Burger's Medicinal Chemistry and Drug Discovery, Nervous System Agents

1080 Pages·2003·53.43 MB·English

by  Donald J. Abraham

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 . A ldrich
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
Contents
xiv
8 ANTIDEPRESSANTS, 483 12 THERAPEUTIC AND
DIAGNOSTIC AGENTS FOR
Leslie Iversen
PARKINSON'S DISEASE, 711
University of Oxford
John L. Neumeyer
Department of Pharmacology
Ross J. Baldessarini
Oxford, United Kingdom
Harvard Medical School
Richard A. Glennon
McLean Hospital
Virginia Commonwealth University Belmont, Massachusetts
School of Pharmacy
Raymond G. Booth
Richmond, Virginia
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
14 COGNITION ENHANCERS, 779
Gaithersburg, Maryland
Clark N. Eid, Jr.
Arnold R. Martin
Yong-Jin Wu
University of Arizona
Division of Central Nervous System
Department of Pharmacology
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
DISORDERS, 837
James David Adams Jr.
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
Department of Cardiovascular and
Thomas F. Woolf
Metabolic Diseases
HyBar BioScience, LLC
Groton, Connecticut
Ann Arbor, Michigan
INDEX, 895
CUMULATIVE INDEX, 923
BURGER'S
MEDICINAL CHEMISTRY
AND
DRUG DISCOVERY
CHAPTER ONE
Adrenergics and Adrenergic-
Blocking Agents
R K. G
OBERT RIFFITH
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,1 6
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 02 003 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 ,a Zd,a nd
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).I n 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)a nd 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., 3x 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 34X daily, neb.
Bitolterol(14) Tornalate Sterling Phenylethylamine 0.74-2.22 inh.
Formoterol(15) Foradil Yamanouchi Phenylethylamine 12 pg, 2x 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.
055.0 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 da ily, 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. 2x 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.., 2x 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 and Comparisons 2002 (14).
"Not all doses and dosage forms are listed. For further information consult reference (14).