the steric factor in medicinal chemistry - springer978-1-4899-2397-4/1.pdfthe steric factor in...
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The Steric Factor in Medicinal Chetnistry Dissymmetrie Pro bes of Pharmacological Receptors
Alan F. easy University 0/ Bath Bath, United Kingdom
With a contribution by
George H. Dewar University 0/ Bath Bath, United Kingdom
Springer Science+Business Media, LLC
llbrary of Congress CataJoglng-ln-PubJlcatlon Data
Casy, Alan F. The steric factor In Medlclnal cheMlstry , dlssYM.etrlc probes of
pharMacological receptors / Alan F. Casy ; wlth a contributlon by George H. Dewar.
p. c •. Includes bibllographlcal references and Index.
1. Drugs--Structure-actlvlty relatlonshlps. 2. Drug receptors. 3. Stereochemistry. I. Dewar, George H. 11. Tltle. RM301.42.C37 1993 615' .7--dc20 93-6290
ISBN 978-1-4899-2399-8 ISBN 978-1-4899-2397-4 (eBook) DOI 10.1007/978-1-4899-2397-4
© 1993 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1993.
Softcover reprint of the hardcover 1 st edition 1993
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher
CIP
Foreword
Stereochemistry was born in the second half of the 19th century with the publications of Pasteur in 1860, van't Hoff in 1874, and Le Bel in 1874, a remarkable period that followed rather closely the progressive appearance of chemistry as we understand it now. But chemical compounds are three-dimensional entities, implying that, in so me sense, the whole of chemistry is stereochemistry. The twodimensional description of chemical structures necessarily results in a loss of information, and this is why stereochemistry is of particular relevance when it comes to designing drugs and other bioactive compounds and investigating their structure-activity relationships.
The study of stereoselective phenomena in chemistry, biochemistry, and pharmacology has proven remarkably fruitful in deepening our understanding of chemical and biological processes. In such investigations, stereoisomeric compounds are probes of particular efficiency, and to neglect or ignore their avail can only lead to scientific impoverishment and limited vision (see Fig. Fl below). There is thus a
'Jhe CW07-fd of Chi7-allty
'Jhe CW07-fd of c4chi7-afity
FIGURE Fl. Ignoring chirality? (Cartoon by Patrick Bertholet. Copyright B. Testa.)
VII
viii FOREWORD
need to confront such ignorance and encourage the study of stereoselective phenomena and the use of stereoisomeric probes, but this must be done without obsession and exclusiveness. Such a reasonable, balanced, and lucid frame of mind inhabits every chapter of the book you now read. It is indeed the merit of Dr. Alan F. easy to bring to these pages a clear and comprehensive view of medicinal stereochemistry, a discipline in wh ich he has been active and successful for many years both as a teacher and a researcher.
Written for graduate students and research workers in medicinal chemistry and pharmacology, this book will contribute significantly toward a better education of scientists by removing the fear of stereochemistry caused by ignorance, moderating the overconfidence of possible zealots, and outlining a broader context. This is what education is about.
Bernard Testa Lausanne, Switzerland
Preface
This book sets out to provide source material on stereochemical influences in medicinal chemistry and pharmacology. While there is much review literature on individual areas of these disciplines, the absence of a coordinated account wh ich presents both the biological data and details (together with evidence) of the spatial characterization of stereoisomeric sets is the prime reason for the present undertaking. A secondary motivation, which I advance as so me jusitification of my role as author of such a work, is my early introduction to the field and the underlying stereochemical theme of much of my research career. I was fortunate when still in my mid-20s to have Arnold H. Beckett as my mentor, a man who was one of the first to recognize the significance of molecular shape in medicinal chemistry and the fact that "nature undoubtedly carries out her reactions on a three-dimensional basis." In the early 1950s, when I joined AHB at Chelsea, stereochemical studies of this kind were relatively rare and restricted to a few areas, but they were rapidly to burgeon and encompass the entire spectrum of biological activity. Today one has only to scan a current issue of the Journal of Medicinal Chemistry to appreciate how many articles carry some aspect of a stereochemical role. Advances in the methodology of both pharmacology and organic stereochemistry have been profound over the past 40 years and have enabled the realization of such a growth of interest.
