2:744-745 NSAIDS, 4229-230 allosteric protein target, P
PRO-SELECT and gastric secretion, 6:113 2:314,2:315
combinatorial docking, 1:318 homeostatic effects, 4233-234 Protein binding extent, 2:636
PROSITE, 1:348-349 and leukotriene biosynthesis, Protein C, 2:209 -
Pro-soft drugs, 2:571-572 4:205 in clotting, 2:301
Prostacyclin, 1:762-763,3:205, pathophysiological effects, plasma concentrations and
3328 4234 half-life, 3:296
for cancer treatment, 5:38 role in clotting, 3:306 warfarin effect on, 2:310
Prostaglandin D, 4230 role in erection, 4:445 Protein classes, 1:262
Prostaglandin D, Prostaglandin synthase inhibi- Protein Data Bank, 1:110,
physiological actions of, tors, 1:718, 1:762-763, 1:353
4271-272 1:764 sequence database, 1:387
radioligand binding studies, Prostaglandin synthesis, 2:86, X-ray crystallography applica-
4278 2:87 tion, 1:478-479
selective ligands and struc- Prostanoid receptors Protein Database
ture-activity relationships, classification and character- and virtual screening,
4282-285 ization, 4:269,4:275-282 1:261-262
signal transduction, 4281 as G-protein-coupled recep- Protein engineering, 2:84-91
Prostaglandin E, 4:230 tors, 4277-278 Protein families
Prostaglandin E, ligand binding site localiza- targeting in libraries for vir-
physiological actions of, tion, 4:295-298 tual screening, 1:251
4272-274 radioligand binding studies, Protein hormones, 446-48
radioligand binding studies, 4:278-281 Protein interactions, 1:334
4:278-280 selective ligands and struc- Protein kinase C
selective ligands and struc- ture-activity relationships, after myocardial infarction,
ture-activity relationships, 4282-295 3:157,3:158
4285-289 signal transduction, hyperglycemia effect on, 4 4
signal transduction, 4281 and a-secretase shift, 6:761
4281-282
Prostaglandin F,a Protein kinase pathways
subtypes and isoforms,
physiological actions of, 4274 gene expression profiling stud-
radioligand binding studies, 4:276-277 ies, 4610-611
4280 Prostanoids, 4266 Protein-ligand docking pro-
selective ligands and struc- biological and therapeutic grams, 1:292
ture-activity relationships, functions, 4267-269 Protein-ligand docking tech-
4289-292 biosynthesis of natural, niques, 1:262-264
signal transduction, 4269-270 Protein-ligand interactions,
4:281-282 clinical use of agents, 1:284-289, 1:322
Prostaglandin H synthase 1, See 4298-305 NMR spectroscopy, 1:510,
COX-1 physiological actions of, 1:517, 1:535-562
Prostaglandin H synthase 2, See 4271-275 QSAR studies, 1:5
COX-2 synthesis, 4266-267 scoring, l:264 -267
Prostaglandin I, synthetic, 4303-305 scoring in virtual screening,
physiological actions of, Prostate-specific antigen (PSA), 1:264-266
4274-275 3:696 Protein-protein interactions,
radioligand binding studies, Protamine, 2:215 1:634
4280 Protaxols, 1:863 characterizing, 1:637
selective ligands and struc- Protease inhibitors. See also Protein S, 2:301
ture-activity relationships, HIV protease inhibitors plasma concentrations and
4292-294 afEnity labels, 1:762 half-life, 3:296
signal transduction, 4282 QSAR studies, 1:5 warfarin effect on, 2:310
Cumulative Index

Proteins. See also Macromolecu- Provigil, 6:170, e l 9 3 p-lactams active against,


lar structure determination Provirus, 5:463 5:632-633
binding and chirality, Prozac, 6:484,6:529, a 5 3 1 Pseudopeptides, 1:635-636,2:6, -
1:786-787 affinities for monoamine re- 2:ll-12
flexibility and docking, ceptors, a 4 9 5 isosteres replacing peptide
1:300-302, 1:322 antidepressant, 6:485,6:486, backbone groups, 1:646
interactions with phosphoro- 6:488 Pseudopolymorphs, 2:651,2:653
thioate oligonucleotides, CYP2D6 substrate, 4627 melting point, 2:655
2:129-132 discovery, 6509-510 Pseudoracemate, 1:799 -800,
phage display selections dose for anxiety, 6:529 1:801 -
against, 2:94 dose for eating disorders, Pseudo-receptor models, 1:261
phylogenetic profding, a849 Pseudotolerance
1:347-348
for eating disorders, 6:857 narcotic analgesics, 6:336
role of insulin in synthesis, 4:2
inhibition of serotonin, norepi- Pseudotropine, 6:121,
second-generation therapeu-
nephrine, and dopamine 6:149-150
tics, 2:84-88
as targets for toxicity, transporters, 6:500 PSGL-1,2:216,2:220
2:615-616 lifestyle drug, 4431 PSI-BLAST, 1:335, 1:347
thyroid's effect on metabo- pharmacokinetic parameters, X-ray crystallography applica-
lism, 3:571 a497 tion, 1:481
and toxicity, 2:621-624 for premature ejaculation, Psilocybine, 5165
Protein structures 4443 Psoriasis
prediction, 1:122-127 side effects profile, a 4 9 3 retinoids used for, 4:373-374
in structure-based virtual PS-5,5670,5671, 5675 Psychosis, 6:600-602,
screening, 1:261-262 in vitro activity, 5:692 6:604-605. See also Anti-
X-ray crystallographic analy- PS-6,5:670,5:671 psychotic agents
sis, 1:496 PS-15 Psychostimulants, 6:168. See
Protein swapping, 5259 antimalarial, 5960 also CNS stimulants
Protein tyrosine phosphatase IB PS-26 PT-141,4450
potential target for diabetes antimalarial, 5960 Pulmonary and activation-regu-
drugs, 2:43 PS-33 lated chemokine (PARC),
Proteoglycans, 2:238,5:12 antimalarial, 5960 4150
Proteolysis P388 screening, for antitumor Pulmonary embolism,
inhibitors of, 5216-217 agents, 5109 3:289-290
Proteome, 1:352 P-selectin Pulsed ultrafiltration-mass spec-
Proteomics, 1:409,2:42 and sickle-cell animal models, trometry, 1:603-606
toxicology implications, 2:623 2:216,2:223-225,2:241 Pure Food and Drug Act of 1906,
Prothiaden, 6:485 P-selectin inhibitors, 2:216, 4424
Prothionamide, 5836 2:223-225,2:241 Purification
efficacy and dosage, 5810, Pseudoaddiction of libraries from multiple par-
5:863 narcotic analgesics, 6:336 allel synthesis, 2:23-28
Prothrombinase complex, Pseudoallescheria boydii, 5883 Purine analog antimetabolites,
3:299-300 Pseudoallescheriasis, 5883 5:76, 581-82
Prothrombin time, 3:291 Pseudocholinesterase, 6:40 Purine biosynthesis inhibitors,
Protooncogenes, 5:45 Pseudococaine, 6:189-190 1:752
Protriptyline Pseudoephedrine Purine derivatives
affinities for monoamine re- adrenergic, 6:2, 6:3 HBV virus antiviral agents,
ceptors, 6:495 applications, &lo, 6:11 5:330-333
antidepressant, 6:485,6:486, over-the-counter status, 4426 RSV antiviral agents, 5:389
6:487 structure-activity relationship, Purine modifications
inhibition of serotonin, norepi- 6:30 caused by oligonucleotide
nephrine, and dopamine Pseudoirreversible enzyme in- therapeutics, 2:146-147
transporters, 6:500 hibitors, 1:771-774 Purine nucleoside phosphorylase
pharmacokinetic parameters, Pseudomom acidophila, 1:873 target of structure-based drug
6:497 Pseudomonas aeruginosa design, 1:459-461
side effects profde, a 4 9 3 intrinsic resistance to p-lac- Purine ribonucleoside,
Proventil, 6:4 tams, 5621-623 1:751-752
Cumulative Index

Purinethol with sulfadoxine, 5958-959 Quality control


antimetabolite, 5 7 6 useful lifetime before resis- in high-throughput screening,
Purity tance develops, 5:930 2:59
multiple parallel synthesis, Pyrimidine analog antimetabo- Quality-of-life drugs, 4431
2:28-29 lites, 576, 579-81 QUANTA, 1:258
Purity verification Pyrimidine derivatives Quantitative structure-activity
as bottleneck in drug discov- HBV virus antiviral agents, relationship, 1:l-4, P
ery, 1:592 5326-330 1:49-52, 1:358. See also
LC-MS-based purification, influenza antiviral agents, Comparative quantitative
1:592-594 5389 structure-activity relation- -
mass spectrometry applica- RSV antiviral agents, 5389 ship; 3D quantitative struc-
tion, 1:594-596 grllmidines
ture-activity relationship
Purkinje fibers, 3:3-4,3:5 biosynthesis inhibitors, 1:752
anti-inflammatory steroids,
Purpurins halogenated, as radiosensitiz-
ers, 5194-195 3:786-792
radiosensitizers, 5:175 applications with interactions
modifications caused by oligo-
Pyelography, 4567. See also Ra- at cellular level, 1:37-38
nucleotide therapeutics,
diopaques applications with interactions
2:144-146
Pyochelin, 3:488 Pyronaridine in vivo, 1:38-39
Pyrantel antimalarial, 5979-981 applications with isolated re-
antihelmintic, 51091, dosage forms, 5935 ceptor interactions, 1:30-37
51094-1095 Pyrosequencing, 4624 2D, 1:52, 1:53
Pyrazinamide, 5836-837 Pyrrolidine-based influenza in- data mining, 1:66-67
drug interactions, 5864 hibitors, 5376-377 defined, 1:409
efficacy and dosage, 5810, Pyrrolidinone acetamide anti- descriptor pharmacophore
5863 convulsants concept, 1:60-63
side effects, 5:837 ADME, 6291 and docking methods,
Pyridostigmine Pyrrolinones 1:304-305
anticholinesterase, 6:90 peptide-like side chains, 1:635, Free-Wilson approach, 1:4,
Pyrido-1,2,4-thiadiazines, 3:75 1:642 1:29-30
Pyridoxal, 4:397 Pyrromycin guiding principals for safe,
Pyridoxalated hemoglobin- antitumor natural product, 1:66
polyoxyethylene conjugate 5:124,5:126,5:130 and library design, 1:68-69
(PHP), 3:397,3:400, Pyruvate carboxylase linear models, 1:26-28, 1:51,
3:419-420 biotin dependent, 4404,4405 1:61-62
Pyruvate dehydrogenase inhibi- model validation, 1:63-66
clinical trials, 3:399
tors, 1:717 and molecular similarityldi-
Pyridoxal phosphate, 4397-398,
Pyruvate kinase, 1:764 versity methods, 1:194
4399,4:400 allostery, 2:306 multiple descriptors of molec-
Pyridoxal phosphate biochemis- ular structure, 1:54-58
try, 4397-398 Qinghaosu (artemisinin), 1:886, nonlinear models, 1:28-29,
Pyridoxal phosphate-dependent 5961 1:51, 1~62-63
enzymes Q-jumping MD, 1:298 parameters used, 1:ll-26
mechanism-based inhibitors, QS-21,2:226 problems with Q2, 1:64-65
1:765-768 QSAR, See Quantitative struc- receptor theory development,
Pyridoxamine, 4397 ture-activity relationship 1:4-7
grlldoxamine phosphate, 4397 QSAR and Modeling Society, standard table, 1:51
Pyridoxine, 4397,4:399,4408 1:360 in structure-based design,
Pyridoxine phosphate, 4397, QSDock, 1295 1:419
4399 QSiAR, 1:53, 1:60 substituent constants for,
Pyrilamine, 6:212,6:214 QSPR, See Quantitative struc- 1:19-23
Pyrimethamine ture-property relationship taxonomy of approaches,
antimalarial, 5936, Quadratic shape descriptors, 1:52-54
5956-957 1:295 tools and techniques of,
with dapsone, 5959 Quadrupole time-of-flight hybrid 1:7-11
dosage forms, 5934 (QqTOF) mass spectrome- training and test set selection,
selective toxicity, 5254, 5:264 try, 1:585, 1:607 1:65-66
Cumulative Index

Quantitative structure-activity Quinine, 1:888-891 Radiopacity, 4531535


relationship (Continued) antimalarial, 5:933-938 Radiopaque elements, 4485
variable selection, 1:60-63 dosage forms, ,5934 Radiopaque materials, 4486 -
as virtual screening tool, P-glycoprotein inhibitor, Radiopaques, 4483-486
1:66-69 4631 applications, 4566-571
Quantitative structure-property Quinocide, 5:950 classification, 4486
relationship, 1:53 Quinolines, 1:889-890 heavy metals and their salts,
and molecular similarityldi- Quinolones 4486-493
versity methods, 1:194 selective toxicity, 5:263 iodized oils, 4493-495
Quantum chemical indices, 1:11, systemic antibacterials, miscellanesous agents, -
1:14-15, 1:54 5:582487 4571477
Quantum mechanics, 1:100-103 Quinones organic iodine compounds,
Quazepam, 6:207,6:549-550 lipid toxicity, 2:617 4495-566
Quazium, 6:207 nucleoside toxicity, 2:616 potential nonionic, 4 5 1 8 4 3 5
Quercetin, 1:865 radiosensitizers, 5:177 Radioprotective agents,
Query features, 1:381 Quinuclidine-based anticholin- 5~151-153
logical operators, 1:406 ergics, 6:129-131 antiradiation testing, 5:154
Query structures, 1:368 Quinupristin, 1:876-877 biochemical shock, 5:169
mapping, 1:380 Quisqualic acid, 1:694 DNA breakdown control,
Questran, 3343 Qxp 5:169-170
for angina treatment, 311 Monte Carlo minimization, free-radical process inhibition,
Quetiapine 1:298 5168
dose, 6:601 heterocyclic compounds,
for Parkinson's disease, a 7 2 5 R-14,2:285 5163-165
pharmacokinetics, biotrans- R-805,4241 hydroxyl-containing com-
formation, and drug interac- R-2956,3:719 pounds, 5 1 6 3
tions, a 6 3 7 R-5020,3:666 metabolic effects, 5:170-172
receptor binding and side ef- R-84760 metabolic inhibitors,
fects, 6:606 analgesic, 6:391,6:392 5~162-163
Quick Pep, a170 R-95867,5:709,5:710 metabolites and naturally oc-
Quinacrine, 1:889, 1:890-891, R-102444,3:328,3:329 curring compounds, 5:166
5:979 R-103757,3:368,3:369 metal ion containing agents,
Quinarnm, 5:934 R-121919,6:578 5:163
Quinazolines, 6:4 R-170591,5:393-394 miscellaneous substances,
metabolism, 6:19 Rabbits 5~166-167
structure-activity relationship, narcosis induction by ROH, mixed disulfide hypothesis,
a3031 1:27 5:168-169
Quinazolinone PARP inhibitors, Racemates, 1:782 physiologically active sub-
6:682,6:686 types of, 1:799-801 stances, 5:165-166
Quinazolinone sulfonamides, Racemization, 1:783-784 polymeric substances,
3:85-86 Radiation-activated prodrugs, 5:166-167
Quinestrol, a 6 3 4 2:518 protection by anoxiahypoxia,
applications, 3:631, 3:632 Radiation damage, 5:153-154 5:154,5:167-168
Quinethazone, 3:83,3:86,3:97 in electron cryomicroscopy, sulfur-containing compounds,
Quinidine, 3:32,3:167 1:612-613, 1:614-615, 5:160-162
antimalarial, 5:933-938 1:616 thiols and thiol derivatives,
ATP-sensitive potassium Radiation therapy. See also Ra- 5:152,5:155-160
channel inhibition, 3:178 dioprotective agents use in radiotherapy and can-
cardiovascular effects, hypoxia improves efficacy, cer chemotherapy,
334-35 3:392 5:172-173
dosage forms, 5:934 radioprotective agents in, Radiosensitizers, 5:173
multiple inhibitory mecha- 5172-173 alteration of energy absorp-
nisms, 3:33 Radiocontrast agents, 4:484, tion, 5:173-175
P-glycoprotein inhibitor, 4567 alteration of oxygen delivery,
4631 Radio-labeled binding studies, 5:183-190
uses and side effects, 3:35 2:73 alteration of primary radio-
Quinimax, 5:933,5:936-937 Radiolucent materials, 4486 lytic products, 5:175-176
Cumulative Index

bacterial sensitizers, 5197 RANTES ligand RD3-4082


for boron neutron capture antibodies to CCR1, 4139 hepatitis C antiviral, 5421,
therapy, 5173-174 and CCR1,4137-138, 5423
depletion of endogenous pro- 4142-143 RD4-6205
tectors, 5190-191 and CCR2,4144 hepatitis C antiviral, 5:422,
electron-affinic drugs in can- and CCR3,4148-150 5423
cer therapy, 5180-183 and CCR5,4153-155,5467 REACCS, 1:398 P
and hypoxia-activated pro- Rapacuronium reaction searching using,
drugs, 5 8 3 removedlrestricted by FDA, 1:383
inhibition of DNA repair, 4642 Reactant-biased, product-based -
5191-193 Rapamune, 5500,5503 (RBPB) algorithm, 1:215,
metal ion complexes, 5:196 1:216, 1:219
Rapamycin, 1:848,5:490
perturbation of cellular me- Reacting centers, 1:366, 1:383,
binding to FKBP, 1:552, 1:554
tabolism, 5193-196 1:398, 1:409
for photodynamic therapy, clinical use for organ trans-
Reaction BrowserlWeb, 1:387
5174-175 plants, 5500-504
Reaction databases, 1:386
reaction with DNA radicals, cytokine IL-2 downregulation,
Reaction field theory, 1:83
5176-180 4175 Reaction indexing, 1:383
thiols, 5196-197 cytokine IL-5 downregulation, Reaction order
unknown mechanism agents, 4177 in large-scale synthesis,
5196-197 Rapid, high-throughput pharma- 2~413-414
RaMinate, 1:791 cology, 2:72-79 Reaction Package, 1:386
0-Raffinose-crosslinked hemo- Rapid, reversible enzyme inhibi- Reactions, See Chemical reac-
globin, 3:415-417,3:418 tors, 1:720, 1:728-734 tions
Raf protein kinase, 522, 5 2 4 Rapid cellular responses, Reaction scheme, 1:409
Raloxifene, 3343, 3:351 2:73-74 Reactive oxygen species, 5:33
applications, 3:631, 3:632 Rapid genome sequencing, 2:42 Reactors
discovery, 3655-656 Rapid sequence screening, 1:334 for large-scale synthesis, 2:415
estrogen receptor affinity, Rare gas interactions, 1:174 Reagents
3659 Ras-farnesyltransferaseinhibi- chemical modification of
glucuronidation, 3:639-640 tors amino acids, 1:755
interaction with estrogen re- non-peptide peptidomimetics, recombinant for screening,
ceptors, 3:646 2:91-92
1:665-667, 1:668, 1:669
selective toxicity, 5276 recombinant for structural
template mimetics, 1:643,
side effects, 3:355,3:631 biology studies, 2:96
1:645
tissue-selectivity, 3652-653 resin-tethered, in solid phase
Raltitrexed MI-1, 513
synthesis, 2:26-27
antimetabolite, 576,577- 78 Ras signaling pathways, 523-24 scale up in high-throughput
Ramachandran plot, 1:92 Rats screening, 2:53-54
and conformational mimicry, ataxia induction by ROH, 1:29 Reagent Selector, 1:387,
1:141 liver DHFR, QSAR inhibition 1:391-392
Ramipril, 1:746 studies, 1:34 Reasonable royalties, patent in-
impact of ACE polymorphisms Ravuconazole, 5898-899 fringement, 2:747
on effectiveness, 4634 Rayleigh scattering, 4485 Reboxetine, 6:496
Rarniprilat, 1:746-747 RB 101,6:441,6:442, 6:443 affinities for monoamine re-
Randomized Aldactone Evalua- RB 120,6:441-443 ceptors, a 4 9 5
tion Study, 3:111-112 RB 6145 antidepressant, 6:485,6:486,
Random peptide library, 2:95 radiosensitizer, 5182 6:488
Random searching RB 90740 inhibition of serotonin, norepi-
in virtual screening, 1:263 radiosensitizer, 5181 nephrine, and dopamine
Ranitidine RB 38A, 6:441,6:442 transporters, 6:500
classification in various coun- Rb gene, 5:27 pharmacokinetic parameters,
tries, 4:430 gene therapy target, 544-45 6:497
fast follow rational design, RD2-4039 RECAP (Retrosynthetic Combi-
2:54 hepatitis C antiviral, 5:421, natorial Analysis Proce-
and P-gp pumps, 2:658 5:423 dure), 1:249
polymorphic forms, 2:414 RD3-0028,5394495 Receptor agonists, 2:72
Cumulative Index

Receptor antagonists, 2:72 compound ADME, 2:320, Recombinant hemoglobins,


Receptor-based design 2:342-343 3:396,3:397498,
NMR spectroscopy for, 1:510, compound databases, 2:343 3:408-412
1:532-562 compound properties, Recombinant human growth
pharmacophore generation, 2:338-343 hormone, 2:6
1:259 compound sources, 2:342 for wasting diseases, 6:854,
Receptor-based 3D QSAR,1:304 future directions, 2:351 6:858 P
Receptor-based transient an- lead discovery, 2:343-351 Recombinate
chor-type chemical delivery and recombinant DNA tech- hemostatic preparation, 3292
systems, 2:595-596 nology, 2:100-105 Recommended Dietary Allow- -
Receptor binding assays, validation and functional ances (RDA), 4361,
2:339-341 genomics, 2:336-338 4363464,4368
Receptor complexes folic acid, 4:411
Receptor theory, 1:4-7
and allosteric modulators, niacin, 4:397
Receptor tyrosine kinases
2:327-328 vitamin A, 4372
ternary complex models, 2:328 and angiogenesis, 6:217-219
vitamin B,, 4389
Receptor gene assays, 2 5 0 and carcinogenesis, 511-12, vitamin B,, 4392
Receptor interacting protein, 522-23 vitamin B,, 4400
517 Receptosome, 2:258 vitamin C, 4:418
Receptor-ligand complexes, 1:78 Reciprocal nearest neighbor, vitamin E, 4384
Receptor-ligand interactions, 1:220 Recommended Nutrient Intakes,
2:339-342 Recombinant DNA technology, 4363
Receptor-ligand mimetics, 1:636 2:81-83. See also Phage dis- Reconstituted chylomicron rem-
Receptor mapping, 1:148-149 play nants, 4:667
Receptor-mediated endocytosis, antibody-based therapeutics, Recrudescence, 5922-923
2:254,2:258-259,2:658 2:88 Recursive partitioning,
of vitamins and metal ions, aptamers as drugs and diag- 1:247-248
2:264-265 nostics, 2:94 Red clover extract
Receptor-mediated oral absorp- cellular adhesion proteins, LC-MS mass spectrum, 1:589,
tion systems, 2:261-264 2:105-106 1:590
Receptor-mediated potocytosis, enzymes as drug targets, Reduced folate carrier, 5285
2:259 2~96-100 5a-Reductase, 3:616,3:618,
Receptor-mediated transcytosis, epitope mapping, 2:88 -89 3689
2:259 -260 future prospects, 2:106-107 and hair loss, 4:435,4439
Receptor-mediated transport, genetically engineered drug 5a-Reductase inhibitors, 3605,
2:254-255,2:258-261 discovery tools, 2:91-106 3722-724,4426,
Receptor pharmacology, 2:73 new therapeutics from, 4439-440
Receptor-relevant subspace, 2~83-84 structure-activity relationship,
1:204,1:222 phage display, 2:94-96 4437-438
Receptors phage display libraries, 2:96 Reductase tumor-activated pro-
anion- and cation-selective, and plasmid DNA-mediated drugs, 5~91-92
2:360 gene therapy, 4652 Reduction
classes, 2:331-333 protein engineering and site- carbon in metabolism,
cloning, 2:104-105 directed mutagenesis, 2:441-445
constitutive activity, 2~84-91 enzyme-mediated asymmetric,
2:328-329 reagents for screening, 1:806
dynamics, 2:330431 2:91-92 nitrogen in metabolism,
inactivation theory, 2:326 reagents for structural biology 2:445-447
molecular biology, 2:35-336 studies, 2:96 sulfur in metabolism,
nomenclature, 2:331-335 receptors as drug targets, 2:447-448
occupancy theory, 2:323-326 2:lOO-105 Reentry excitation, 3:3041,
rate theory, 2:326 second-generation protein 3:160-161
Receptor targets, 2:319-320 therapeutics, 2:84 -88 ReFacto
antisense compounds, 2:351 SELEX or in vitro evolution, hemostatic preparation, 3:292
basic concepts, 2:322-327 2:92-94 Refining, search queries, 1:409
and cellular communication, Recombinant globin gene vec- Refludan, 3:286,3:316
2:320-322 tors, 3468-469 Reflux esophagitis, 494-95
Cumulative Index

REFMAC, 1:478 Renal cancer Research and development, 2:38


Refractory period, of myocardial cell characterization by gene and delay of marketplace en-
cells, 3 4 expression profiling, 4:607, try of new drugs, 2:705
and reentry, 3 3 0 4608 Resedorm, 6:204
Regimen Bayer, 3287 Renal drug clearance, 2:638 Reserpine
Registration, of chemical infor- Renal failure antiadrenergic, 6:4
mation, 1:377-379 vitamin D analogs used in, applications, 6:15 7
Registry number, 1:378-379, 4377-379 radioprotedive agent, 5:165
1:409 Renal toxins, 2:612 Resiniferatoxin, 1:854
Regitine, 6:4 Renal tubules, 3:57-60 Resins
Reglan Renese, 3:77 early use in tea bag methods,
dose for eating disorders, Renilla luciferase, 2:75 2:4,2:5
6:852 in multiple parallel synthesis,
Renin
Regramostim, 3260 2:26-30
mediation of release, 3:195
Regulatory issues, 2:683-688. for peptide arrays, 2:6-13
secretion in kidneys, 3:56 Resin-tethered reagents, use in
See also Food and Drug Ad-
Renin-angiotensin-aldosterone solid phase synthesis,
ministration
clinical trial safety, 2:697-698 system, 3:114,3:195 2:26-27
prodrug design, 2:502-503 and endothelin, 3:203 Resiquimod
Reifenstein syndrome, 3698 inhibitors and antgonists, for herpes, 5325
Reissue patents, 2:738-739 3197-199 Resochin, 5934
Relational databases, 1:363, Renin inhibitors, 1:432, Resperidone
1:373, 1:409 3:197-198 receptor binding and side ef-
Relative diversitylsimilarity, molecular modeling, 1:123, fects, 6:606
1:209 1:153 RespiGam, 5:361,5:395
Relaxation parameters, in NMR, recombinant DNA technology Respiratory syncytial virus
1:511, 1~512 applications, 2:98 antiviral agents, 5390-398
changes on binding, transition state analogs, 1:647 Restoration (chemical radiopro-
1:536-537 Renshaw cells, 2:389 tection), 5153
and ligand dynamics, ReoPro, 3:29, 3:287, 3318 Restoril, 6:207
1:528-531 REOS filtering tool, 1:225 Restrained electrostatic poten-
and NMR screening, Repaglinide, 411, 414-17, 419, tial, 1:102
1:571-573 4:20-21 Restriction fragment length
in receptor-based design, binding parameters, 4:18 polymorphisms
1:534 (-)-Repandine and carcinogenesis, 5:6
Relaxin, 3229, 3230 antimalarial, 5997 genotyping, 4622-623
Relenza, 5364 Reperfusion injury, 3405 Result set, 1:409, 1:411
structure-based design, 1:451 Reperfusion therapy, 3:156 Resveratrol
Relibase, 1:315 Repolarization, of myocardial for sickle-cell anemia, 3:464
Remacemide cells, 3:5 Reteplase, 3:166,3:167
anticonvulsant, 6:313,6:319 Repolarization prolongators clot selectivity, 3290
Remeron, 6:485 (Class I11 antiarrhythmics), Reticulocytes, 3253
Remestan, 6:207 3:31, 3:32, 340-43,3:167 Reticuloendothelial macro-
Remicade, 4182-183,6:229, Requests for production, in phages, 3496
5233 patent infringement cases, Retigabine
Remifentanil, 2:545-546,6:383 2:749 anticonvulsant, 6:313
dose, 6:334 Requests to admit, in patent in- Retigotine, 1:783
Reminyl, 1:892 fringement cases, 2:749 Retina
for Alzheimer's disease, 6:762 Requip nicotinic acetylcholine recep-
for cognition enhancement, for Parkinson's disease, 6:722, tors, 2:385,2:389
a781 6:725 Retin-A, 4320,4:373
REM sleep, 6:225 RES 701-1 Retinal, 4319,4362,4368,
nonhypnotic drugs affecting endothelin receptor antago- 4369,4370
OFF switch, a227 nist, 3:206 conversion to retinol, 4324,
nonhypnotic drugs affecting RESEARCH 4325-326
ON switch, 6:225-227 Monte Carlo simulated an- Retinaldehyde, 4323
REM sleep rebound, 6:203 nealing, 1:297 Retinoblastoma, 5:27,6:28
Cumulative Index I
I
Retinoic acid, 4319,4362, used in malignancy treatment, Reverse transcriptase/polymer- I
4368,4369370,4374 4374 ase chain reaction (RT-
active isomers, 4 3 2 6 3 2 7 used in psoriasis treatment, PCR)
docking and homology model- 4:373-374 for antisense drug screening, I
ing, 1:305 Retinoid X receptor, 4326 2:128
important signaling retinoid, apo-receptors interact with Reversible enzyme inhibitors,
4325-326 transcriptional corepressor 1:720 T
non-receptor binding proteins, complexes, 4341-344 Rev-Eyes, 6:4
4328 binding domains, 4340 -341 Rexigen Forte, 6:171
RAR/RXR bind response ele- bind response elements, RFI-641, 5:390-393
ments, 4339-340 k339-340 RGD peptide sequence mimics,
signaling pathways, 4335340 holo complexes interact with 1:129, 1:643, 1:645,
stereoisomer analogs, 1:707 1:662-665
two classes of transcrip-
X-ray crystallographic studies, Rgroups, 1:368, 1:373, 1:397,
tional coactivators,
1:492-493 1:405, 1:409-410
4344-345 and combinatorial library de-
Retinoic acid-APL syndrome,
4:320 ligand binding domain, 4341 sign, 1:221
Retinoic acid receptor, 4326 ligand-independent transcrip- RHbl.1, 3:400, 3:408-412
apo-receptors interact with tional activation, 4345 RHb3011,3:404
transcriptional corepressor novel uses for RXR-active Rheumatoid arthritis, 3:780
complexes, 4341-344 compounds, 4350-351 Rhinacanthins
binding domains, 4340-341 X-ray crystallographic studies, influenza antiviral agents,
bind response elements, 1:493 5:389
4339340 Retinol, 4368-370. See also Vi- Rhinoviruses
holo complexes interact with tamin A family comparative molecular field
two classes of transcrip- fate of intracellular, analysis, 1:153
tional coactivators, 4324325 molecular modeling of antivi-
4344-345 oxidation, 4325 ral binding to HRV-14,
ligand binding domain, 4341 Retinol binding protein, 4:324 1:120, 1:122
ligand-independent transcrip- Retinol dehydrogenases, 4325 target of structure-based drug
tional activation, 4:345 Retinyl esters design, 1:454-456
Retinoids, 4318319. See also biosynthesis, 4323-324 Rhizobactin, 3:488
Vitamin A family Retrometabolic drug design, Rhizoferrin, 3:488
anti-AP1activity, 4 3 4 9 3 5 0 synthesis, 3:530-532
2:533-537. See also Soft
biosynthesis, 4319-328 Rhizopus, 5:883
@-caroteneasymmetrical drugs Rhodacyanine dye analog, cat-
soft drugs contrasted with ionic
cleavage, 4322-323
@-carotenesymmetrical cleav- chemical delivery systems, selective toxicity, 5:258
age, 4321322 2:537 Rhodococcus
CD437: atypical retinoid, soft drugs contrasted with penicillin-binding protein,
4:350 hard and prodrugs, 5:615
clinical applications, 2:536-537 Rhodomycins
4318319 Retrometabolic drug design loop, antitumor natural products,
and color vision, 4334-335 2:535 5:124,5:126
fate of dietary sources, Retrosynthetic analysis, 1:409 Rhodopeptin
4320-321 Retrothiorphan, 1:650, 1:651 template mimetics, 1:644,
future directions, 4345-351 opioid peptide metabolism in- 1:645
gene-specific, 4348-349 hibitor, 6:442 Rhodopsin, 4324-325,4:362,
14-hydroxy-4,14-retro-retinol, Retroviruses. See also HIV virus 4368
4327-328 defined, 5459 chemokine similarity, 4:135
metabolism, 4:328-330 vectors for cancer gene ther- cycle, 4370, 4371
receptor- and receptor sub- apy, 5:40-42 Rhodotorulic acid, 3:486,3:487
type-selective, 4345-348 Rev-5901,4217 Riamet, 5:935
role in vision transduction, Revasc, 3:285 Ribavirin
4:330-335 Reverse nuclear Overhauser ef- activity against orthopoxvi-
used in acne treatment, fects pumping, 1:573 ruses, 5:439,5:440
4372-373 Reverse phase HPLC, 4 4 8 flavivirus antiviral, 5:428-429
Cumulative Index

for herpes virus, 5321 Rifamycin 0 , 5 8 4 7 pharmacokinetics, biotrans-


with interferon-a for hepatitis Rifamycin S, 5847 formation, and drug interac-
C, k363-364 Rifamycins, 1:870, 1:872 tions, 6:639
for poxviruses, 5:341 antimycobacterial application, Ritalin, See Methylphenidate .
Ribbed melilot, drugs derived 5:811,5:846-853 Ritanserin, 6:576:570-571
from, 1:882 Rifamycin SV, 5:847,5:848 Rite-Hite v. Kelley, 2:747
Riboflavin, 4392,4393. See also efficacy and dosage, 5:811 Ritipenem acoxil, 5659,5660 r
Vitamin B, Rifamycin T9,5:847,5:850, Ritodrine
radiosensitizer, 5196 5853 P-agonist, 6:4
receptor-mediated endocyto- Rifapentine applications, 6:14 -
sis, 2:264-265 structure-activity relationship,
antimycobacterial application,
Riboflavin adenine dinucleotide, 6:30
5:811,5:847,5:850,5:852
4:393 Ritonavir, 1:648,1:659
efficacy and dosage, 5:811 anti-HIV drug, 5475-476
Riboflavin phosphate, 4392 Rifazalil
Ribosome-inactivating proteins asymmetric synthesis,
antimycobacterial application, 1:807-808, 1:809
(RIPS),2:263
5:859 CYP3A4/5/7 substrate, 4627
Ribosomes, 2:168
lessons learned from com- Rifocin, 5811 P-glycoprotein inhibitor,
plexes with drugs, Right shifters, for hemoglobin, 4631
2:194-198 3:386,3:388-394 P-glycoprotein substrate,
structure and function, Right-to-know laws, 2:767 4631
2:169-175 Rigid analogs, 1:694-699 selective toxicity, 5:267
Ribozymes Rigid body rotations, in molecu- structure-based design, 1:438,
influenza antiviral agents, lar modeling, 1:90-91 1:440
5:385-386 Rigid docking, 1:262-263, 1:293 Rituxan, 5:228,5:230
oligonucleotide therapeutic Rigid geometry approximation, Rituximab, 5:228,5:230-231
effects on, 2:119-120 in molecular modeling, 1:89 Rivastigmine, 1:774
Richmond-Sykes classification, Riluzole for Alzheimer's disease, 6:762
of p-lactamases, 5:619-620 for U S , 6:674 for cognition enhancement,
Ricin, 2:263 NMDA receptor antagonist, 6:781,6:782
Rickets, 4:374, 4376 6:695 structure-based design,
Rifabutin 1:449-450
for Parkinson's disease, 6:733,
antimycobacterial application, RJR-2403
a734
5811, 5:847,5:850,5:852 for Alzheimer's disease, 6:764
Rimactane, 5:811 cognition enhancer,
drug interactions, 5:864 Rimantadine, 5361
efficacy and dosage, k811, 6:799-800
selective toxicity, 5:266,5:267 RNA
5863
Rimexolone, 3:750,3:753,3:768, molecular modeling, 1:154
Rifadin, 5811
3:821 NMR structural determina-
Rifalazil, 5:847, 5850,
55352-853 Rimonabant, 6:883-885 tion, 1:535
Rifampicin Ring-position isomer analogs, structure, 2:121
antimycobacterial application, 1:699-704 T, effect on synthesis, 3:565
k811,5:850-852 Rings as therapeutic agent, 2:117
drug interactions, 5862, in druglikeness screening, in vitro evolution (SELEX),
5864 1:245 2:92-94
efficacy and dosage, 5811, molecular comparisons, 1:139 RNA cleaving groups, 2:149
5:863 in molecular modeling, 1:91 RNA polymerase inhibitors,
inhibitor of amyloid P-peptide Ring-size change analogs, 1:717
aggregation, 6:758 1:699-704 RNA polymerases, 4619,5295
Rifampin, 5:850 Ringwormttinea, 5883 RNase, double-stranded
drug interactions, 5267 Rink resin, 2:30 activation by antisense drugs,
effect on cyclosporine bioavail- Ripazepam, 6:554 2:119,2:128
ability, 2:639 Risedronate RNase H
efficacy and dosage, k811 selective toxicity, 5273 activation by antisense drugs,
P-glycoprotein inducer, 4631 Risperdal, 6:601 2:126-128,2:149
selective toxicity, 5:266 Risperidone, 6:646-647, a648 inhibition by protein binding,
Rifamycin B, 5:847,5:848 dose, 6:601 2:122
Cumulative Index

RNase H (Continued) ROCS, 1256, 1259 Royal Society of Chemistry


2'-modified oligonucleotides shape-based superposition, Chemical Information
with ability to activate, 1:260 Group, 1:360
2:152 (-)-Roemrefidine RP23618,4:139
RNase HI, 2:127 antimalarial, 5:997, 5998 RP60180
RNase HZ, 2:127 Roentgenography, 4486 analgesic, 6:392
RNase P, 2:119 Rofecoxib, 4:234-235 RPR103611 v
RNA-targeted drugs, 2:167-175. for Alzheimer's disease, a767 anti-HIV drug, 5:469
See also Erythromycin; assays, selectivities, and po- RPR109353,1:211
Gentamicin; Neomycin; tencies, 4245 RPR111844 -
Streptomycin; Tetracycline clinical efficacy and safety, endothelin receptor antago-
aminoglycoside toxicity, 4248-249 nist, 3:206
2:184-185,2:615 selective toxicity, 5274 RPR209685,3:324,3:325
multivalency in carbohydrate- in vivo models, 4246 rPSGL-Ig, 2:216,2:220
based, 2233-234 Rogaine, 4433 rRNA, 2:169-170
non-ribosomal, 2:197 Rohypnol, 6207, 6:550 bacterial, 5738
ribosome structure and func- Rokitamycin, 5:763 RS 61443,5:490,5:518,5:519
tion, 2:169-170 Rolcapone R,S descriptors, for chiral mole-
RNA viruses, 5:360361. See for Parkinson's disease, 6:730, cules, 1:365, 1:783
3
also Antiviral agents, RNA 6:731 RS Discovery System, 1:377,
Ro-5-3335, 2291 Rolidon, 3124 1:385
Ro-09-3143, 5907 Rolipram, 6:508 RSHZ19
Ro-11-3245, 6:553-554 Roll-up, 1:410 RSV antiviral agent, 5395
Ro-19-8928,5:678,5:680 Root structure, 1:368, 1:404, RSR-4,3:388,3:390
Ro-24-7429, 2:91 1:410 RSR-13,1:422-423,2:314-315,
Ro-31-8959, 1:121 Ropinirole 3388,3390
Ro-32-7315, 1:652, 12653 for Parkinson's disease, 6:722, radiosensitizer, 5:184-190
Ro-42-1611 6:725-726 RSR-56, 1:422, 1:423
antimalarial, 5984-985 ROSDAL notation, 1:368, 1:410 RSU 1069
Ro-42-5892,3:197-198 Ros growth factor receptor, 5:22 radiosensitizer, 5181-182
Rosiglitazone, 424, 425, 428, RTECS, 1:246
Ro-46-2005, 1:673, 1:676
RTEM p-lactamase, 2:90-91
endothelin receptor antago- 430
RTI 012,3:842,3:843,3844
nist, 3206 binding affinities, 4 2 7
RTI 15, &I90
Ro-47-0203 Rosuvastatin, 1:848, 1:880-881,
RTI 55
endothelin receptor antago- 3:343,3:345,3:368 Parkinson's disease diagnostic
nist, 3206 ADME, 3:356 radioligand, 6:735
Ro-48-1220, 5:710,5:711 enzyme activity, 3364 RTI 5989-29,6:378
Ro-60-0175, 6:886 side effects, 3:354 RTI 6413-003,3:843
Ro-61-0612 Rosy periwinkle, vinca alkaloids RTI 6413-018,3:843
endothelin receptor antago- from, 1:858 RTI 6413-033,39343
nist, 3206 Rotatable bonds RU-486, 2:104-105,3:651
Ro-63-9141, 5:703,5:704 in druglikeness screening, anti-inflammatory properties,
Ro-64-6198 1245 3:839,3:841-845
opioid analgesic, 6:447,6:449 in molecular modeling, RU-35926
Robinul, 6:137 1:90-91 for Alzheimer's disease, 6:763
Robotics Rotaviruses, 5:430 RU-39305,3839-840
in DNA microarray fabrica- antiviral agents, 5:430-431 RU-43044,3839
tion, 4601 Rotenone RU-44790,5668, 5669
in high-throughput screening, multi-endpoint toxicity analy- RU-58841
2:40,2:64-65 sis, 2:625 experimental hair growth
in solid phase organic synthe- renal and hepatic toxicity, drug, 4441
sis, 2:5 2:615 RU 51599
Robustaflavone Roxifiban, 3:319,3:320 analgesic, 6:389,6:391
influenza antiviral agent, Roxindole, a650 Rubella virus, 5:431
5389 Roxithromycin, 5:763 antiviral agents, 5431-432
Cumulative Index