Clearly, no one book (let alone one with a single author) can present the entire field of stereochemical medicinal chemistry. Because of my own special interest, I have chosen to select material that relates to well-investigated neurotransmitterreceptor systems, namely, ligands of adrenergic, dopaminergic, cholinergic, histaminergic, and serotoninergic receptors, and also to opioid receptors. The stereochemical aspects of each type are treated in depth with a literature coverage extending up to the end of 1990 (with some later additions). The book opens with an introductory chapter that covers bibliographical sources, the objects of stereochemical investigations, important concepts, and the pattern of presentation. The second chapter deals briefly with matters of nomenclature and methodology with emphasis on modern developments, while the third is devoted to pharmacokinetics. Specific topics are presented in Chapters 4 through 14. The Appendix and Postscript provides some concluding remarks and guides the reader to stereochemical studies of areas not covered in the main text.
ix
x PREFACE
While the book is directed at medicinal chemists and pharmacologists actively engaged in research, whether in academia or the pharmaceutical industry, it is hoped that this volume will prove valuable and enlightening to postgraduate and senior undergraduate students of chemistry, medicinal chemistry, pharmacology, pharmacy, and biochemistry (and to students of the life sciences in general).
Colleagues who have responded so generously to my many letters of enquiry and requests are too numerous to be listed here in entirety. I should, however, like to express special appreciation to Bernard Testa who has kindly provided the Foreword, and George Dewar for his contribution to Chapter 10 on neuromuscular blocking agents. Thanks are also due to Richard Barlow, Robin Ganellin, Arthur Jacobson and Kenner Rice (of NIH, Bethesda), Häkan Wikström, VIi Hacksell, and Anette Johansson (of the Vppsala group), Günther Lambrecht, John Neumeyer, Popat Patil, Robert Ruffolo, Walter Schunack, Jan Tollenaere, and Bill Trager. Finally I thank my typist, He1en Thame, for her careful and patient work, and Robert Parfitt for his encouragement and support.
ACKNOWLEDGMENTS. The author is grateful to authors and publishers for permission to reproduce certain figures, schemes, and other material. Sources are given in the figure caption andjor text and the full references are inc1uded in lists at the end of each chapter.
Alan F. Casy Bath
Abbreviations
ACE ACh
AC hE ACTM ADTM
AGP Ar
ATP AUC
ax BOC
c c-AMP
CBM CD
CNA CNS
COMT CPM
CP-MAS CSP CSR DA
4-DAMP DCI
DMF DOPA DPAT
E EAQ ED 50
EHT
angiotensin converting enzyme acetylcholine acetylcholinesterase l-acetoxy-2-trimethylammoniumcyclopropane (ACh agonist) aminodihydroxytetralin (DA agonist) alpha (a 1 )-glycoprotein aryl adenosine triphosphate area under curve (pharmacokinetic usage) axial t-butyloxycarbonyl cis cyclic adenosine monophosphate cyclobutylmethyl circular dichroism chlornaltrexamine central nervous system catechol-O-methyl transferase cyclopropylmethyl cross-polarization magie-angle spinning (solid-state NMR) chiral stationary phase chiral shift reagent dopamine benzilate of l-methyl-4-piperidinol methiodide dichloroisopropenaline dimethylformamide dihydroxyphenylalanine 2-dipropylaminotetralin entgegen eudismic affinity quotient effective dose in 50% of a population extended Hücke1 treatment (MO methods)
xi
xii
EI EKC
EM EPMR
eq ER
FNA GC
GC-MS GI
GITC GP
GPI GTP
HPLC HSA
5-HTP HYP IC50
ICYP INPEA
IR IV
J
LAH mAChR
MAO MHP
MO MTPA
NA nAChR
NIH NMR NMS NOE NPA
NSAID ORD OXO
OXO-M pA2
PBZ PCP
PI
eudismic index ethylketazocine extensive metabolizers equipotent molar ratio equatorial eudismic ratio funaltrexamine gas chromatography
ABBREVIATIONS
gas chromatography - mass spectrometry (in combination) gastrointestinal (tract) 2,3,4,6-tetra-O-acetyl-ß-D-glucopyranosyl isothiocyanate guinea pig guinea pig ileum guanosine triphosphate high performance liquid chromatography human serum albumin 5-hydroxytryptophan hydroxypindolol concentration of drug that displaces 50% of a radioactive ligand (in binding assays) iodocyanopindolol 4-nitro analogue of isoprenaline infrared (spectroscopy) intravenous coupling constant in Hz, 2 J over two, 3 J over three bonds etc. (in NMR spectroscopy) lithium aluminum hydride muscarinic cholinergic receptor monoamine oxidase mouse hot-plate (opioid assay) molecular orbital 2-methoxy-2-triftuoromethylphenylacetic acid noradrenaline (NE norepinephrine) nicotinic cholinergic receptor National Institutes of Health (Bethesda, MD) nuclear magnetic resonance (spectroscopy) N-methylscopolamine nuclear Overhauser enhancement (in NMR) n-propylapomorphine nonsteroidal antiinftammatory drug optical rota tory dispersion oxotremorine methiodide of oxotremorine negative logarithm of dose of antagonist that converts response to a double dose of agonist to that of a single dose phenoxybenzamine phencyclidine phosphoinositol
ABBREVIATIONS
Pi PM
PNMT 3-PPP QNB R (S)
r RIA
RVD SSB
t
TiPS TLC
TMQ Ts Tz
UV Z
Pharrnaceutical Journal poor metabolizers phenylethanolamine N-methyltransferase 3-(m-hydroxyphenyl)-1-n-propylpiperidine benzilate ester of 3-quinuc1idinol
xiii
Rectus (Sinister) configurational symbols of the CahnIngold-Prelog protocol reference (configurational usage) radioimmunoassay rat vas deferens stereospecific binding trans Trends in Pharmacological Sciences thin layer chromatography trimetoquinol tosyl (p-tolylsulfonyl) telenzepine ultraviolet (spectroscopy) zusammen