Rubex over-the-counter drugs, 4427 Sarachine


antitumor natural product, phosphorothioate oligonucleo- antimalarial, 5999
5:128 tides, 2:142-143 Sarafotoxin-6c, 3:202
RUBICON, 1:386 St John's Wort Saralasin, 3:198-199
virtual screening application, P-glycoprotein inducer, 4631 SAR-by-NMR approach, 1:508,
1:254 Saintopin 1:516
Rubidomycin dual topoisomerase ID1 inhibi- in NMR screening, 1:564-56%
antitumor natural product, tor, 5:73 1:576
$126-128 Salbutamol, 1:885, 1:886 &arcin, 2:263
Rubreserine applications, 6:14 Sargramostim, 3260, 3261 -
anticholinesterase, 6:88 Salicylate sunscreens Sarin, 1:774,6:91,6:92
Rufigallol structure-activity relationship, Saripidem, a562
4468-469 Sarizotan
antimalarial, 5987
Salicylic acid for Parkinson's disease, 6:733,
Rufinamide
permeation enhancer, 2:675, 6:734
anticonvulsant, 6:313-314, 2:676 Sarpogrelate, 3:328,3:329
6:319 uricosuric agent, 3138-139 Satiety signals, 6:873
"Rule of 5," See Lipinski's "rule Salivation, 6:110 Satraplatin
of 5" Salmeterol, 1:885, 1:886 alkylating agent, 5:54,5:60
Ruptured berry aneurysm, 6:676 P-agonist, 6:4 Saturated rings
RWJ-37868, a297 applications, 6:14 analogs based on substitution
RWJ-38293,6:562 enzyme-mediated reduction, of aromatic for saturated
RWJ-51204, &580 1:806, 1:808 ring; or the converse,
RWJ-51304, &563 structure-activity relationship, 1:699-704
RWJ-54428,5:703,5:704 6:29 Saturation diversity approach,
RWJ-58259,3:327,3:328 Salmonella 1:223
RWJ-270201,5:364,5:374-376 mutagenicity prediction, Saturation transfer difference
RWJ-333441,5703,5:704 1:829, 1:831-832, 1:840, NMR, 1:568-570
RXR (retinoid X receptor), l:842- 843 SB-201993,4:228
3566-567 Salt bridges, 1:285 SB-202026
Ryanodine, 3:160, 3:171 and virtual screening, 1:272 for Alzheimer's disease, 6:763
Salts, 2:651-652 SB-203580
S-2242 formation for Class I1 drugs, structure-based design, 1:457
for adenoviruses, 5:340 2:668 SB-204269
for herpes virus, 5:317-318, Salts definitions, 1:376 anticonvulsant, 6:316-318
5:321 Salts search, 1:388 SB-206999,5:699
for poxviruses, 5:341 Saltucin, 3:76 SB-209247,4228,4:229
S-2474,4247 Saluron, 3:77 SB-209670, 1:211, 1:675
S-4661, 5708 Sampatrilat, 1:651 endothelin receptor antago-
S-8921,2:285 Sandimmune, 5:491,5:492 nist, a206
S-18886,3:326,3:327 Sandoptal, 6:205 SB-209763
S-18986-1 Sanfetrinem, 5:684,5:685, RSV antiviral agent, 5:395
for Alzheimer's disease, 6:764 5:686,5:693-694 SB-214857, 1:213
5-37435, 1:675 in vitro activity, 5:692 SB-217242
S. aureus vaccine, 2:221-222, Sanitizers, 5539 endothelin receptor antago-
2:226 SA node, See Sinoatrial (SA) nist, 3:206
Sabcomeline node SB-240563,4178
for Alzheimer's disease, a 7 6 3 Sanorex, a845 SB-242084, a 5 7 1
Saccharomyces cerevisiae Saporin, 2:263 SB-242253
genome sequencing, 1:344 Saquinavir, 1:648, 1:659, 1:717 structure-based design, 1:458
Saccharopolyspora erythraea, anti-HIV drug, 5:475-476 SB-273779
1:874 CYP3A4/5/7 substrate, 4627 calcitonin gene-related peptide
Safety P-glycoprotein substrate, antagonist, 3222
of clinical trials, and IND pro- 4631 SB-277011,6:643
cess, 2:697-698 selective toxicity, 5:267 SB-408075
in large-scale synthesis, 2:417, structure-based design, tumor-activated prodrug,
2:420 1:435-437, 1:440 5:83,5:94
Cumulative Index

SB-480848,3:374 Schistosomiasis, 5:1035 SDZ 880-061


SB 206848,6:368, 6:369 Schizokinen, 3486, 3487 picornavirus antiviral,
SB-334867-A, 6:887-888 synthesis, 3:524 5:401-402
SB-205588B, 6:368,6:369 Schizophrenia, 6:600-602. See SEAL, 1:316, 1:321
SC-263,4235,4239 also Antipsychotic agents Search queries, 1:368
SC-588,4232,4235 and dopamine, 6:602-603 Secobarbital, a204
SC-22716,4219-220 and glutamate, 6:603-604 Second, 6204 +?
SC-46542,3:134 and serotonin, 6:603 a-Secretase, 6:752
SC-48334,2914-215,2:220 Schrodinger equation, 1:79, p-Secretase, 6:753
SC-53228,4:227-228 1:363 y-Secretase, 6:754 -
SC-57666,4236,4237 Scientific and Technical Infor- p-Secretase inhibitors
SC-58125,4235 mation Network, 1:597 transition state analogs, 1:649
SC-58451,4235 a-Secretase shift, 6:761
SciFinder, 1:385
SC-65872,4935 Secreted placental alkaline phos-
Scintillation proximity assays,
SC-57416A, 4220 phatase, 4 2 7
2:46,2:47,2:66-67 Sectral, 3:28,6:5
SCALCS program, 2:379
Scaled particle theory, 1:84 SCOP, 1:353 Sedative-hypnotics, 6:202-203
Scale-up X-ray crystallography applica- ADME, 6:211-223
and delay of marketplace en- tion, 1:494 classification, 6202
try of new drugs, 2:705 Scopolamine currently used drugs, 6903
of large-scale synthesis, mydriatic and cycloplegic ac- evaluation, 6228
2:408-420 tivity, a 1 5 3 future developments,
nevirapine example synthesis, relative anticholinergic activ- 6955-256
2:422-427 ity, 6:156 history, 6235-237
of reagents for high-through- in solanaceous alkaloids, miscellaneous compounds,
put screening, 2:53-54 6:120-126 6214-215
SCH 29482,5:659,5:660,5:698 stereoisomerism, 6:147-149 pharmacology, 6:228-235
SCH 34343,5:660 therapeutic use, &I17 physiology of sleep, 6:223-228
SCH 34826,3:136-137 ScoreDock recent developments,
SCH 39370,3:136-137 assessment, 1:303 6251-255
SCH 42495,3:136 Scoring functions, 1961, side effects and drug interac-
SCH 47307,1:667 1:264-266, 1~306-312, tions, 6903-211
SCH 48461, 3366 1:322 structure-activity relation-
SCH 48973 assessment, 1:312-315 ships, 6237-251
picornavirus antiviral, basic concepts, 1:289-290 Seizures, 6:264-265,6991-292,
5:400-401 and molecular modeling, 6298
SCH 54726 1:115-116 from antipsychotics, a608
experimental hair growth overview of, 1:307 SelecT, 2:49
drug, 4441 penalty terms, 1:313 Selectan group, 4495
SCH 55700,4178 Screening. See also Combinato- Selectins, 2:223-225. See also
SCH 57050,3:664,3:668 rial chemistry; High- E-selectin; L-selectin; P-
SCH 57068,3664 throughput screening; Vir- selectin
SCH 57790 tual screening and chemokine-induced trans-
for Alzheimer's disease, a 7 6 3 history of, 2:38-41 migration of leukocytes,
SCH 57939, 1:808, 1:810 mass spectrometry-based, 4131
SCH 66701,1:667 1:597-598 cloning, 2:106
SCH 68631 solid phase mass spectromet- Selective estrogen receptor mod-
hepatitis C antiviral, 5422, ric, 1:606-607 ulators, 3:631,3:652-654
5:424 Screening assays, See Bioassays discovery of, 3:655-656
SCH 72788 Screening Investigational New glucuronidation, 3640
for Alzheimer's disease, 6:763 Drugs, 2:689 selective toxicity, 5:276-277
SCH 351633 Screenscore, 1:319 Selective toxicity, 5:250-252
hepatitis C antiviral, 5:422, Sculpt, 1:387 aminoglycosides, 5260-261
5:424 Scurvy, 4417 antibacterial agents,
Schedule V Controlled Sub- SD/Ol (Filgrastim), 3264 5:539-543
stances, 4:423 SDF-la ligand antifungal drugs, 5:254,
Schild analysis, 2:73 and CXCR4,4:166 5266-268, 5:886
Cumulative Index

antihistamines, 52'75-276 for Parkinson's disease, 6:729, 5-HT, receptor, 6:503


antiinfectives, 5259-263 6:730-731 mixed function ligands,
antimycobacterial drugs, Selenium 6:505-506
5266 and vitamin E, 4381 receptor populations,
antiparasite drugs, 5:254, Selestoject, 3:770 6:502-503
5268 SELEX (invitro evolution), Serotonergic regulation of food
antiviral drugs, 5254,5:266 2:92-94 intake, 6:873-874 T
bisphosphonates, 5273-274 Self-emulsifying drug delivery Serotonin, 2:391
cancer chemotherapy exam- systems, 2:673-674 and anxiety, 6:541-543,
ples, 5:257-259 Self-medication, 4423 6:578-579 -
cationic rhodacyanine dye an- Self-microemulsifyingdrug de- and body weight, 6:855
alog, 5:258 livery systems, 2:673 conformationally restricted
cisplatinlcarboplatin, Self-organizingMap method,
analog, 1:696
5257-258 1:65, k 6 6
gating of anion-selective chan-
comparative biochemistry, Semirigid analogs, 1:694-699
5253-254 Senile placques, 6:744 nels, 2:360
comparative cytology, 5254 Separation inhibition by depressants,
comparative distribution, chromatographic, of chiral a500
5252-253 molecules, 1:787-793 radioprotective agent, 5:165,
comparative stereochemistry, in large-scale drug synthesis, 5167
5254-257 2:416 ring position analogs,
COX inhibitors, 5:274-275 Sequence assembly, 1:342 1~703-704
diphtheria toxin, 5259 Sequence comparison, 1:334 role in clotting, 3:304,3:306
and dopaminergic receptors, bioinformatics for, 1:346347, role in CNS stimulant action,
5259 1:352-353 6:182-183
and drug chirality, 5268-273 Sequence databases, 1:387 and schizophrenia, 6:603
estrogen receptor modulators, Sequences, 1:363-364 Serotonin agonists
5276-277 Sequenom, 4:624 for Parkinson's disease, 6:734
imatinib, 5:257 Sequential docking, k317 Serotonin 5-HT,, receptor,
insect growth regulators, Sequential simplex strategy, 6:502,6:503-505
5278 1:11 Serotonin 5-HT,, receptor, a502
insecticides, 5:277-279 Serax, 6:529 Serotonin 5-HTIDreceptor,
p-lactams, 5:254,5:260 SERCA, 3:572,3:575 6:502
macrolides, 5261-263 Serentil, 6:601 Serotonin 5-HTIEreceptor,
monoclonal antibodies, 5257 Serevent, 1:806,6:4 6:502
neonicotinoids, 5278 Serial analysis of gene expres- Serotonin 5-HT, receptor, 6:502
paclitaxel antibody conjugate, sion (SAGE), 1:344 and anxiety, 6:542
5258 cancer studies using, 5 3 6 3 7 Serotonin 5-HT2receptor, 6:502,
phosphodiesterase inhibitors, Serine 6:503
5277 chemical modification re- and anxiety, 6:542
quinolones/fluoroquinolones, agents, 1:755 Serotonin 5-HT, receptor, a502
5:263 Serine kinases, 5 2 4 and anxiety, a542
spinosyns, 5278 Serine peptidase inhibitors cation-selective, 2:360
sulfonamides/sulfanilamides, transition state analogs, Serotonin 5-HT, receptor, 6:502
5263-264 1:652-655 Serotonin 5-HT6receptor, 6:502
target organism examples, Serine protease factor VIIa in- Serotonin 5-HTGreceptor, 6:502
5264-268 hibitors, 2:95 Serotonin 5-HT7receptor, a502
tetracyclines, 5:261 Serine protease inhibitors Serotonin receptors
tricyclic thiophene, 5258-259 affinity labels, 1:762 antiplatelet agent target,
Selector, 1:387 common structural motifs, 3:327329
SELECT program, 1:218-219, 1:494 and anxiety, 6541-543
1:221 QSAR studies, 1:5 and cognition enhancement,
SELECT statement, 1:404, Seromycin, 5811 6:811-817
1:406 Seroquel, 6:601 types of, 6:502
Selegiline Serostim, 6:854 Serotonin-selective reuptake
for Alzheimer's disease, Serotonergic agents, 6:486 inhibitors, 6:484,6:485-486
6:758-759,6:768 5-HT,, receptor, 6:503-505 additional indications, 6:490
Cumulative Index

Serotonin-selective reuptake thyroid hormone binding, Siamycin


inhibitors (Continued) a569 anti-HIV drug, 5:469
for anxiety disorders, Serum complement, 5:224 SIB-1553A
6:531-532 Serzone, 6:485 cognition enhancer,
for eating disorders, Sex hormones. See also Female 6:805-806
6:849-850,6:857-858, sex hormones; Male sex hor- Sibrdban, a319
6:859 mones Sibutramine 'T
efficacy relative placebo, 6:489 biosynthesis, 3:616-618 absorption and metabolism,
norepinephrine-selectivecon- Sex steroid binding /3-globulin, 6:860-861
trasted, 6:501 3:686,3:703 anorectic agent, 6:855856,
pharmacokinetics, 6:496-497 Sexual disorder drugs, 6:875
side effects, 6:493-494 4:440-442 discovery, 6:874-875
structure-activity relationship, adverse effects, 4443-444 dose, 6:844
chemistry and structure-activ- side effects, 1:859
6:511-512,6:513-515
ity relationship, 4446-447 SIB-1508Y
Serotonin syndrome, 6:494
clinical use, 4442-444 cognition enhancer, 6:799
Serotonin transporter, 6:488,
erectile dysfunction causes, Sickle-cell anemia, l:4l9 -425
6:498 4445446 animal models, 3:459
inhibition by antidepressants, erection physiology, 5-azacytidine therapy, 3:464
6:500 4444-445 bone marrow transplantaion,
Serotonin transporter (SERT) history and future trends, 3:465-466
gene, 6:490 4447-450 butyrate therapy, 3:465
Serotransferrin p pharmacokinetics, 4444 and cyanate, 3:460-461
X-ray crystallographic studies, physiology and pharmacology, cyanate for, 3:460-461
1:493 4:444-446 and endothelium, 3:458-459
Seroxat, 6:485 role of nitric oxide, 4445 Flucor for, 3:462
Serpins, 3:307-308 SFCHECK program, 1:478 globin gene regulation,
Sertindole, 6:548,6:647 SGB-017 3~466-469
Sertraline, 6:530 anticonvulsant, a306 hematopoietic stem cell re-
affinities for monoamine re- SGN-15 sponse modification,
ceptors, 6:495 tumor-activated prodrug, 3:469-470
antidepressant, 6:485,6:486, 5:83,5:92 and hereditary persistence of
6:488 Sgroups, 1:373, 1:397, 1:405, fetal hemoglobin, a457
dose for anxiety, a529 1:410 hydroxyurea therapy, a464
dose for eating disorders, Shake and Bake, 1:477, 1:478 modifiers of, 3:452-454
6:849 SHAPES and nitric oxide, 3:462-463
for eating disorders, a857 NMR screening libraries, pathophysiology, 3:443-452
inhibition of serotonin, norepi- 1:575 sickle hemoglobin polymeriza-
nephrine, and dopamine and SAR-by-NMR, 1:568 tion and disease manifesta-
transporters, 6:500 Shared research arrangements, tion, 3:448-449
pharmacokinetic parameters, 2:705 and a-Thalassemia,
6:497 SHARP, 1:478 3:454-456
side effects profile, 6:493 SHELX, 1:478 and p-Thalassemia, 3:456
Serum albumin Sherley Amendment, 2:685 therapeutic decrease of micro-
binding of androgens to, 3686 Shiga toxin, 2:214,2:234 vascular entrapment,
binding of drugs to, 2:637 Shingles, 5:298 3:462-463
binding of enantiomers, 1:786 Shonin (OTC regulatory ap- therapeutic induction of fetal
binding to contrast agents, proval in Japan), 4430 hemoglobin, 3:463-465
4:556-557,4:558 SH3-SH2 binding interactions therapy approaches,
binding with antisense drugs, fluorescence polarization stud- 3:459-461
2:131 ies, 2:48 Sickle hemoglobin. See also Fe-
mass-spectrometric binding SHU9119,462 tal hemoglobin
assay screening, 1:604 Sialic acid, 1:450-451, chemical modifiers, 3:461
for plasma volume expanders, 2:208-209 low deoxygenated solubility
3:429,3:430,3:431-432 Sialidase and polymerization,
target of NMR screening stud- genetic algorithm study of 3:450-451
ies, 1:567-568, 1:573 docking, 1:88-89 polymerization, 3:447-450
Cumulative index

polymerization inhibition, Simulated annealing. See also polymorphisms in drug trans-


3:459-460 Monte Carlo simulated an- porter genes, 4:631-632
polymerization kinetics, nealing scanning for using DNA mi-
3:450,3:451 and combinatorial library de- croarrays, 4601
"sparing" effect of fetal, sign, 1:217 single gene studies in genes
3456-457 with FOCUS-2D method, 1:68 influencing disease progres-
structure, 3:444-445 hydrogen bonds, 1:107 sion, 4636-641 t
Sickle syndromes, 3:453,3:456 in molecular similarity/diver- synonymous and nonsynony-
Sickle trait, 3:457-458 sity methods, 1:205 mous, 4620
and malaria, 5:931 with QSAR, 1:53, 1:61 Single photon emission com-
Sick sinus syndrome, 3:31 in virtual screening, 1:263 puted tomography (SPECT)
Side chains Simulated moving bed chroma- for Parkinson's disease diag-
of known drugs, and druglike- nosis, 6:734-735
tography Single-strand conformation poly-
ness screening, 1:248-249 for enantiomer separation,
morphism analysis, 4621
peptide-like, 1:635, 1:642 1:787, 1:789-793, 1:821
Single-wavelength anomalous
Siderophores, 3:483-488 Simulcet, 5:510,5:513 diffraction phasing (SAD),
Siglecs, 2:242 Simvastatin, 1:719, 1:744, 1:879, 1~477-478
Signal peptidase enzymes, 1:880,3:343,3:345,3:609 Singulair (MK-04761,4223-224,
5:712 ADME, 3:356 4226
Signal transducer and transcrip- for Alzheimer's disease, a757 Sinlestal, a343
tion factor 3 (STAT-3), for angina treatment, 3:11 Sinoatrial (SA) node, 3:3,3:4,3:5
&885 enzyme activity, 3:364 and disorders of signal genera-
Signature with ezetimibe, 3:349 tion, 3:29
molecular similarity methods, single nucleotide polyrnor- and reentry excitation,
1:i88 phisms influencing response 3:30-31
Sila-difenidol anticholinergics, to, 4639-641,4644 Sinus arrhythmia, 3:31
&I32 Sindbis virus, 5431 Sinus bradycardia, 3:9
Silandrone, 3:714 Sinequan, 6:485 Sinus tachycardia, 3:9,3:31
Silatecans Single base primer extension Sirolimus, 1:848, 15349, 5:489,
antitumor natural products, genotyping, 4623- 624 5:490
5:133 Single-channel conductance clinical use for organ trans-
Sildenafil (Viagra),4440, 4442 nicotinic acetylcholine recep- plants, 5:500-504
adverse effects, 4443 tors (neuronal), 2:387-388 P-glycoprotein substrate, 4631
Single nucleotide polymorphism pharmacokinetics, 5:500
CYP3A4/5/7 substrate, 4627
(SNP) identification, 2:42 pharmacology, 5:500-503
development of, 4448-449
Slngle nucleotide polymorphism side effects, 5:503-504
mechanism of action, 4446 (SNP)maps, 1:338-340,4620 structure-activity relationship,
pharmacokinetics, 4:444 Single nucleotide polymor- k503
selective toxicity, 5277 phism~(SNPs), 4618-620. Sis growth factor, 5:22
structure-activity relationship, See also Pharmacogenomics Sitaxsentan
4446-447 and carcinogenesis, 5:6 endothelin receptor antago-
Silencing mediator of retinoic classification, 4:620-621 nist, 3:206
and thyroid receptor defined, 4620 Site-based pharmacophores,
(SMRT), a567 discovery, 4621-626 1:235-237
Silver salts drug response and toxicity Site-directed chemical cleavage,
topical antibacterials, 5553 variability, 4618-619 2:271-272
Similarity searching, 1:379, frequency, 4620 Site-directed excimer fluores-
1:382-383, 1:410. See also gene expression profiling of cence, 2:271
Molecular similarity/diver- drug response, 4:610 Site-directed mutagenesis,
sity methods influence on clinical trials, 2:84-91
in molecular modeling, 4641-644 Site-exposure enhancement fac-
1:135-138 patentability, 2:719 tor, 2:580
and QSAR, 1:67-68 polymorphisms in drug metab- Site-specific enzyme-activated
SQL for, 1:395 olizing enzymes, 4626-631 chemical delivery systems,
Simple hypercholesterolemia, polymorphisms in drug target 2:591-595
2:342 genes, 4632-636 Site-targeting index, 2:580
Cumulative Index

Sitostanol, 3352, 3367 Slow-binding enzyme inhibitors, SNX-111, 1:851-852


0-Sitosterol, 3:351352,3:367 1:720, 1:734-740, 1:749 SO3
Size-exclusion chromatography, Slow channel congenital myoas- antimalarial, 5:957 -
1:599 thenic syndrome, 2:376 Social anxiety disorder,
Size reduction, See Particle size Slow reacting substance of ana- 6:526-527
reduction phylaxis (SRS-A),4208 Social phobia, 6:526-527
Sizofilan, 1:849 Slow-tight-binding enzyme in- SOCRATES, 1:361 F
SKF 10047,6:375 hibitors, 1:720, 1:734-740 Sodium
ligand to characterize delta SM-7338,5:668-669 and coronary artery disease,
receptor, 6:342 SM-9018,6:647 3:11 -
SKF 38393, a182 SM-19712 reabsorption in kidneys,
for Parkinson's disease, 6:727 endothelin-converting enzyme 358-59,362-63
SKF 81297 inhibitor, 3208 role in heartbeat, 3:4-5
for Parkinson's disease, 6:727, endothelin receptor antago- Sodiumc/Calcium2+exchanger
6:728 nist, 3:207 after myocardial infarction,
SKF 82958 Small dense LDL (sdLDL), 3341 3156,3:158
for Parkinson's disease, 6:727, Smallpox, 5:435-440 in kidneys, 3:59
6:728 SMART, 1:349 Sodium+/Calcium2+exchanger
SKF 94901,3:581-582,3:587 functional group filters, 1:246 antagonists, 3173-175
tissue-selective thyromimetic, SMILES notation, 1:254, 1:410 Sodium channel blockers, 3:6
3:570 and canonical renumbering, increased mortality from, 3 4 5
SKF 104353,4222,4226 1:378 Sodium channels, 3:7
SKF 105657,3:723-724 described, 1:368-369, 1:371 Sodium cromoglycate,
SKF 106203,4:222 use with comparative QSAR, 1:883-884
SKF 107260, 1:663 1:39 Sodium cysteinethiosulfate
Skin cancer, 4458 SmoG, 1:311 radioprotective agent, 5:161
Skin-derived dendritic (Langer- Smoking cessation agents, Sodium 2,3-dimercaptopropane
hans) cells, 5:224 4450-451 sulfonate
Skin tanning, 4464-465 adverse effects, 4451-453 radioprotective agent, 5:157
Skopalate, 6:117 chemistry and structure-activ- Sodium+/HydrogenCexchanger
Skopyl, a117 ity relationship, 4455-457 in kidneys, 3 5 8
SL-650472,3:328,3:329 clinical use, 4451-453 Sodium iodide
SL-651498,6:580 history and future trends, neurotoxicity, 4555
SLC ligand 4:457-458 Sodium iodomethamate, 4497
and CCR7,4160-161 nicotine's action, 4454-455 properties, 4511
Sleep, 6:202,6:223-228. See also pharmacokinetics, 4453 Sodium ipodate
Sedative-hypnotics physiology and pharmacology, protein binding, 4557
and neurotransmitters, 6:225, 4454-455 Sodium mercaptomerin, 3 6 7
6:227-228 SMS-201,995,6:437 Sodium pantothenate, 4401,4402
REM, 6:225 SN-6999, 1:544 SodiumC,Potassium+-ATPase
states of, a224 SN-24771 inhibitors, 1:718
Sleep cycle, 6:225 radiosensitizer, 5196 Sodium+/PotassiumC-ATPase
Sleep studies, 6:224 Snail ACh-binding protein, Pump
SLIDE 2:362-364 after myocardial infarction,
anchor and grow algorithm, Snake venom peptides, 1:881, 3:159,3:162
1:296 2:6 in kidneys, 3:58
combinatorial docking, 1:317 Snapshot, 4624 up-regulation by thyroid hor-
explicit water molecules, SNC 80,6:395399 mones, 3570
1:302 Snowdrops, drugs derived from, Sodium salicylate, 3138-139
geometric/combinatorial 1:892 Sodium selenate
search, 1:295 SNPcode kits, 4624 radioprotective agent, 5162
ligand handling, 1:293 SNP Consortium, 4622 Sodium stibogluconate
protein flexibility, 1:301 SNPs, See Single nucleotide for leishmaniasis, 51051
receptor representation in, polymorphisms Soergel distance, 1:68
1:291 SNPStream 25K, 4624 Soft analogs, 2:560
SLN (Sybyl Line Notation), SNPware 96,4624 ACE inhibitors, 2:565
1:369, 1:410 SNuPe, 4:624 antiarrhythmic agents, 2:562
Cumulative Index

anticholinergics, 2:558-560 characterization, 2:665 template mimetics,


antimicrobials, 2:560-562 hydrate pseudopolymorphs, 1:643-644, 1:645
calcium channel blockers, 2:653 TSH modulation, 3568
2:566 polymorphs, 2:652 Sombem, 6:209
cannabinoids, 2:566 salts, 2:651 Sombulex, 6:204
DHFR inhibitors, 2:565-566 Solid supports Sonata, a 2 1 1
Soft drugs for carbohydrate-based drug Sonepiprazole, 6:40 .t
activated, 2:570 synthesis, 2:230 Sorangium cellulosum, epothi-
active metabolite-based, in multiple parallel synthesis, lones from, 1:864
2:568-576 2:29-30 Sorbitol -
p,-agonists, 2:554-555 for peptide arrays, 2:6-13 osmotic diuretic, 3:64
p-blockers, 2:540-544 Solubility, See Aqueous solubil- Sordarins, 6:907-908
bufuralol analogs, 2:543-544 ity
Soretolide
chemical delivery systems con- Soluble intercellular adhesion
anticonvulsant, 6:315
trasted, 2:537 molecule-1
corticosteroids, 2:547-560 SoRI 9409,6:369
picornavirus antiviral agent,
estrogens, 2553-554 6:403-404 Soriatene, 4373
hard and prodrugs contrasted, Solu-Cortef, 3:770 Sotalol
2:536-537 Solu-Medrol, 3771 p-antagonist, 6:5
inactive metabolite-based, Solute carrier genetic superfam- applications, 6:16
2:539-560 ily, 2:267 D-Sotalol, 3167
insecticides and pesticides, Solution molecular dynamics, D,L-Sotalol, 3:32, 3:41
2:555-558 1:528 cardiovascular effects, 3:42
opioid analgesics, 2:544-547 Solution phase combinatorial increased use of, 3:45
pro-soft drugs, 2:571472 chemistry, 2:5 multiple inhibitory mecha-
Soft ferrites Solution phase combinatorial nisms, 3:33
radiopaque material, 4:489 libraries uses and side effects, 3:40
Solanaceous alkaloids, small druggable molecules, L-Sotalol,3:32
6:120-124 2:14-31 cardiovascular effects, 339,
semisynthetic derivatives, Solution stability 3:40
6:124-126 characterization, 2:664 - 665 uses and side effects, 3 3 8
Solange, 4320 Solvates, 2:651 Southeast Asian ovalocytosis
Solar keratosis, 4466 pseudopolymorphs, 2:653 and malaria, kg31
Solasulfone, 5:830 Solvation effects Spacolin, 6:158
Soldactone, 3: 117-1 18 and docking scoring functions, Spantide, 3:224
Solid dispersions, 2:669-670 1:307, 1:308, 1:310 Sparfloxacin, 5:855
Solid form selection, 2:650-654. drug-receptor complexes, Sparine, a 6 0 1
See also Oral dosage form 1:177-179 Sparteine hydroxylase, 4:627
Solid phase organic synthesis, molecular modeling, 1:83-85 Spasms, 6:111,6:116-118
2:2-6 SOLVE, 1:478 SPC model, 1:175
carbohydrate-based drugs, Solvents Specific phobias, 6527
2:230-231 selection for large-scale drug Specific structure, 1:368, 1:403
history of development, 2:4-5 synthesis, 2:412-413 Spectazole, 5:891
lipid arrays, 2:13-14 Soman, 6:91,6:92 Speda, 6:205
nucleoside arrays, 2:13 Somastatin-14 Spergualin, 5504
oligosaccharide arrays, 2:13 similarity to urotensin-11, Sphere coloring, 1:296
peptide arrays, 2:6-13 3:212-213 Sphere-exclusion, 1:207
Solid Phase Synthesis database, Somatostatin, 3:228-229 Sphingolipids, 2:616
1:385 conformationally restricted Spindle poisons, 1:867
Solids handling peptidomimetics, 1:129, Spin-label NMR screening,
in large-scale synthesis, 1:637, 1:638 1~573-574
2:416-417 mu-receptor opioid antago- Spin-lattice relaxation, 4:490
Solid state properties nists derived from, Spinosyns
of active pharmaceutical in- 6:437-438 selective toxicity, k278
gredients, 2:414 receptor agonists found Spin-spin relaxation, 4:490
Solid state stability through combinatorial Spiradoline
amorphous solids, 2:653 chemistry, 1:657 analgesic, a389
Cumulative Index

Spiral computer-assisted tomog- SR-1214634 3201 side effects, adverse effects,


raphy Src-homology domains, 5:23, drug interactions, and con-
radiopaques applications, 5:25 traindications, 3:352-354 -
4495,4568 Src tyrosine kinase, 6:22 single nucleotide polymor-
Spiramycin, 5:763 SRR-SB3 phism~influencing response -
Spirodioxolane, 6:60 anti-HIV drug, 5:469,5:470 to, 4639-641,4644
Spirolactams, 3:115-116 SRS (Sequence Retrieval Sys- solid phase organic synthesis iZ
Spironolactone, 3:111-120, tem), 1:335 library, 2:11
3:142 SSR 591813 structure-activity relationship,
Splenohepatography, 4567. See experimental smoking cessa- 3:363-364 -
also Radiopaques tion agent, 4459 Statistical mechanics, 1:94-95
SPLICE, 1:89, 1:113 Stable angina, 3:9,3:290 Statutory invention registration,
Splice site mutations, 4:620 Stachyflin 2:770-771
Splicing, 4619
influenza antiviral agent, Staurosporine
Split and mix method, in solid
5~379380 radiosensitizer, k193
phase organic synthesis, 2:9
Split and pool method, in solid Stadol, a 3 3 5 toxicity testing, 2:627
phase organic synthesis, 2:8 Stanazolol, 3:712,3:715 Stavudine
Spongothymidine, 1:867-868 anabolic activity, 3:716 selective toxicity, 5:267
Spongouridine, 1:867-868 Standard Review, in New Drug Stay Alert, a170
Sporanox, 5:890,5:891 Approval, 2:698,2:700 Stay Awake, 6:170
Sporothrix schenkii, 5:883 Stanolone, See 5a-Dihydrotes- Steel factor, See Stem cell factor
Sporotrichosis, 6:883 tosterone Stelazine, 6:601
Spotted DNA microarrays, Staphlokinase, a323 Stem cell factor, 3:266-267
4604-605 Staphylococcus bioactivity, 3:267-268
Spray drying bridge in peptidoglycans, preparations, 3:268
and solid state structure, 5:612 role in blood cell development,
2:669 penicillin-binding protein, 3:252, 3:253,3:255
SPRESI, 1:254 5:615 therapeutic implications,
SPRESI'95, 1:385 Staphylococcus aureus 3:272
SQ 26180,5:664,5:665 antibiotics active against, therapeutic indications, side
SQ 28603,3:136 5:631-632 effects, and pharmacokinet-
SQ 29072, a136 iron uptake by, 3:494-495 ics, 3:268
SQ 32547,3:46 X-ray crystallographic studies,
methicillin-resistant,
SQ 32926,3:46 1:493
6:617-618
SQ 83360,5:668 Stem cell leukemia (SCWTal-1)
Starbucks, e l 7 0 transcription factors
SQL (Structured Query Lan-
guage), 1:395, 1:410 Starfish ligand, 2:234 and sickle-cell anemia, a467
Squalene Starlix, 4 1 4 Stem cells
conversion to cholesterol, Star schema, 1:390, 1:391, 1:410 organ transplant rejection ap-
3:608-609,3:612 Statins, 1:718, 1:719, plications, Z523-524
formation, 3:611 1:744-746, 1:848,3:609 in toxicity testing, 2:626-627
Squamous cell carcinoma, 4465 ADME, 3355-357 Stereoisomer analogs,
SR-4233 for Alzheimer's disease, 1:704-707
radiosensitizer, 5:181 6:756-758 Stereoisomers, 1:365366,
SR-4482 for angina treatment, 3:11 1:783-785
radiosensitizer, 5:181 and cholesterol synthesis, and anticholinergic activity,
SR-48968, 1:670 3:608 6:147-150
SR-140333,3:223 clinical applications, large-scale synthesis, 2:412
SR-141716 3342-346 and obviousness of patent
experimental smoking cessa- history of development of, claims, 2:732
tion agent, 4459 3:362-363 Stereoplex, 1:387
SR-142801 multisubstrate analogs, Stereoselective synthesis, See
tachykinin antagonist, a224 1:744-746 Asymmetric synthesis
SR-3727A new treatments for lowering Steric parameters
for herpes virus, 5:316 LDL and TG, 3:368-370 in QSAR, 1:23-25, 1:52
SR-120107A, 1:670,1:673 with niacin, 3:350 Sterilization, 5:539
Cumulative Index

STERIMOL parameters, 124, Storage, of chemical informa- Striatum


1:50 tion, 1:373-377 nicotinic acetylcholine recep-
5a-Steroid, 3:596 Streptavidin tors, 2:385
5P-Steroid, 3:596 free energies of binding, 1:286 STRL-22,4159
Steroidal aldosterone antago- FRET studies of biotin bind- Stroke, 6:675-676. See also
nists ing, 2:48-49 Neurodegenerative condi-
diuretic agents, 3:111-120 genetic algorithm study of bi- tions P
Steroid aromatization, otin docking to, 1:89 and cellular energetics,
3619-620,3:642-643 interaction with biotin, 6:679-680
androgens, 3:690 1:181-183 DNA damage caused by, 6:677 -
estrogens, 3:642- 643 Streptococcus Stroma-free hemoglobin,
Steroid biochemistry, a606 bridge in peptidoglycans, 3:396-397, a 4 0 3
hormone action, 3:622-624 5:612 Stromelysin, 2:119
flexible docking studies, 1265
Steroid hormones, 3:593-595. penicillin-binding protein,
NMR binding studies,
See also Anti-inflammatory 5:615,5:617
1:555-557
steroids; Female sex hor- Streptococcus pneumonia target of NMR screening stud-
mones; Male sex hormones P-lactam resistance, 5613, ies using SAR-by-NMR,
affinity for binding proteins, 5:712 1:566
1:147 Streptogramins, 12376-877, target of structure-based drug
for Alzheimer's disease, &767 5:785-787 design, 1:443-444
biosynthesis inhibition, 1:770 Streptokinase, 3:165,3:322 Stromelysins, 5:13
chemical reactions, 3:604-606 clinical trials, a294 Structural data mining, 1:410
chemical synthesis, 3:599-602 clot selectivity, 3290 Structural frameworks of known
microbial transformation, treatment regimens, 3298 drugs
3:602-604 Streptomyces, 1:876, 1:891, and druglikeness screening,
for neurodegenerative condi- 5:111, 5:609 1:248-249
tions, &675 Streptomyces argillaceus, 5122, Structural genomics, 1:283
nomenclature, 3:597-599 5123 and bioinformatics, 1:352-354
structure and physical proper- Streptomyces caespitosus, 5:120 and X-ray crystallography,
ties, 3:595-597 Streptomyces cattleya, 1:872 1:481, 1:494-496
Steroid metabolism, 3:620-622 Streptomyces clavuligerus, 1:869 Structural homology, See Ho-
Steroidogenesis, 3:606-620 Streptomyces erythreus, 1:874 mology
and trophic hormones, a614 Streptomyces griseus, 1:869 Structural similarity, 15255
Steroidogenic acute regulatory Streptomyces peucetius, 5:124 Structure-activity relationship,
protein, a610 Streptomyces plicatus, 5:122 2:40,2:610. See also Quan-
Steroid receptors, 3:622-624 Streptomyces tanashiensis, 5:123 titative structure-activitv"
Steroid receptor superfamily, Streptomyces venezuelae, 1:870 relationship; specific drugs
2:334 Streptomyces verticillus, 5:115 and bioassay design, 2:44
Steroid 5a-reductase inhibitors, Streptomycin, 1:869-870,2:168, and data mining, 1:66-67
1:717, 1:768-770 2:207,5:748 development using peptide
QSAR studies, 1:37-38 antimycobacterial application, arrays, 2:s
Sterol esters 5:811,5:840-842 and molecular modeling, 1:134
formation, 2:459-460 drug interactions, 5:864 nonlinear, 1:62
STI571,5:284 efficacy and dosage, 5:811, pharmacophore searching for
Stille coupling 5:863 generating, 1955,
use in solid phase organic syn- mechanism of action, 1:272-273
thesis, 2:17 2:170-171,2:195, receptor targeting drugs,
Stilnox, 6211 k84l- 842 2:338-339
Stimulants, 6:168. See also CNS selective toxicity, 5960-261 and toxicity prediction,
stimulants structure-activity relationship, 1:828-843
Stiripentol 2:171-183,5:840-841 Structure-based drug design,
anticonvulsant, a314 toxicity, 2:184-185,2:615 1:358, 1:417-419,
STN Express, 1:385 Streptozotocin 1:467-469
STN International, 1:385 alkylating agent, 5 5 4 , 5 6 5 antifolate targets, 1:425-432
STO-3G basis set, 1:175 Stress proteins, 5:819 and combinatorial chemistry,
Stoichiometry, 2:413-414 Stretohydrazid, 2:175-176 1:227
Cumulative Index

Structure-based drug design Substances, 1:368, 1:410,2:502 p-lactamase inhibitory activ-


(Continued) Substantia nigra ity, 5:695
combinatorial library design, nicotinic acetylcholine recep- use recommendations, 5:626 .
1:225-228 tors, 2:385 Sulbenicillin, 5:632
and docking studies, 1:282, Substituent constants, for Sulconazole, 5904
1:321-322 QSAR, 1:19-23 formulations and indications,
hemoglobin, 1:419-425 Substitution/omission method, 5891 v
hydrolases, 1:449-454 in solid phase organic syn- Sulfadoxine, 5957
iterative cycles, 1:282, 1:463 thesis, 2:9-10 with pyrimethamine,
NMR spectroscopy for, 1:419, Substrate analog enzyme inhibi- 5958-959 -
1:516-517 tors, 1:733 useful lifetime before resis-
oxidoreductases, 1:445-449 tance develops, 5:930
Substructure searching, 1:255,
phosphoryl transferases, Sulfalene, 5957
1:379, 1:381-382,
1:456-461 dosage forms, 5:935
1:410-411 Sulfamate anticonvulsants
picornaviruses, 1:454-456
and QSAR, 1:67 ADME, 6:291
proteases, 1:432-445
SQL for, 1:395 Sulfamethoxazole, 5:957
and virtual screening, 1:244
Structure-based inhibitor de- Substructure search keys, 1:375, dosage forms, 5934
sign, 1:418 1:376, 1:378, 1:410 m-Sulfamoylbenzoic acid hydra-
Structure-based virtual screen- molecular similarityldiversity zides, 3:81-84
ing, 1:260-267 methods, 1:189, 1:221 Sulfanilamide, 3:56,3:69
Structure elucidation Subtilases Elixir Sulfanilamide poison-
NMR spectroscopy for, homology modeling, 1:123 ings, 2:685
1:517-525 Succinate dehydrogenase, 1:733 makes urine alkaline, 3:68
Structure table, 1:376 Succinic semialdehyde dehydro- selective toxicity, 5:263-264
Structure toxicity relationship, genase inhibitors, 1:718 Sulfated glycolipids
2:621 Succinimide anticonvulsants, interaction with sickled cells,
Structure verification a271 3458
as bottleneck in drug discov- ADME, 6:282 Sulfation
ery, 1:592 Succinylcholine, 2:539 in metabolism, 2:452-453
mass spectrometry applica- apnea from, 4618-619 Sulfazecin, 5:609,5:664,5:665
tion, 1:594-596 Succinyldicholine Sulfentanil, 2:544
Strychnine conformationally restricted Sulfinpyrazone, 3:139,
nicotinic receptor antagonist, analogs, 1:699 3:140-141
2:389,2:395 Sucrase-isomaltase, 4:33-36 Sulfisoxazole, 5:957
SU5416 Sucrose dosage forms, 5934
antiangiogenic agent, osmotic diuretic, 3:64 Sulfoarecoline. 6:69
5218-219 Sucrose polyesters Sulfonamide anticonvulsants
SU6668 in lipid formulations, 2:671 ADME, 6:286
antiangiogenic agent, Sufenta, 6:334 Sulfonamide diurectic-antihy-
5218-219 Sufentanil, 6:383 pertensive agents, 3:86-87
Subcellular toxicity targets, cytochrome P,,, isozyme sub- Sulfonamides
2:615 strate, 6:339 antimalarial, 5:957-958
Subgraph isomorphism, 1:67, dose, a334 aromatic diuretic agents, 3:68,
1:405, 1:410 SUGARBASE, 2:232 370-73
Sublimaze, 6:334 Sugars nonaromatic diuretic agents,
Subreum, 15349 chirality, 1:784 3:68,3:81-89
Substance K, 3:221 Suggestive marks, 25'58 pharmacophore points, 1:249
Substance P, 6:517 Suicide gene therapy, 5 9 0 residues in pseudopeptide ar-
biological action, 3:222-224 for cancer, 5 3 9 , 5 4 4 rays, 2:12
biosynthesis, 3:221-222 Suicide substrate MMP inhibi- selective toxicity, 5263-264
discovery, 3:194 tors, 1:651-652 systemic antibacterials,
Substance P antagonists, Suicide substrates, 1:756 5557-582
1:669-671 Sulbactam, 1:718,5:697 Sulfones
Substance P-NK1 receptor an- amoxycillin MIC, 5695 antimalarial, 5957-958
tagonists, 6:517 antimycobacterial application, antimycobacterial, 5:829-830
Substance P receptors, 3222 5858 pharmacophore points, 1:249
Cumulative Index

systemic antibacterials, for combinatorial library puri- Symmetrel


5:557-582 fication, 1:594 for Parkinson's disease,
Sulfonyl halides Superoxide, 3:502-503 6:733-734
filtering from virtual screens, Superoxide dismutase, 3:502 Sympathetic nerves nerves, 6:27
1:246 Supersaturation, 2:668 Sympathomimetic chemicals,
4-Sulfonylphenyl COX-2 class, Superstar, 1:315 6:27
4234-241 Superstructure search, 1:255, Synagis, 5:227 P
Sulfonylurea insulinotropic 1:257, 1:411 RSV antiviral agent, k395
agents, 411-20 Supervised data mining, Synalgos-DC, 6:335
Sulfonylurea receptors, a 1 7 7 1:66-67, 1:411 Synercid, 1:848, 1:849, 1:876, -
Sulfonylureas Supraventricular arrhythmias, k793
selective toxicity, k264 3:31 Synergis, k361
Sulfur-containing compounds Supraventricular tachycardia,
Synkovit
radioprotective agents, k152, 3:9,3:31,3:161
radiosensitizer, 6: 196
k155-162 Suramin
SYNLIB, 1:361
Sulfur oxidation and reduction for African trypanosomiasis,
in metabolism, 2:447-448 k1037-1039 Synonymous single nucleotide
Sulindac, 2:516-517 antihelmintic, k1091, polymorphisms, 4620
Sulisobenzone 5~1095-1096 Synsorb, 2:214,2:220
absorption and disposition, Surfactants, 2:671 Synthesis, See Drug synthesis;
4462,4463 as absorption enhancers in Solid phase organic synthe-
sunscreen, 4460 lipid formulations, 2:674 sis
Sulphonamides, 1:717 permeation enhancers, 2:676 Synthetic antibacterials
Sulprostone, 4:304 table of pharmaceutically ac- systemic, k557-594
Sultamicillin, k697 ceptable, 2:672 topical, k539-557
Sulukast, 4222 topical antibacterials, Synthetic pathways
Summary judgment, patent in- k555-557 evaluating alternatives for
fringement, 2:749-750 Suriclone, 6:558-559 synthesis, 2:410-411
SUN 5555,5:659,5:660 Surital, 6:204 Synthokine, 3:271
Sunamed, 5:763, kg35 Surmontil, 6:485 Synthroid, a576
Sunburn, 4464 Sustained-release prodrugs, Syntropan, a 1 3 4
Sunepitron, 6:569, a 5 8 1 2:512-513 a-Synuclein, 6:715-716
Sun protection factor, 4467 Suxamethonium, 1:857 Syrups, 2:654
Sunscreens, 4458-460 effect on nicotinic receptors, SYSDOC
absorption and disposition, 2:370-371 ligand handling, 1:293
4:462-463 Suzuki coupling Systematic search
acute effects of ultraviolet ra- use in multiple parallel syn- and Active Analog Approach,
diation, 4464 thesis, 2:27 1:144-145
adverse effects, 4461-462 Sweating, 6:110 and conformational analysis,
chemistry and structure-activ- Sweden 1:89-93
ity relationship, 4467-470 patentable subject matter, in docking methods, 1:292
chronic effects of ultraviolet 2:720 in molecular modeling,
radiation, 4464-466 Sweet clover, drugs derived 1:89-94, 1:116
clinical use, 4460-463 from, 1:882 Systems-based drug discovery,
history and future trends, Sweet wormwood, drugs derived 2:54-56
4470-473 from, 1:886
physiology and pharmacology, SWISS-PROT, 1:335, 1:345-346 T-705
4463-467 SX-3933 influenza antiviral agent,
protection factor, 4467 binding affinity with GABAA/ k390
Sunshine-type laws, 2:767 Bz, a 7 9 5 T,, See Thyroid hormone T,
Supercritical fluid chromatogra- SYBYL, 1:130 T,, See Thyroid hormone T,
P ~ Y Sybyl Programming Language, T22
for enantiomer separation, 1:378, 1:410 CXCR4 antagonist, 4167-168
1:787 Sycotol, 6:136 T140
Supercritical fluid chromatogra- Sygen, 2:213,2:220 CXCR4 antagonist, 4168
phy-mass spectrometry Syltherm, heat transfer mate- T5575,5:637
(SFC-MS) rial, 2:415 T5578,5:637
Cumulative Index

TI57602 CCR2 antagonist, 4146-147 Tanimoto coefficient, 1:68,


for herpes, 5:323 CCR5 antagonist, 4156-157 1:202, 1:411
T. gondii DHFR, QSAR inhibi- Talambrol, 6:209 cluster-based methods with, .
tion studies, 1:33 Talampanel 1:206
Tablet fillers, 2:678 anticonvulsant, 6:307 and similarity searching,
Tabular storage, 1:369-371 Talampicillin, 2:510,5:632 1:382, 1:410
Tabun, 6:91,6:92 Talbutal, 6:204 for virtual screening, 1:210
Tabu search Talipexole, 6:650 Tanimoto Dissimilarity, 1:220
with docking methods, 1:292, Tallimustine Tankyrase, a679
1:299 alkylating agent, 5:57-58 Tanomastat -
in virtual screening, 1:263 Tallysomycins structure-based design,
Tace, 3:632 antitumor natural products, 1:444-445, 1:446
Tachycardia, 3:9,3:31,3:161 5:115,5:117 Tantalum
from hyperthyroidism, 3:574 Talompicillin, 5:609 radiopaque material,
and reentry, 3:30 Talsaclidine 4486-487
Tachykinin antagonists, 3:224 for Alzheimer's disease, 6:763 Tantalum oxide
Tachykinin receptors, 1:669, Talwin, 6:335 radiopaque material,
a222 Tamiflu, 5:364 4:492-493
Tachykinins Tamoxifen, 3:343,3:351,3:630, TAPS (transcytosis-associated
biological actions, 3:222-224 3:661-665 proteins), 2:259
biosynthesis, metabolism, and applications, 3:631,3:632 TAP (tick anticoagulant pep-
structure, 3:221-222 discovery, 3:655-656 tide), 3:324,3:325
Tachysterol, 4375 electrophilic metabolites, Taqman assay, 4625-626
Tacrine, 1 5 8 3:638-639 TARC ligand
for Alzheimer's disease, interaction with estrogen re- and CCR4,4153
6:761-762 ceptors, a 6 4 6 Tardive dyskinesia
for cognition enhancement, oxidative metabolism, 3:636, from antipsychotic agents,
6:781,6:782 a637 a607
reversible noncovalent anti- P-glycoprotein inhibitor, TargetBASE, 1:348
cholinesterases related to, 4631 Target class approach, 1:188,
6:86-88 selective toxicity, 5:276 1:228-234
structure-based design, 1:449 side effects, 3:355, a 6 3 1 Target-directed pharmacology,
Tacrolimus, 1:848, 1:849,5:489, tissue-selectivity, 3:652-653 2:73-74
5:490. See also FK 506 Tamoxifen combinatorial li- Target discovery. See also Drug
clinical use for organ trans- brary, 2:27,2:28 targets
plants, 5:494-500 Tamper-resistant packaging, bioinformatics for, 1:335,
CYP3A4/5/7 substrate, 4627 2:687 1:338-345
with leflunomide, 5:523 Tamsulosin, 6:33 Targeted mustards, 5 5 7
P-glycoprotein inhibitor, applications, 6:16 Targretin, 4320,4374
4631 metabolism, 6:17-18 TAR RNA inhibitors, 1:103
P-glycoprotein substrate, selective a,-antagonist, 6:4 antisense drugs, 2:124
4:631 structure-activity relationship, TAS 103
Tadpoles 6:28,6:31 dual topoisomerase ID1 inhibi-
narcotic action of ROH, TAN 67 tor, 5:68,5:73,5:74
1:28-29 analgesic, 6:399-400 Tasmar
Tafenoquine, 5:953 Tandem mass spectrometry for Parkinson's disease, 6:730,
Tagamet (MS-MS), 1590-591 6:731
selective toxicity, 5275 of combinatorial libraries, Taste
Tagging approaches, 1:596-597 1592 improvement of prodrug,
TAK-029, 1:213 for structure determination of 2:513
TAK-044 bioactive peptides, 1:518 Tat peptide
endothelin receptor antago- types of mass spectrometers, CXCR4 antagonist, 4168
nist, 3:206 1:585 Tau protein
TAK-147 Tandospirone, 6:531, a 5 6 6 and Alzheimer's disease, a748
structure-based design, 1:450 TA-NIC Tautomerization
TAK-779 experimental smoking cessa- NMR spectroscopy, 1:526-528
anti-HJV drug, 5:468 tion agent, 4:459 Tautomers, 1:366
Cumulative index

Tautomer search, 1:388, Team Works, 1:377 Tenofovir


1:405-406 Tebrazid, 5:810 anti-HIV drug, 5:471,5:472
Taxol, 1:843, 1:848, 1:861-863 Tebuquine, 6982 Tenormin, 3:28,6:5
antitumor natural product, Tedisamil Tentative final monographs,
5:110,5:136-138 potassium channel subtype over-the-counter drugs,
HMBC spectroscopy, 1:518 selective, 3:45 4425
NMR spectroscopy, 1:525-526, Teflon membranes Tenuate, 6:171,6:185 T
1:531 resins for combinatorial li- Tenuate propion, 6:845
SXR receptor activation, 2:79 brary synthesis, 2:29 Teprotide, 1:746, 1:881
Taxol side-chain, 1:803-804 Tegison, 4373 TER1,4:161 -
Taxotere Teicoplanin, 1:849 Terabyte, 1:411
antimalarial, 5:990 Telenzepine Terazole, 5:891
antitumor natural product, Terazosin
anticholinergic, 6:129
5:138-139 applications, 6:15-16
Telithromycin, 1:848, 15376,
Taxus baccata (English yew), metabolism, 6:19
5:763 selective a,-antagonist, 6:4
1:861-862
Taxus brevifolia (Pacificyew), structure, 2:193 structure-activity relationship,
1~861-862 Telogen phase, of hair growth, 6:31
Taxus diterpenes 4425 Terbinahe, 1:717,5:899-900
antitumor natural product, Telomerase, kll formulations and indications,
5:110,5:136-139 Telomeres, 5:11 5:890,5:891
Tazarotene Gel, 4320,4373, Teloxantrone selective toxicity, 5:268
4374 topoisomerase I1 inhibitor, Terbogrel, 3:326,3:327
Tazobactam, 5:697-698 5:72 Terbutaline, 2:554
amoxycillin MIC, 5:695 Temacrazine p-agonist, 6:4
antimycobacterial application, anti-HIV drug, 5:474 applications, 6:14
5:858 Temazepam, 6:207 prodrug, 2:504
p-lactamase inhibitory activ- TEM-1 p-lactamase, 2:90 Terconazole, 5:904
ity, 5:695 Temocillin, 5:609,5:636 formulations and indications,
use recommendations, 5:626 in vitro antibacterial activity, 6891
Tazorac, 4320 5:635 selective toxicity, 5:268
TB36 Temodar Terfenadine
structure-based design, alkylating agent, 5:54 removedhestricted by FDA,
1~424-425 Temozolomide 4642
TBC-3214, 1:674, 1:676 alkylating agent, 5:54,5:65, solubility of salts, 2:651
TBC-11251 5:67 Terguride, 6:649
endothelin receptor antago- Temperature Terlipressin, 3:200
nist, 3:206 large-scale synthesis, 2:413 Terminal elimination half-life,
TC-2559 molecular dynamic simula- 2:643
for Alzheimer's disease, 6:764 tion, 1:96 Terodiline
T-cell growth factor, 4174 Template mimetics (peptidomi- bioavailability and half-life,
T-cell receptors, 5:224 metics), k643-644 318
T-cells, 3:253,3:254 Tempo1 cardiovascular effects,
activation by dendritic cells, radioprotective agent, 3:19-20
5:235-236 6163-164,5:171 Testes, 3:680
and adaptive immunity, (+)-Temuconine Testlac, 3:697,3:700
6224-226 antimalarial, 6996 Testoderm, 3:697
chemokinelcytokine receptors, Tendamistat Testolactone, 3697, a698
4133 NMR relaxation measure- Testopel, 3:697
exosome secretion, 5:241 ments, 1:528-529, 1:535 Testosterone, 1:36, 1:768, 1:771,
HIV infection, 5:458-464 Tenecteplase, 3:166, a 3 2 3 3:598-599, a 6 8 1
organ transplant drugs block- clot selectivity, 3:290 absorption, distribution, and
ing function, 5:489-513 Tenex, 6:3 metabolism, 3:620,3:621,
role in organ rejection, Tenidap, 4179-180 3:685-692
5:487-488 Teniposide, 1:867 for Alzheimer's disease, 65'66
Tea bag solid phase synthesis antitumor natural product, biosynthesis, 3:616-618,
methods, 2:4,2:7 5:110,6135-136 3:682-685
Cumulative Index

Testosterone (Continued) Tetrahydrobiopterin Theophylline, 3:124


CYP3A41517 substrate, 4627 nitric oxide synthase binding CNS stimulant, 6:169,6:174
and estrogen biosynthesis, site, 6:698 diuretic action, 3:121
3:642 A,-Tetrahydrocannabinol dosing interval, 2:642-643
and hair growth, 4435,4439 (THC), 1:852-853 PARP inhibitor, a681
mechanism of action, Tetrahydrofolate, 1:425 RNA aptamer against, 2:94
32692-697 Tetrahydrozoline Therapeutic area screening F
occurrence and roles, a,-agonist, 6:3 molecular similarityldiversity
3~681-682 applications, 6:13 methods, 1:191
prodrugs, 2:505 structure-activity relationship, Therapeutic gain, radiosensitiz- -
relative androgenicity and re- 6:31 ers, 5:173
'ceptor binding of analogs, Tetrahymena pyriformis Therapeutic index, 2:535,2:613
3:702 growth inhibition, 1:27,
Theratope, 2:217,2:220
and a-secretase shift, 6:761 1:3738
Thermodynamic cycle integra-
synthesis from cholesterol, Tetraiodophenolphthalein, 4:495
tion, 1:99-100, 1:120-121
3:604 cholecystography application,
Testosterone butyrate, a714 4570 Thermofluor bioassay approach,
Testosterone cypionate, 3:697, D,L-Tetramethylparabactin, 2:53
3:703 a494 Thermogenesis, 6:857
Testosterone enathate, 3:697, spiro-Tetraoxacycloalkanes Thermogenic agents, 6:843,
3703 ring-size analogs, 1:702-703 6:846-847
Testosterone-estradiol binding Tetraoxane clinical applications, 6:857
globulin, 3:686 antimalarial, 5986 Thermolysin inhibitors
Testosterone gel, a697 Tetraplatin genetic algorithm study of ac-
Testosterone patch, 4450 alkylating agent, 5:54,5:59, tive site, 1:89
Testosterone pellets, 3:697
- 5:61 molecular modeling, 1:117,
Testosterone propionate, 3:703 Tetrazepam, 6550 1:120, 1:121, 1:151-153
Testosterone valerate, a714 Tetrazoles, 1:135 novel lead identification, 1:321
Testred, a697 as surrogates for cis-amide transition-state analogs,
Tetracyclines, 2:184,2:195 bond, 1:141-142 12749-750
antimalarials, 5:935, Tezosentan Thiabendazole
5:982-983 endothelin receptor antago- antihelmintic, 5:1090-1091,
biosynthesis, 5742-743 nist, a206 51091
clinical use and currently used Thalamus
Thiamine, 4387392.See also
drugs, 5:739-741 nicotinic acetylcholine recep-
Vitamin B,
drug resistance, 5743-746 tors, 2:389
mechanism of action, a-Thalassemia, 3456 Thiamine diphosphate
2:184-185 animal models, a534 radiosensitizer, 5196
pharmacology and mode of and sickle-cell anemia, Thiamine hydrochoride, 4388
action, 5:741-742 3:454-456 Thiamine kinase, 4388489
radioprotective agents, 5:166 and sickle trait, 3458 Thiamine nitrate, 4:388
recent developments, p-Thalassemia, a456 Thiamine pyrophosphate, 4388,
5~746-747 animal models, 3:534-535 4389,4390-391
selective toxicity, 5:261 bone marrow transplantation, Thiamylal, 6:204
side effects, toxicity, and con- 3:465 Thiazide diuretics, 3:73-78,
traindications, 5741 and sickle-cell anemia, a456 3:142
structure-activity relationship, Thalidomide, 1:783-784, 1:785 selective toxicity, 5264
2~185-188 birth defects caused by, 2:686 with triamterene, a128
Tetraethyl pyrophosphate Thebaine, 1:850, 1:851,6:361, Thiazolidinediones, 424-31
(TEPP), 6:92 a371 Thick clients, 1:400-401, 1:411
Tetrafluorophenoxazine, 2:144, Theilheimer/ChiraslMetalysi Thiele arrangement, 2:655
2:145 database, 1:386 Thienamycin, 1:872, 1:874,
1,2,3,4-Tetrahydro-9-aminoacri- T-helper lymphocytes, 5:609, 5:669,5:670
dine 5224-225 activity, Z688- 693
reversible noncovalent acetyl- Theobromine synthesis, 5672-674
cholinesterase inhibitors CNS stimulant, 6:169 Thin clients, 1:363, 1:392, 1:401,
related to, 6:86-88 PARP inhibitor, 6:681 1:411
Cumulative Index

Thioacetazone, 5:832 Thiouracil antithyroid agents 3D query features, 1:368,


efficacy and dosage, 5810, nitric oxide synthase inhibi- 1:381-382, 1:398
5863 tors, a 7 0 5 3DSEARCH, 1:111, 1:259
side effects, 5:832-833 Thiourea 3D structure databases, 1:387
Thiobiotin radioprotective agent, 5152, 3-Point pharmacophores, 1:376,
binding to avidin, 1:181, 1:182 5:170 1:408
Thiocarbarnate antifungal Thioxanthene antipsychotics molecular similarity methods, y
agents, 5:903 pharmacokinetics, biotrans- 1:189, 1:195-196, 1:198
Thiocarlide formation, and drug interac- for virtual screening, 1:210
efficacy and dosage, 5810 tions, 6:635 Threonine kinases, 5 2 4 -
Thiocitrulline Thiphenarnil Threo- prefix, 1:784
nitric oxide synthase inhibi- anticholinergic, e l 3 8 Threose
tor, 6:698-699 Thiry-Vella fistules, 6:116-117 enantiomers, 1:784
Thioesters Thrombin, 3:284,3:285
Thorazine, 6:601
Thrombin-activatable fibrinoly-
filtering from virtual screens, Thor database manager, 1:386
sis inhibitor, 2:301
1:246 Thorium dioxide Thrombin inhibitors, 1:227
P-ThioGARdideazafolate (P-TG- radiopaque material, 4493 cell-specific targeting, 2:95-96
DDF), 1:742-743 Thorium oxide combinatorial docking, 1:318
Thioglycolic acid neurotoxicity, 4555 from concept to drug,
radioprotective agent, 5161 Thorotrast, 4493 3:310318
6-Thioguanine Thor system, 1:377 force field-based scoring study,
antimetabolite, 5:76, 5 8 1 exact match searching, 1:307
Thiolactomycins 1:380-381 hirudin and hirudin-like,
antimycobacterial application, Threading, 1:123-125 3316-318
5:859-860 3D descriptors molecular modeling, 1:116
Thiol proteases molecular similarityldiversity non-peptide peptidomimetics,
QSAR studies, 1:5 methods, 1:55-58, 1:660-662, 1:663,1:664
Thiols 1:191-201 seeding experiments, 1:319
radioprotective agents, 5152, validation, 1:211-2 13 site-based pharmacophores,
5155-160 Three-dimensional electron 1:235-236
radiosensitizers, 5:192-193, cryomicroscopy, 1:615-616 small-molecule direct,
5196-197 3D models, 1:363, 1:366-367, 3:311316
Thiomerin, 3:67 1:397-398 target of structure-based drug
Thiomesterone, 3711 3D-MORSE(Molecular Repre- design, 1:442-443
Thiomuscimol, 1:690 sentation of Structures for thrombolytic therapy,
Thiopental, 6:204 based on Electron Diffrac- 3:166
Thiopurine methyltransferase tion), 3792 Thrombin rebound effect, 2:310
single nucleotide polymor- 3D pharmacophores Thrombolysis, 3:156
phism~,4630-631 filter cascade, 1:267 Thrombolytic agents (clot-dis-
4-Thioquinone fluoromethide, for molecular similarity/diver- solving), 3:165-167
1:770 sity methods, 1:194-201 calcium channel blockers, 3:29
Thioridazine, 12305, 15406 for searching, 1:381-382 challenges, 3284
dose, 6:601 similarity searching, 1:189, mechanisms, 3322-323
receptor binding and side ef- 1:383 Thrombomodulin, 3301
fects, 6:606 for virtual screening, 1:210, Thrombopoietin, 3252
Thiorphan, 1:650, 1:651 1:255-259 therapeutic uses, 3:270-271
diuretic effects, 3134-135 3D quantitative structure-activ- Thrombosis, 2:204,3:156,3:284,
opioid peptide metabolism in- ity relationship (3D-QSAR), 3:342
hibitor, 6:442 1:52, 1:53, 1:58-60 antithrombotic treatment reg-
Thiothixene anti-inflammatory steroids, imen, 3:298-299
dose, 6:601 3:793-796 carbohydrate-based drugs to
pharmacokinetics, biotrans- and molecular modeling, market last decade,
formation, and drug interac- 1:115, 1~138 2:209-210
tions, a 6 3 5 3D quantitative structure-me- carbohydrate-based therapeu-
receptor binding and side ef- tabolism relationship (3D- tics in development,
fects, 6:606 QSMRs), 2:481-483 2:215-216
Cumulative Index

Thrombosis (Continued) Thyroid hormone response ele- Thyroid releasing hormone


molecular mechanisms, ments, 3:566 (TRH), 3:568
3:299308 Thyroid hormones, 3563564 Thyroid stimulating hormone .
Thrombospondin biological actions, 3:570-571 (TSH), 3:567569
interaction with sickled cells, biosynthesis, 3568-569 Thyroliberin
3:458,3:459,3:462 coadivators and corepressors, peptidomimetics, 1:129
Thrombotic thrombocytopenic 3567 Thyromimetics, 3:564, P
purpura, 3294 effect on bone and skeletal 3575-576
Thromboxane &, 1:762-763, muscle, 3:572-573 design, 3:586-587
3:326,4230 effect on carbohydrate metab- structure-activity relationship, -
physiological actions of, 4:275 olism, 3571 3:576-585
radioligand binding studies, effect on heart and cardiovas- Thyroperoxidase, 3:568,3:569
4280 Thyrotoxicosis, 3:565,3:574
cular system, 3571-572
selective ligands and struc- Thyrotropin, 3568
effect on lipid metabolism,
ture-activity relationships, Thyrotropin-releasing hormone,
3571
4294-295 1:637
signal transduction, 4282 effect on liver, 3572 analogs, 2:589-591
Thromboxane receptor inhibi- effect on metabolic rate, prodrug approach, 2:507-508
tors, 3:326 3:570-571 Thyroxine, 3:565. See also Thy-
Thromboxanes, 3:303,4:233 effect on protein metabolism, roid hormone T,
and leukotriene biosynthesis, 3:571 NMR spectroscopy, 1:529-531
4205 molecular mechanism of hor- Thyroxine-binding globulin,
Thromboxane synthase inhibi- mone action, 3565567 3:569
tors, 3:326 NMR spectroscopy, 1:529-531 Tiagabine
Thrush, 5:882 physiology of hormone action, ADME, 6286
Thymidine 3:568-570 anticonvulsant, 6265, 6:268,
PARP inhibitor, a 6 8 1 recent developments, 6:269,6:295-296,6298
Thymidine kinase 3:585-587 clinical efficacy, 6273
plasmid DNA-mediated gene regulation, 3:568 development, 6:303
therapy study, 4668 structure-activity relationship, dose, a270
Thymidine kinase inhibitors, 3576-585 pediatric indications, 6974
1:717 therapeutic potential of ana- side effects, 6279
role of water in docking, 1:303 logs, 3:575-576 Tiaspirone, 6:647
X-ray crystallographic studies, transcriptional regulation, Tibolone, 3:650,3:668
1:493 3:566-567 Ticarcillin, 5:632,5:633
Thyrnidylate synthase inhibi- transport, 3569 antimycobacterial application,
tors, 1:227, 1:717 uptake and metabolism, 5:858
antimetabolites, 5:76-77 3:569-570 indications, 5:625
recombinant DNA technology Thyroid hormone T,, 3:564, pharmacokinetics, 5624
application, 2:97 3:565 use recommendations, 5:626
target of structure-based drug analogs, 3:578-585 in vitro antibacterial activity,
design, 1:425, 1:426-429 biosynthesis, 3:568-569 5635
Thymine, 4619 regulation, 3568 Ticlid, 3287
Thymitaq, 1:428 sythetic, 3:576 Ticlopidine, 3285, 3320
antimetabolite, 5:76,5:79 transport, uptake, and metab- ADME, 3297
Thyroglobulin, 3:568 olism, 3:569-570 clinical trials, 3:293
Thyroidal hypothyroidism, 3:574 Thyroid hormone T,, 3:564, formula weight, mechanism of
Thyroid diseases, 3574 3565 action, and route of admin-
Thyroid gland, 3:565 analogs, 3578-585 istration, 3287
Thyroid hormone, as anti-obe- biosynthesis, 3:568-569 structure, 3289
sity agent, 6:843 regulation, 3568 for thrombolytic therapy,
dose, a847 , synthetic, 3:576 3166
Thyroid hormone antagonists, transport, uptake, and metab- Tifluadom
3:585-586 olism, 3569-570 analgesic, 6:387
Thyroid hormone receptors, uptake and metabolism, Tifocogin, 3:325
3:564,3:565566 3569-570 Tigemonam, 5:666
isoform knockouts, 3573-574 Thyroid receptor beta, 1:263 in vitro activity, 5667
Cumulative Index

Tight-binding enzyme inhibi- for thrombolytic therapy, Tolazoline


tors, 1:720, 1:734-740, 3:165-166 a-antagonist, 6:4
1:749 treatment regimen, a298 applications, 6:15
Tight junctions, 2251 Tissue targeting structure-activity relationship,
and permeability, 2:658 prodrugs, 2515 6:31
Timentin, 5695 Tissue transplantation, a486 Tolbutamide, 4 1 1 , 4 1 2 , 4 1 5
use recommendations. 5:626 Titanium dioxide binding parameters, 4 1 8 a
Time-of-flight mass spectrome- absorption and disposition, CYP2C9 substrate, 4627
try, 1:585,1:607 4463 dosing interval, 2:643
Timolol history of use as sunscreen, Tolerable upper intake level
0-antagonist, 6:5 4:470 folic acid, 4411
applications, 6:16 structure-activity relationship: niacin, 4:397
CYP2D6 substrate, 4627 4470
vitamin A, 4371,4372
renal clearance, 1:38 sunscreen, 4460
vitamin B,, 4400
Timoptic, 6:5 Titrations
Timoxicillin, 5:633 NMR application, 1:545 vitamin C, 4418
Tinactin, 5:891 Tizolemide, 3:87, 3:89 vitamin D, 4:379
Ting, 5:891 T-lymphoblasts, 3:253 vitamin E, 4384-385
Tinzaparin T-lymphocytes, See T-cells vitamins, 4368
formula weight, mechanism of TMC-66 Tolerance
action, and route of admin- endothelin-converting enzyme narcotic analgesics, 6:336
istration, 3:286 inhibitor, 3:208 Tolinase, 4 1 2
Tioconazole, 5904 T103N, 2:85 Tolnaftate, 5:903
formulations and indications, TNFa converting enzyme formulations and indications,
5:891 (TACE), 1:652,4:182 5:891
TIP3P model, 1:175 TNFR-associated death domain, selective toxicity, k268
TIPP (Tyr-Tic-Phe-Phe), 5:17 Tolrestat
6:425-428 TNFa receptor. See also Tumor structure-based design, 1:448
Tipranavir, 1:812,1:813 necrosis factor-a Tolterodine
anti-HIV drug, 5:476-477 antisense inhibitor, CYP2D6 substrate, 462'7
Tirapazamine 2:128-129,2:130 Tomelukast, 4221-222
radiosensitizer, 5:181 glucocorticoid downregulation, Tomexiprole, 4242
tumor-activated prodrug, 4172 Tomudex, 1:427
5:83,5:84,5:85, 5:86 modulator studies, 4182-183 antimetabolite, 5:76,5:77-78
Tirazone Tn MBRl Lewis y KLH, 2:226 Toolkits, 1:386, 1:411
tumor-activated prodrug, 5:83 TOC-39,5:703,5:705 Toothpick plant, drugs derived
Tirilazad mesylate, 15349 TOC-50,5:703,5:705 from, 1:883
Tirofiban, 3:29,3:285,3:318 Tocainide, 3:32,3:34, a167 TOPAS, 1:192
ADME, 3:297 cardiovascular effects, 3:36 Topical administration
clinical trials, 3:293, a294 multiple inhibitory mecha- phosphorothioate oligonucleo-
formula weight, mechanism of nisms, 3:33 tides, 2:134
action, and route of admin- uses and side effects, 3:35 Topimax, 6:882,6:885
istration, 3:287 rac-a-Tocopherol,4381 Topiramate, 2:207,2:212
structure, 3:289 a-Tocopherol, 3:372,4380-384, ADME, 6:291
for thrombolytic therapy, 4399 anticonvulsant, 6:265, 6:268,
3:167 inhibitor of amyloid 0-peptide 6:269,6:295,6:298
treatment regimen, 3:298 aggregation, 6:758 anti-obesity agent, 6:882,
Tissue factor, 3:290 Tocopherols, 4380384. See 6:885
in clotting, 3:299-308 also Vitamin E family clinical efficacy, a273
Tissue factor pathway inhibitor, Tocotrienols, 4380381. See development, 6:303-304
3:300,3:301 also Vitamin E family dose, 6:270
Tissue inhibitor of matrix metal- Tofranil, 6:485 pediatric indications, 6:274
loproteinases-1, 5:12 dose for eating disorders, side effects, 6:279
Tissue plasminogein activator 6:850 TOPKAT, 1:246,2:621
(t-PA), 2:84-85 Tolamolol Topographical data, 1:411
clinical trials, 3:293, 3:294 renal clearance, 1:38 Topographical mimetics (pep-
in clotting, a307 Tolazamide, 411,412, 4:16 tidomimetics), 1:636
Cumulative Index

Topoisomerase I, 5:67-68 emerging technologies for as- problem prevention rather


X-ray crystallographic studies, sessing, 2:62O -628 than problem solving,
1:487 lipids as targets for, 2:611-612
Topoisomerase 11, 5:67-68, 2:616-617 receptor targeting drugs,
5:135 nucleic acids as targets for, 2:320
Topoisomerase I1 inhibitors, 2:616 Toxicophores, 1:829-831
1:717 and physiological changes in- associated with allergic con- r
dual UII inhibitors, 5:72-75 duced by compound, 3:62 tact dermatitis, 1:830
etoposide, 5:135 profiling gene expression, pro- and metabolism, 2:490-492
gene expression profiling teins, and metabolites, C-Toxiferine 1, 1:856, 1:857 -
study of drug response, 2~621-624 Toxin inhibitors
4609 proteins as targets for, multivalency in carbohydrate-
resistance to, 5:284
2:615-616 based, 2234
synthetic, 5:68-72
salts, 2:651 TPCK, 1:760-761, 1:762
tenoposide, 5:136
Topoisomerase I inhibitors and single nucleotide polymor- Trace elements
camptothecins, 5:131,5:132 phism~,4618-619 vitamins contrasted,
dual UII inhibitors, 5:72-75 subcellular targets of, 2:615 4361362
Topological descriptors Toxicity databases, 1:246, 1:386 Traceless linkers, 2:17
for druglikeness screening, development, 1:828-829 Trademark Counterfeiting Act
1:247-249 Toxicity prediction, 1:827-843 of 1984,2:757
estimation systems, Toxicity screeningltesting.See Trademark infringement, 2:761
1:388-389 also Cardiotoxicity screen- Trademark Revision Act of 1988,
with QSAR, 1:54-55 ing 2:763
Topotecan, 1:848, 1:849, 1:861 as bottleneck in drug discov- Trademarks, 2:704-708,
antitumor natural product, ery, 1:592 2:756-764
5:110,5:131 cellular assays, 2:76-77 enforcement, 2:761,
P-glycoprotein substrate, and functional group filters, 2:763-764
4631 1946-247 proper use, 2:761-762
Toprol, 3:28 high-content, 2:626 registration, 2:759-761
Toprol-XI+6:5 multi-endpoint analysis, worldwide, 2:762-763
Toradiur, 3:89 2:624-626 Trademark Trial and Appeal
Torasemide, 3:89,3:107-108 as part of IND process, 2:691, Board, 2:761
Toremifene, 3:343,3:351,3:662 2:692- 693 Trade secrets, 2:704-708,
applications, 3631, a632 pulsed ultrafdtration applica- 2:764-766
oxidative metabolism, 3:636 tion, 1:605 enforcement, 2:766
side effects, 3:355 stem cell applications, and patents, 2:766-767
Tornalate, 6:4 2:626-627 worldwide, 2:768-770
Torpedo ray, nicotinic receptors in vitro cell-based, 2:624-628 Trade Secrets Act, 2:764-765,
in, 2:358,2:360361,2:374, in vivo, 2:619-620 2:767
2:396 Toxicogenomics, 2:622 tra genes, 5:614
Torsade de pointes, 2:76, 3:168, Toxicology, 2:609-612 Trail, 4339
3:170-171 adaptive response, 2:617-618 Tral, 6:139
Torsemide consideration in synthesis de- Trarnadol, 1:782,6:408
CYP2C9 substrate, 4627 velopment, 2:408 chromatographic separation,
Torsional potential, 1:80 direct cellular injury, 1:792
Tox-Cluster Assay System, 2:612-617 classical resolution, 1:795-796
2:624-625 DNA microarray application, metabolism, 1:786-787
Toxic concentration, 2:636 4604 Trandate, 3:28
Toxicity. See also Selective toxic- gene expression profiling ap- Trandolapril
ity; specific drugs and plication, 4614 with verapamil, 3:169
classes of drugs mechanism of adverse effects, Tranquilosedatiyes, &600
aminoglycosides, 2:184-185, 2:612-619 Transcellular transport, 2:250
2:615,5:748-749 pharmacologically mediated Transcortin, 3:686,3:703
cell membrane-associated, effects, 2:618-619 Transcription
2:613-615 phosphorothioate oligonucleo- control by thyroid hormones,
and dose adjustment, 2:641 tides, 2:139-142 3:565-567
Cumulative Index

Transcriptional arrest Transpeptidases, 5:610 TRH analogs


by antisense drugs, 2:118-119 inhibition of bacterial by molecular packaging,
Transcriptome, 2:621 P-lactams, 5:611-613 2:589-591
Transcytosis, receptor-mediated, Transplant rejection, 5:486-487 Triac, 3:579,3:581
2:259-260 Transthyretin, 3:569 Triacetyloleandomycin, 5763
Transdermal absorption Transverse relaxation-optimized Triacylglycerol, 2:616
prodrugs, 2:518-519 spectroscopy (TROSY), Triad (permeability, solubility, t
Transesterification 1:515 and dose), 2:658
enzyme-mediated asymmetric, for macromolecular structure Trial courts, patent infringe-
1~805-806 determination, 1:533, 1534 ment cases, 2:740-742
Transferred NOE technique, Tranxene, 6:207,6:529 Triamcinolone, 3:750,3:752,
1:532 Tranylcypromine 3:758-759,3:768,
and NMR screening, antidepressant, 6:485, 6:486, 3:775-776,3:789,3:797,
1:572-573 6:488 3:800, a803
Transferrin, 3:496-498 for Parkinson's disease, 6:729, half life, a776
plasmid DNA-mediated gene 6:730 Triamcinolone acetonide, 3:750,
therapy study, 4668 pharmacokinetic parameters, 3:752,3:759,3:772,3:786,
pM values, 3:484 6:497 3:788,3:797,3:800,3:803,
receptor-mediated endocyto- side effects profile, 6:493 3:808-809,3:821,3:824
sis, 2:265 Trasentine, e l 3 4 2,4,7-Triamino-6-phenylpteri-
regulation, 3:499-501 influence of cyclic radicals on dine, 3126
transcytosis, 2:259 anticholinergic activity, 2,4,7-Triamino-5-phe-
Transferrin receptor, 3:496-498 6:143 nylpyrimido[4,5-&yrimi-
Transforming growth factor p, Trastuzumab, 5:228,5:230 dine, 3127
5:226 selective toxicity, 5:257 Triamterene, 3:124,3:125-128,
and carcinogenesis, 5:30-32 Traumatic head injury 3:132,3:142
Transfusional iron overload, and Alzheimer's disease, hydrochlorothiazide-triam-
3504 6:748-749 terene, 3:78
Transgene Trazodone, 4449-450, with xipamide, a107
in plasmid DNA-mediated 6:494-496 Triarylethylenes, 3655,
gene therapy, 4652 affinities for monoamine re- 3:661-665
Transgenic animals ceptors, a495 oxidative metabolism,
patentability, 2:719 antidepressant, 6:485,6:486, 3:636-637
Transgenic mice, 2:88 a489 Triazenes
IL-1,4173 CYP3A41517 substrate, 4627 alkylating agents, 5:54,
IL-2,4175 inhibition of serotonin, norepi- 5:65-67
IL-4,4176 nephrine, and dopamine Triazine anticonvulsants
IL-5,4177 transporters, a500 ADME, 6:284-285
IL-6,4179 pharmacokinetic parameters, Triazines, 3:123-125
IL-12,4:180 a497 QSAR studies of cellular
IL-13,4181 side effects profile, 6:493 growth inhibition, 1:37-38
INFy, 4183 Treatment Investigational New QSAR studies of DHFR inhibi-
TNFcr, 4182 Drugs application, 2:690 tion, 1:31-33
Transglycosylases, 5:610 Trecator, 5:810 Triazolam, 6:207
inhibition of bacterial by Trecetilide, 3:41 CYP3A41517 substrate, 4627
p-lactams, 5:611-613 cardiovascular effects, 3 4 2 Trichlormethiazide, 3:77,3:81
Transition-state analog enzyme potassium channel subtype Triciribine
inhibitors, 1:720, 1:748-754 selective, 3:45 for herpes, k322-323
Transition state analog inhibi- Trees, 1:376377, 1:411 Triclofos, 6:208, 6:209
tors, 1:646 TrEMBL, 1:335, 1:346 Triclos, a209
peptide bond isosteres, 1:644 Tremorine, 6:71 Tricoloid, 6:139
Translational arrest Trest Tricomin
by antisense drugs, 2:124 anticholinergic, 6:128, a 1 3 5 experimental hair growth
7-Transmembrane G-protein- Tretinoin, 4372373 drug, 4441
coupled receptors, Trevintix, 5:8lO Tricor, 3:343
1:229-234 TRH, See Thyrotropin-releasing Tricyclamol
Transpeptidase inhibitors, 1:717 hormone anticholinergic, e l 3 9
Cumulative Index

Tricyclamol (Continued) new treatments for lowering interaction with dihydrofolate


relative anticholinergic activ- while raising HDL, redudase, NMR spectros-
ity, a157 3370-372 copy, 1:531, 1:557-559
stereoisomerism, 6:149 reduced by thyroid hormones, soft analogs of, 2:567
Tricyclic antidepressants, 3:571 Trimipramine
6:484-485, a486 Trihexethyl affinities for monoamine re-
for anxiety disorders, a528 relative anticholinergic activ- ceptors, 6:495 P
for eating disorders, ity, 6:157 antidepressant, 6:485,6:486,
6:850-851,6:858,6:859 Trihexyphenidyl 6:487
efficacy relative placebo, 6:489 for Parkinson's disease, 6:731, inhibition of serotonin, norepi- _
with opioid analgesics, 6:333 6:732 nephrine, and dopamine
pharmacokinetics, 6:496 Triiodoanilide radiopaques, transporters, 6:500
side effects, 6:492-493 4:497 pharmacokinetic parameters,
structure-activity relationship, Triiodobenzamide radiopaques, 6:497
6:510-512 4497 side effects profile, 6:493
Tricyclic antipsychotics Triiodo-l,3-benzenedicarboxam- Trinems, 5:609,5:683-688
discovery of, 6:618 ide radiopaques, 4497 anti-gram-positive, 5:703-705
structure-activity relation- 2,4,6-Triiodobenzoate biological properties,
ships, 6:619-625 neurotoxicity, 4554 5:688-694
Tricyclic benzodiazepine anti- Triiodobenzoate radiopaques, orally active, 5:709-710
cholinergics, 6:128-129 4497 Trioxifene, 3655
Tricyclic thiophene 2,3,5-Triiodobenzoicacid Triphenamil
selective toxicity, $258-259 protein binding, 4558 relative anticholinergic activ-
Tridegin, 3:330 Triiodoisophthalamate ra- ity, 6:157
Tridihexethyl diopaques, 4497 Triple resonance spectra, 1:514
anticholinergic, &I39 Triiodophenoxy alkanoate ra- Tripos, Inc. databases, 1:387
Triethanolamine salicylate diopaques, 4497 Tripos force field, 1:80
structure-activity relationship, Triiodophenyl alkanoate ra- Triptramine
4468 diopaques, 4497 anticholinergic, 6:131
sunscreen, 4460 Triiodophenyl-D-gluconoamide Tris (2-amino-2-(hydroxymethy1)-
Triflocin, 3107 radiopaques, 4497 1,3-propanediol),4541
Trifluoperazine Trilafon, 6:601 Tris(iothalamic)acid, 4497
arenavirus antiviral, 5:430 Trimetaphan properties, 4:511
nicotinic receptor antagonist, TRK-820
dose, 6:601
2:396 opioid analgesic, 6:363, 6:387,
receptor binding and side ef-
Trimethadione 6:447
fects, 6:606 ADME, 6284 Trk growth factor, $22
Trifluoromethyl hydrate resi- anticonvulsant, 6265, 6267, TRNA, 2:169
dues 6:268,6:297,6:298 bacterial, $738
residues in pseudopeptide ar- dose, 6270 and ribosome function, 2:170
rays, 2:13 side effects, 6278 TRNA guanine transglycosylase
Triflupromazine Trimethoprim, 1:717, 1:719, inhibitors
dose, 6:601 $956 novel lead identification, 1:321
Triggered activity, 3:159 dosage forms, 5934 Trocinate, 6:138
Triglycerides, 3340-342 interaction with dihydrofolate Troglitazone, 4 2 4
accumulation in hyperglyce- reductase, 1:151, 1:183 binding affinities, 4 2 7
mia, 4 3 , 4 2 8 recombinant DNA studies of removedlrestricted by FDA,
androgen effects on, 3:706 interaction with DHFR, 4642
and coronary artery disease, 2:97 Trojan horse inactivators, 1:756
3:10 selective toxicity, 5264 Trolamine salicylate
current drugs to lower, structure-based design, 1:425 sunscreen, 4460
3342-352 a,o-bis-Trimethylammonium Trophectoderm, 2:626
insulin's role in synthesis, 4 2 polymethylene compounds, Tropical Disease Research List
new treatments for lowering 1:710 (WHO), 5:1035
while lowering LDL, Trimetrexate Tropicamide
3:368370 antimetabolite, $76, $79 anticholinergic, &I38
Cumulative Index

mydriatic and cycloplegic ac- D-Tubocurarine Tungsten


tivity, a153 drugs derived from, 1:856, radiopaque material, 4487
Tropine, 6:149-150 1:857 Turosteride
in solanaceous alkaloids, fragment analogs, 1:708-710 experimental hair growth
6:120-126 Tubulin drug, 4:441
Tropine-modified atropines, antitumor natural products TV 1901
a123 interfering with, 5:110, anticonvulsant, 6:310 T
Tropisetron 5136-143 2D descriptors
cognition enhancer, 6:816 a-Tubulin, 5:136 molecular similarity/diversity
Trovafloxacin 0-Tubulin, 5136 methods, 1:191-194 -
antimalarial, 5:983-984 X-ray crystallographic studies, with QSAR, 1:54-55
removedlrestricted by FDA, 1:483 validation, 1:211-213
4642 Tubulosine Two-dimensional gel electro-
Troxolon antimalarial, 6:997,5:998 phoresis
for crosslinked hemoglobin, Tumor-activated prodrugs, 544, proteomics application, 2:623
3:417 5~82-83 2D pharmacophore searching,
Trusopt, 3:67 for antibody-directed enzyme- 1:383
Trypsin inhibitors prodrug therapy (ADEPT), filter cascade, 1:267
molecular modeling, 1:120 5:83,5:87-90 virtual screening, 1:255
QSAR studies, 1:5, 1:25 antibody-toxin conjugates 2D quantitative structure-activ-
site-based pharmacophores, (armed antibodies), 5:83, ity relationship (2D-QSAR),
12235-236 592-94 1:52, 1:53
Trypsinogen inhibitors for gene-directed enzyme-pro- 2D query features, 1:397
molecular modeling, 1:116 drug therapy (GDEPT), 2D structures, 1:364-366, 1:397
Tryptanthrin 583,5:90-92 conversion of names to, 1:373
antimycobacterial application, hypoxia-activated prodrugs, 2-Point pharmacophores, 1:376
5859 5~83-87 Tylenol poisonings, 2:687
Tryptophan Tumorigenesis, 52-3 Type 1 diabetes mellitus, See
chemical modification re- and genetic variability, 55-7 Diabetes mellitus, type 1
agents, 1:755 Tumor-infiltrating lymphocytes, Type 2 diabetes mellitus, See
niacin synthesis from, 4:361, 5226 Diabetes mellitus, type 2
4394,4:396,6:688-689 Tumor lysates, 5239-240 Typhoid Vi vaccine, 2:209,2:212
TSAA21,3:719 Tumor necrosis factor-a, 4656. Tyropanoate, 4570
TSCA database, 1:386 See also TNFa receptor biotransformation, 4565
TSE-424,3:660 enhances IL-11,3264 Tyropanoic acid, 4497
TTA-386 and mycobacterial infection, properties, 4505
endothelin receptor antago- 5822 Tyrosine
nist, 3:206 plasmid DNA-mediated gene chemical modification re-
T-tropic HIV, 5468 therapy study, 4670 agents, 1:755
T-type calcium channels, 3:7, radioprotective agent, 5:171 Tyrosine kinase inhibitors
3:8, 3:168 radiosensitizer, 5194 molecular modeling, 1:130
and anticonvulsants, 6:297 and stem cell factor, a267
Tubby gene X-ray crystallographic studies, U-50,488
X-ray crystallographic func- 1:493 analgesic, 6:387-392, a406
tion elucidation, 1:494 Tumor necrosis factor-B U-69,066
Tube curare, 1:856 plasmid DNA-mediated gene analgesic, 6:389
Tuberculin, 5818-819 therapy study, 4656 U-69,593
Tuberculosis, 5809-813,5:1035 Tumor necrosis factors, 5 1 7 analgesic, 6:389,6:390,6:406
pathogenesis and epidemiol- Tumor promoter TPA-respon- U-85548
OD, 5~821-825 sive element, 5 2 5 structure-based design,
recent developments and Tumors, 5:225-226 1:436-437, 1:438
present status of chemo- Tumor suppressor genes, 5:3, U-100480
therapy, 5:860-864 5:26-32 antimycobacterial, 5859
(+)-Tubocurarine methylation and drug resis- U-466619,3:326
nicotinic receptor antagonist, tance, 5:289 2164U90,2:285
2:370-371,2:374,2:382, targeting loss of function, U-594494A
2:384,2:386,2:390, 2:397 5:44-45 anticonvulsant, 6:315-316
Cumulative Index

Ubiquinone, 3:353354 United States Pharmacopeial Uruguay Round Agreements Act


UCB 35625,4150 Convention, Inc., 2:700, of 1994,2:688
Ugi reaction, 1:229, 1:231, 2:701 USEPA Suite, 1:390
1232, 1236 Unithiol Utility, requirement of patent-
use in solid phase organic syn- radioprotective agent, 5:157 able invention, 2:719-720 -
thesis, 2:15 UNITY, 12259, 1:377 Utility patents, 2:708. See also
UH232,6:650 descriptors, 1:192, 1:201 Patents P
UK-109,496,5:897 in molecular modeling, 1:111
UK QSAR and Cheminformatics novel lead identification, 1:320 V-002,5:902
Group, 1:360 UNITY 2D, 1:212 Vaccinia immune globulin
-
Ukrain, 1:849 UNITY 3D, 1:363, 1:387 for smallpox, 5:435
Ulcer disease, 4:91-92 University of Manchester Bioin- Vaccinia virus
Ultiva, 6:334 vector for cancer gene ther-
formatics Education and
Ultra-high-throughput screen- apy, 5:41
Research site (UMBER),
ing, 2:40 Vagistat, 5:891
1:335 Valaciclovir, 2:508
Ultrasmall superparamagnetic
iron oxide particles, 4491 Unix, 1:396, 1:411 Val-2-AM (dactinomycin),5:111
Ultrasound contrast agents, Unstable angina, 3:10,3:290 Valciclovir
4567 Unsupervised data mining, for herpes virus, k309,5:310
Ultraviolet radiation, 4458-460 1:66-67, 1:412 Valdecoxib, 4:235
acute effects of, 4:464 Upstroke, of heartbeat, 3 5 Valethamate
and carcinogenesis, 5 4 Urea anticholinergic, 6:138
chronic effects of, 4464-466 osmotic diuretic, 3:64 relative anticholinergic activ-
Unasyn pharmacophore points, 1249 ity, 6:156
use recommendations, 5:626 residues in pseudopeptide ar- Validamine, 434-36
Unat, 3 8 9 rays, 2:13 VALIDATE, 1:116, 1:310
Uncompetitive inhibitors, Urea cycle, 3138 Validation
1:729-730 Ureaphil in large-scale synthesis,
Uncoupling proteins osmotic diuretic, 3:64 2:418-420
effect of thyroid hormones, Ureido resonance, 1:182 Valienamine, 4:34-36
3:570 Urethane Valinomycin
Undecylenate, kg06 radioprotective agent, 5:165 membrane function disrup-
formulations and indications, Uric acid, 356,3138-142 tion, 2:614
5:891 effect of diuretic therapy on, Valiolamine, 4 3 4 3 6
Unfractionated heparin, 363 Valium, 6:529. See also Diaze-
3:308-309 Uricase, 3 6 2 Pam
Unicode, 1:411 Uricosuric agents, 356, discovery, a547
Unidirectional conduction block, 3:138-142. See also Diuretic Valnoctamide, 6:214,6:215
3:29,3:30-31 agents Valpin, e l 1 7
Uniform Trade Secrets Act, animal studies, 3:62 Valproic acid
2:764-765,2:767 Uridine diphosphate (UDP) glu- ADME, 6:275,6:282
Unisom, a214 curonyl transferases, 3:640 anticonvulsant, 6:265, 6266,
United Kingdom Urinary excretion rate, 2:638 6:267,6:298
over-the-counter classification, Urography, 4567. See also Ra- clinical efficacy, 6273
4428 diopaques side effects, 6277
patentable subject matter, pharmacokinetics of ra- structure-activity relationship,
2:720 diopaques, 4:559-562 6:310-311
trade secret protection, 2:769 radiopaques applications, Valrocemide
United States 4571 anticonvulsant, 6:310-311
patents in, See Patents Urokinase, 3:308 Valrubicin
United States Court of Federal Uroselectan antitumor natural product,
Claims, 2:740 urography application, 4571 5:110,5:124,5:128-130
United States International Urotensin-I1 Valsartan, 3:198,3:199
Trade Commission, 2:740 biological actions, 3213-214 Vancomycin, 1:770,2:221,2:226
United States Pharmacopeia and biosynthesis, metabolism, and with aztreonam, 5:625
National Formulary, 22684, structure, 3212-213 in vivo efficacy in systemic
2:700-701 Urotensin-I1 receptor, 3213 murine infections, 5:685
Cumulative Index

Vancomycin-peptide complex Vasoactive intestinal peptide, Ventricular remodeling, 3:164


binding affinity, 1:119 3:226-228 prevention, 3:180-181
Van der Waals forces, 1:174, discovery, 3:194 Ventricular tachycardia, 3:9,
1:285 Vasoactive peptides, 3:193-195. 3:31
and docking scoring, 1:308 See also specific peptides Ventriculography, 4567. See
enzyme inhibitors, 1:723-724 Vasoconstrictors also Radiopaques
and molar refraction, 1:24 adrenergics, 6:2 Verapamil, 3:15,3:18,3:32, T
molecular modeling, 1:79-80, Vasodilan, 6:5 3:160,3:161,3:168-169
1:81, 1542, 1:89 Vasodilators, 3:ll-15. See also ATP-sensitive potassium
and QSAR, 1:6, 1:7 Antianginal agents channel inhibition, 3:178
Van der Wads radius, 1:79, future directions, 3:46-47 bioavailability and half-life,
1:81,1:173 pharmacokinetics and toler- 3:18
Vanillin ance of organic nitrates, cardiovaacular effects, 3:17,
3:19,3:43-44
allosteric effector, 2:314, 3:15
classical resolution, 1:798
2:315 Vasomolol, 2:542-543
CYP3A4/5/7 substrate, 4627
allosteric effector of hemoglo- Vasopressin, 4 6 7 dihydropyridines contrasted,
bin, 3:388,3:394-395 biological actions, 3:200-201 3:27-28
antisickling agent, 1:419-420 biosynthesis, metabolism, and multiple inhibitory mecha-
sickle hemoglobin modifier, structure, 3:199-200 nisms, 3:33
3:461 Vasopressin antagonists, 3:201 P-glycoprotein inhibitor,
Vanilloid receptors, 1:853-854 Vasopressin receptors, a200 4631
reporter gene assays studies, Vasospastic angina, 3:9-10 selective toxicity, 5270-271
2:51 Vasoxyl, 6:3 uses and side effects, 3:43
Vaniqa, 4:433 Vaspit, 2:550 vascular-to-cardiac selectivity
Vanity drugs, 4431 Vector maps, 1:140-142 ratio, 3:172
Vanlafaxine Vectren, 3:83 Verapamilic acid, k798
antidepressant, 6:485,6:486, Vedaclidine Verazide, 5834
a488 cholinergic, 6:78 Verlukast, 4223,4224
VanX inhibitors, 1:770-771, Veins, 5:216 Very late antigen activator 4
1:772 Velban (VLA-4)
VARCHAR data type, 1:412 antitumor natural product, interaction with sickled cells,
VARCHAR2 data type, 1:412 5~140-142 a458
Vardend, 4450 Venlafaxine, 6:494,6:531, a875 Very low density lipoproteins
selective toxicity, 5277 affinities for monoamine re- (VLDL),a 3 4 0 3 4 1
Variant angina, 3 9 ceptors, 6:495 and coronary artery disease,
Varicella zoster virus, 5298 CYP2D6 substrate, 4627 3:lO
Varlane, 2:550 dose for anxiety, 6:529 transport, 3:358359
Vascular adhesion molecule 1 inhibition of serotonin, norepi- Vesamicol, 2:392
(VCAM-1) nephrine, and dopamine cholinergic, 6:40
interaction with sickled cells, transporters, a500 Vesanoid, 4320
3:458-459,3:464 pharmacokinetic parameters, Vesicles
Vascular dementia, 6:780 a497 hemoglobin encapsulation,
Vascular endothelial growth fac- side effects profile, 6:493 3:420, a 4 2 1
tor, 5217-218 Venography, 4567. See also Ra- Vesicular monoamine transport-
and angiogenesis, 520-21 diopaques ers, 6:499
plasmid DNA-mediated gene Venous thrombosis, 3:289-290 Vespoerone, a 2 0 5
therapy study, 4656 antithrombotic treatment reg- Vesptin, 6:601
Vascular endothelial growth fac- imen, 3:298 Vestibules, in nicotinic acetyl-
tor inhibitors Vent gas treatment, in large- choline receptors (muscle-
antiangiogenic agents, scale synthesis, 2:418 type), 2:361-362
5:218-219 Ventolin, 6:4 Vevesca (OGT-918), 2:218,
antisense drug, 2:120 Ventricles, 3:3,3:4 2:220,2:240
Vascular receptor, 3:200 Ventricular arrhythmias, 3:31 Vfend, 5890,5897-898
Vascular tone, 3:194 Ventricular fibrillation, 3:9, VH-AH-37
Vasoactive intestinal constrictor, 3:31,3:157,3:159-164 anticholinergic, 6:129
a202 and long QT syndrome, 2:76 Viagra, See Sildenafil
Cumulative Index

Vibramycin, 5:740, 5:935 Viomycin pharmacophore screening,


L-Vibriobactin, 3:483, 3485, antimycobacterial application, 12252-260
3:490 5:811,5:844-846 QSAR as tool for, 1:66-69 -
synthesis, 3:522-524 efficacy and dosage, 5:811, seeding experiments,
Vicodin, 6:335 5:863 1:318-319
Vicoprofen, 6:335 side effects, 5:845-846 structure-based, 1:260-267
Victomycins Vio-Thene, a136 weak inhibitors, 1:319 P
antitumor natural products, Vioxx, 2:86-87,4:204,4:233, Virus-directed enzyme prodrug
5:117 4234-235 therapy, 2:518
Vidarabine, 1:717 clinical efficacy and safety, Viruses, 5:294. See also Antivi-
for herpes virus, 5:309,6:315 4248-249 ral agents, DNA; Antiviral
for papillomavirus, 5:338 selective toxicity, 5:274 agents, RNA
Vigabatrin, 1:718, 1:766, 1:767, Viracept, 1:659 chemokine receptors,
1:782 structure-based design, 1:440, 4170-172
ADME, 6:284 1:442 classes of, Z294-305
anticonvulsant, 6:265, 6:268, Viral DNA polymerase inhibi- progency production,
6:295,6:298 tors, 1:717 5:295-296
clinical efficacy, 6:273 Viral hemagglutinins, 2:263 vectors for gene therapy,
development, 6:299-300 Viral inhibitors 4652
dose, 6:270 multivalency in carbohydrate- Viscumin, 2:263
side effects, a278 based, 2:233 Visken, 6:5
Vinbarbital, a 2 0 5 Viral vedors Vismione H
Vinblastine, 1:858-859, 1:860 for gene therapy, 4652 antimalarial, 5:997, kg98
antitumor natural product, Virilon, 3697 Vista search program, 1:387
5:110,5:140-142 Virtual chemistry space, 1:67 Visual cascade, 4325
P-glycoprotein substrate, Virtual libraries, 1:237, 1:283, Vital m i n e , 4368
4:631 1:315 Vitamin A family, 4368-369.
Vinca alkaloids, 1:858-860,5:52 handling large, 1:220-221 See also Retinoids
antitumor natural product, and QSAR, 1:61 antimalarial, kg89
5:110,5:139-143 Virtual rings, 1:91 biochemical functions and de-
Vincasar PFS Virtual screening, 1:244-245, ficiency, 4:370
antitumor natural product, 1:271-274, 1:315-317, and cancer risk, 5:33
5142 1:412. See also Docking Dietary Reference Intakes,
Vincristine, 1:858-859, 1:860 methods; Scoring functions 4:371-372
antitumor natural product, applications, 1:267-271 dosage forms, 4370
5:110,5:142 basic concepts, 1:289-290 duel role of, 4362
CYP3A41517 substrate, 4627 combinatorial docking, hypercarotenosis, 4371
with dactinomycin, 5:111 1:317-318 hypervitaminosis A, 4319,
P-glycoprotein substrate, consensus scoring, 1:265-266, 4370-371
4631 1~291,1~319-320 mobilization of body stores,
Vindesine, 1:859-860 docking as virtual screening 4324
antitumor natural product, tool, 1:266-267 pharmacologically active reti-
5: 142 druglikeness screening, noids, 4372-374
P-glycoprotein substrate, 1:245-250 storage of 6-9 month supply,
4631 filter cascade, 1:267 4362
Vinflunine focused screening libraries for uptake and metabolism,
antitumor natural product, lead identification, 4369-370
5:142-143 1:250-252 vitamin status assays, 4366
Vinorelbine, 1:849 hydrogen bonding and hydro- Vitamin B, (thiamine),
antitumor natural product, phobic interactions, 1:319 4387388
5:110,5:142-143 ligand-based, 1:188, deficiencies, 4389
P-glycoprotein substrate, 1:209-214 Dietary Reference Intakes,
4631 molecular similarityldiversity 4389-392
Vinylbital, 6:205 methods for, 1:188, 1:190, f i s t vitamin whose structure
Vinylogous polyamides 1:209-214 determined, 4:368
residues in pseudopeptide ar- novel lead identification, hypervitaminosis thiamine,
rays, 2:12 1:320-321 4389
Cumulative Index

uptake and metabolism, hypervitaminosis D, 4379 uptake and metabolism, 4386


4388489 uptake and metabolism, vitamin status assays, 4366
vitamin status assays, 4366 4375-376 Vitamin K oxide, 4386
Vitamin B, (Riboflavin), 4392 vitamin status assays, 4366 Vitamin replacement therapy,
dosage and coenzyme forms, Vitamin D receptors, 43'76 5:251
4393 X-ray crystallographic studies, Vitamins
vitamin status assays, 4366 1:493 adequate intake, 4368 9
Vitamin B,, 6:687. See also Nia- Vitamin deficiencies, 4362 biochemical function satura-
cin; Nicotinamide biotin, 4405 tion, 4:363
Vitamin B, family, 4:397 causes of, 4:362,4364-367 and cancer prevention, 5:33
deficiencies, 4398-399 comparison of intake in areas causes of deficiency, 4362
Dietary Reference Intakes, comparison of intake in areas
withlwithout deficiency dis-
4400 withlwithout deficiency dis-
ease, 4363
drug interactions, 4399-400 ease, 4363
hypervitaminosis pyridoxine, folic acid, 4407-411
defined, 4:361
4:400 vitamin A family, 4370
Dietary Reference Intakes,
for Parkinson's disease, a724 vitamin B,, (cobalamin),
4363468
pyridoxal phosphate biochem- 4:415 estimated average require-
istry, 4397498 vitamin B, family, 4398-399 ment, 4363
radioprotective derivatives, vitamin B, (riboflavin), 4392 fat and water soluble, 4368
5:166 vitamin B, (thiamine), 4389 functions. 4361362
uptake and metabolism, 4397 vitamin C, 4417 human metabolic balance
vitamin status assays, 4367 vitamin D family, 4376-379 studies, 4363
Vitamin B,, (cobalamin), 4408, vitamin E family, 4383-384 recommended dietary allow-
4411-413 vitamin K family, 4386-387 ances, 4363-368
deficiency, 4415 Vitamin E family, 4380-381 serum levels, 4363
Dietary Reference Intakes, for Alzheimer's disease, 6:674, tolerable upper intake level,
4415 6:768 4368
hypervitaminosis B,,, 4415 biochemical function, 4383 valid dose determination,
receptor-mediated endocyto- deficiencies, 4383-384 4362-363
sis, 2:265 Dietary Reference Intakes, vitamin status assays,
recycling, 4362 4384385 4366367
uptake and metabolism, dosage forms, 4384 Vitamins and Minerals Amend-
4413-415 hypervitaminosis E, 4384 ments of 1976,2:687
vitamin status assays, 4367 for lipid lowering, 3:372-373 Vitravene, 2:141
Vitamin C (ascorbic acid), 4415 in sunscreens, 4472 Vivactil, 6:485
deficiency, 4417 uptake and metabolism, Vivarin, 6:170
Dietary Reference Intakes, 4381383 VJH-085,466
4418 vitamin status assays, 4366 VK19911
hypervitaminosis C, 4417 Vitamin K,, 4386 structure-based design, 1:458
uptake and metabolism, NAD glycohydrolase inhibitor, VLDL,See Very low density li-
4415-417 6:687 poproteins
vitamin status assays, 4367 Vitamin &, 4386 VML530,4219
Vitamin D,, 4374,4376 NAD glycohydrolase inhibitor, Voglibose, 1:849,2:205-206,
not normal constituent of diet, 6:687 2:212,4:32,4:33,434
4361 Vitamin &Hz, 4386 VolSurf program, 1:202
Vitamin D, (cholecalciferol), Vitamin K,, 4385-386 Voltage gating, 3:6
4:374-380 Vitamin K base, 4386 Volume
not normal constituent of diet, Vitamin-K dependent inhibitors, molecular dynamic simula-
4361 3:285, a310 tion, 1:96
Vitamin D family, 4374-375 Vitamin K family, 4385-386 Volume mapping, 1:139-140
biochemical function, biochemical function and defi- Volume of distribution, 2:636,
4376379 ciency, 4386-387 2:639-641
Dietary Reference Intakes, and clotting, a300 characterization for IND pro-
4:379 Dietary Reference Intakes, cess, 2:645
dosage forms, 4379 4387 Von Hippel-Lindau gene, 5:8,
drug interactions, 4 3 7 9 4 8 0 hypervitaminosis K, 4:387 5:lO
Cumulative Index

von Willebrand disease, 3:291 WARP, 1:478 WIN 51711


von Willebrand factor, a290 Warts, 5301 picornavirus antiviral, 5400
in clotting, 3:303 Wasting disease drugs, 6:843, structure-based design,
in hemostatic preparations, 6:854 1:454-455
3:292 absorption and metabolism, WIN 54954
interaction with sickled cells, 6:866-867 picornavirus antiviral, 5399
3:459,3:462 clinical applications, 6:858 structure-based design, 1:455 r
Voriconazole, 5897-898 Wasting diseases, 6:838,6:840 WIN 59075
formulations and indications, guidelines for treatment, radiosensitizer, 5:181
5:890 6:842-843 WIN 61893 -
Voronoi QSAR technique, 1:53 Water. See also OctanoVwater picornavirus antiviral, 5399
Vorozole, 3:643, a668 partitioning system WIN 63843
VP-14637, 5393
gas phase association thermo- structure-based design,
V-PARP, 6:679
dynamic functions, 1:178 1~455-456
VRML (Virtual Reality Markup
Language), 1:405 importance of bound in struc- Wine-and-cheese syndrome,
V-sis, 5 2 2 ture-based design, 1:409 6:491, a 5 3 2
V-type allosteric effects, 2:296, molecular modeling, 1:85 Wiswesser line notation,
2:303 and protein-ligand interac- 1~368-369
L-Vulnibactin, 3:483,3:485 tions, 1:288 WIZARD, 1:255, 1:260
synthesis, 3:522-524 role in docking, 1:302-303, WMC-26
VX-497 1:313-314 dual topoisomerase VII inhibi-
hepatitis C virus antiviral solvating effect in enzyme in- tor, 5:75
agents, 5426-42'7 hibitors, 1:722-723 Wolff-Parkinson-White syn-
for herpes, 5322 Water soluble vitamins, 4368 drome, 3:19,3:31,3:38
structure-based design, 1:447 Watson-Crick hybridization, World Drug Index (WDI), 1:379,
VX-745 2:116,2:117-118,2:144 1:386, 1:387
structure-based design, 1:458 Wax D, 5817 World Patents Index (WPI),
WAY-100135,6:570 1:386
W1807 WAY-150138 World Trade Organization
allosteric effectors, 2:314, for herpes virus, 5314-315 (WTO)
2:315 WAY-154641,5:390-393 and patent interference,
WAL 20 14 Weak acids, Z:66O - 662 25'36-737
for Alzheimer's disease, 6:763 Weak bases, 2:660-662 WR1065
Wang resin, 2:30 Welchol, 3:343 radioprotective agent,
Warfarin, 1:882-883,3:285 for angina treatment, 3:11 5167-168
ADME, 3:295-296 Wellbutrin, 6:485. See also Bu- WR2721
binding to serum albumin, propion radioprotective agent, 5:157,
2:131 anorectic agent, 6:883,6:885 5167,5172
clinical trials, 3:292-293 Wellcome Registry, 1:222 WR33,063
CYP2C9 substrate, 4627 Welldorm, 6:209 antimalarial, 5946
enantiomers, 1:786 Wellvone, 5935 WR99210
formula weight, mechanism of Wernicke-Korsakoff syndrome, antimalarial, 5:960
action, and route of admin- 4389 WR122,455
istration, 3:286 Western blot, 2:621 antimalarial, 5946
HIV protease inhibitor, 1:659, West Nile virus, 5:427, 5428 WR148,999
1:661 Wetting agents, 2:678,2:679 antimalarial, 5:986
limitations of use, a 3 2 3 Wheeler-Lea Act, 2:685 WR182,393
mechanism and sites of action, White-Bovill force field, 1:80 antimalarial, 5954
3310 Willful patent infringement, en- WR225,448
nonclassical resolution, 1:801 hanced damages for, 2:747 antimalarial, 5:952-953
prothrombin time, 3:291 WIN 5723,5853 WR238,605
selective toxicity, 5271 WIN 35065-2 antimalarial, 5 9 5 2 9 5 3
structure, 3:288 CNS stimulant, 6:191 WR242,511
treatment regimen, 3:298 dopamine transporter inhibi- antimalarial, 5 9 5 2 9 5 3
and variant CYP2C9 alleles, tor, 1:268 WR250,417
3:297 WIN 44441, a 3 7 5 antimalarial, 5960
Cumulative Index

WR268,954 databases for, 1:478-479 Ytterbium-DTPA


antimalarial, 5:942 data collection, 1:474-476 radiopaque material, 4490
WT-1 gene, 5:27 drug targets with published Yukawa-Tsuno equation, 1:14
Wyamine, 6:3 structures, 1:482-493 Yutopar, 6:4
Wygesic, 6:335 membrane transport proteins,
Wytensin, 6:3 2:269 2-100, 1:849
and molecular modeling, 1:78 Zacopride T
Xanax, 6:529 phase problem, 1:476-478 cognition enhancer, 6:816
dose for eating disorders, and QSAR, 1:5 Zafirlukast, 4225-226
6:852 recombinant DNA applica- selective toxicity, 5252 -
Xanomeline tions, 2:96 Zalcitabine
for Alzheimer's disease, 6:763 and structural genomics, anti-HIV drug, 5:471,5:472
Xanthates 1:481, 1:494-496 selective toxicity, 5:267
radioprotective agent, Zaleplon, 6:210,6:211
in structure-based drug de-
5:161-162
sign, 1:418, 1:419, 1:420 ADME, 6:223
Xanthine-guanine phosphoribo-
and structure-based library CYP3A4/5/7 substrate, 4627
syltransferase
X-ray crystallographic studies, design, 1:225 Zanamivir, 1:717,2:208-209,
1:493 and virtual screening, 1:244 2:212, 2:240,5:361
Xanthine oxidase, 3:138,3:141 X-ray diffraction, 1:472-473, for influenza, 5:365368
Xanthine oxidase inhibitors, 1:614 selective toxicity, 5:266,5:267
1:718 X-ray lenses, 1:612 structure-based design, 1:451
Xanthines, 3:121-122 X-rays, 4484-486. See also Ra- Zanosar
Xanthopterin, 3:125 dioprotective agents alkylating agent, 5:54
XC 1 receptor, 4133 antiradiation testing, 5154 Zanoterone, a719
Xemilofiban, 3:319 Xylometazoline Zantryl, 6:171
Xenical, 4474, a844 a,-agonist, 6:3 Zaprinast, 4449
Xenobiotic metabolism, 2:432, applications, 6:13 Zaroxolyn, 3:83
2:433,2:503 structure-activity relationship, ZD0473
pharmacodynamic conse- 6:31 alkylating agent, 5:54,5:60,
quences of, 2:434-435 5:61
specificities and selectivities, Y7131,6:554 ZD1611
2:433-434 Yalkowsky-Valvani equation, endothelin receptor antago-
Xenotransplantation, 5:489 2:657 nist, 3:206
future developments, 5:526 Yeast genes ZD1839,5:12
Xeroderma pigmentosum, 5:32 with microarrays for expres- ZD2138,4215-216
XFIT graphics program, 1:478 sion profiling, 4612 ZD2767
Ximelagatran, 3:314,3:315 Yellow fever virus, 5427 tumor-activated prodrug,
structure-based design, 1:442 Yellow sweet clover, drugs de- 5:83,5:88
Xipamide, 3:88,3:104-107 rived from, 1:882 ZD4190
XML (extensible Markup Lan- Yew tree, paclitaxel from, antiangiogenic agent,
guage), 1:371, 1:405, 1:412 1:861-862 5218-219
XMLQuery, 1:412 Yield, in synthesis, 2:410-411 ZD4407,4216
Xopenex, 6:4 Yingzhaosu A Zebeta, 3:28,6:5
XR-5000 antimalarial, 5:984-985 Zein, 4395
dual topoisomerase I/II inhibi- Yingzhaosu C Zemplar, 4378
tor, 5:68,5:73 antimalarial, 5:984-985 Zenepax, 5:510
XR-5118,3:330,3:331 YM-022, 1:856 Zetia, 3:343
XR-5944 YM-337,3:319 Ziconotide
dual topoisomerase UII inhibi- Yohimbine NMR spectroscopy,
tor, 5:75 adverse effects, 4443 1:518-523, 1:526, 1:534
X-ray contrast agents, 4567 history of use, 4447-448 Zidovudine, 1:717
X-ray crystallography, 1:351, mechanism of action, 4446 anti-HIV drug, 5:471-472
1:471-473, 1:612 and neuropeptide Y, 6:545 chemical delivery system,
applications, 1:479-481 pharmacokinetics, 4444 2:580-583
crystallization for, 1:473-474, structure-activity relationship, and CXCR4,4:167
1:480-481 4447 selective toxicity, 5:267
Cumulative Index

Zileuton, 4213-214 ZK 93423, a557 Zonisamide


impact of 5-lipoxygenase poly- binding affinity with ADME, a286
morphism~on effectiveness, GABAA/Bzreceptor, 6:788 anticonvulsant, 6:265, 6:268, -
4:635 ZK 93426 6:269,6:297,6:298, a319
selective toxicity, 5252 cognition enhancer, clinical efficacy, 6:273
Zinamide, 5810 6:794-795 development, a 3 0 3
Zinc aspartate ZK 98299,3:651 dose, 6:270 .T

radioprotective agent, 5163 ZK 119010 pediatric indications, 6:274


Zinc oxide estrogen receptor affinity, side effects, 6:279
absorption and disposition, 3:659 Zonula occludens toxin, 2:252,
ZK 169978 2:255
4:463
estrogen receptor affinity, Zopiclone, 6:210,6:211,6:558-559
history of use as sunscreen,
3:659 binding affinity with GABAA/
4470 ZK 807834,3324 Bz, 6:795
structure-activity relationship, ZM 189154 Zopliclone
4470 estrogen receptor afiinity, 3659 ADME, 6:221
sunscreen, 4460 ZM 211965,4:215 Zorbamycins
Zingerone Zocor, 3:343, 3:609 antitumor natural products,
allergenicity prediction, Zofran, 6:815 5:115,5117
1:835 Zolazepam, a554 Zorbonamycins
Ziprasidone, 6:648 Zollinger-Ellison syndrome, antitumor natural products,
dose, 6:601 486,492-93 5:117
for Parkinson's disease. 6:725 Zoloft, 6:485, 6:529 Zosyn
pharmacokinetics, biotrans- dose for eating disorders, 6:849 use recommendations, 5626
formation, and drug interac- Zolpidem, 6:210, 6:211, Zotepine, 6:648-649
tions, 6:639 6:561-562 Zuclopentixol, 2:512
receptor binding and side ef- ADME, 6~221-223 Zyban, 4452
fects, a606 binding affinity with GABA,/ Zyflo, 4211,4213-214,
Zispin, 6:485 Bz, 6:795 4226-227
Zithromax, 5:763,5:935 CYP3A4/5/7 substrate, 4627 Zymosterol, 5:887
ZK 91587,3118 discovery, 6:236237 Zyprexa, 6:601
"An essential addition to the libraries of any
.. .an outstanding work . . . highly praised a:
information in drug studies and research."

new edition of Dr. Alfred durger's internatlona~~y celepratec


assic helps researchers acquaint themselves with both traditional
dnd state-of-the-art principles and practices governing rPTTT
medicinal drug research and development. Completely upd:
and revised to reflect the many monumental changes I - - ~ ~
have occurred in the field, this latest edition brings togethe
contributions by experts in a wide range of related fields to explorl
recent advances in the understanding of the structural biolog:
of drug action, as well as cutting-edge tech '--ies > for d
discovery now in use around the world.
his Sixth Edition of Bur~er'sMedicinal
biscovery has been expanded to six volur
Volume 1: Drug Discovery
Volume 2: Drug Discovery and Drug Development
Volume 3: Cardiovascular Agents and Endocrines
Volume 4: Autocoids, Diagnostics, and Drugs from New Biologv
Volume 5 : Chemotherapeutic Agents
Volume 6: Nervous System Agents

bONALD A. A B R A W , PHD, is Professor and Chairman


of the Department of Medicinal Chemistry at the Virginia
Commonwealth University School of Pharmacy. A world-renowned
leader in medicinal chemistry and biotechnology, he is the author
of more than 140 journal citations and twenty-five patents. He
was selected by the ~ C Board
P of Directors as the recipient of the
200 otechnology Award.

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