Contents
1. Introduction .................................................... .
1.1. Purpose and Value of Stereochemical Investigations in Medicinal Chemistry ........................................ 2
1.2. Concepts.................................................. 3 1.3. Conformational Effects .......... . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.4. Pfeiffer's Rule . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.5. Ogston's Ideas and Prochirality .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1.6. Pattern of Presentation ...................................... 8 1.7. Notes on References ........................................ 9 References ...................................................... 9
2. Nomenclature and Methodology .................................... 11
2.1. Introduction............................................... 11 2.2. Stereochemical Nomenc1ature and Methodology ................ 11
2.2.1. Cyc1ic Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 2.2.2. Geometrical Isomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
2.3. Methods of Establishing Relative and Absolute Stereochemistry ... 21 2.4. Computational Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.5. Sources of Stereoisomers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.5.1. Resolution ........................................... 27 2.5.2. Use of Chiral Building Blocks. . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.5.3. Use of Enzymes in Chiral Synthesis . . . . . . . . . . . . . . . . . . . . . . 28 2.5.4. Use of Chiral Auxiliaries ............................... 30
2.6. Chiral Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.6.1. Chromatographie Methods ............................. 33 2.6.2. Chiral Recognition via Host-Guest Complexation ......... 34 2.6.3. NMR Procedures ..................................... 37
2.7. Pseudoracemates ........................................... 41 2.8. Radioimmunoassay......................................... 43 2.9. Pharmacological Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.9.1. Whole Animal (in Vivo) Experiments. . . . . . . . . . . . . . . . . . . . . 43
xv
xvi CONTENTS
2.9.2. Isolated Tissue (in Vitra) Proeedures ..................... 43 2.9.3. Binding Experiments .................................. 43 2.9.4. Bioehemieal Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 2.9.5. General Remark ...................................... 45
References ...................................................... 45
3. Pharmacokinetics: Including Use of Racemic Mixtures in Therapy . . . . . . . . 49
3.1. Introduetion............................................... 49 3.2. Distribution and Protein Binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.2.1. Warfarin .. . ... . ... . .... ... . . ... . .... ... . ... . . ... . .... 52 3.3. Metabolism................................................ 53 3.4. Examples.................................................. 55
3.4.1. Hexobarbital ......................................... 55 3.4.2. Pentobarbital . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55 3.4.3. Mephenytoin .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 3.4.4. Antieoagulants ....................................... 58 3.4.5. Aeenoeoumarol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 3.4.6. Verapamil ........................................... 59 3.4.7. Terbutaline .......................................... 60
3.5. Therapeutie Use of Chiral Drugs in Raeemie Mixture Form. . . . . . . 61 3.6. Metabolie Interaetions between Enantiomers ................... 65 3.7. Biliary and Renal Exeretion .................................. 66 3.8. Signifieance................................................ 67 References ................................ . . . . . . . . . . . . . . . . . . . . . . 67
4. Adrenergic Ligands: Chiefly Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.1. Introduetion............................................... 73 4.2. Natural Cateeholamines and Synthetic Agents with Direet Action 74 4.3. Aspeets of in Viva Synthesis .................................. 78 4.4. Isoprenaline and Other Agents of Primarily ß-Agonist Charaeter 83 4.5. Labetalol and Other Combined a, ß blockers ................... 88 4.6. The Easson and Stedman Hypothesis ..................... . . . . . 91 4.7. Phenethylamines with a-Carbon Chirality ...................... 94 4.8. Oetopamines and Synephrines ................................ 98 4.9. Imidazolines............................................... 101 4.10. Trimetoquinol (TMQ) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 103 4.11. Adrenergie Agents with Indireet and Mixed Aetions
(False Transmitters) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 105 4.12. Conformational Studies ..................................... 109 4.13. Spectral Analysis ........................................... 111 4.14. Conformational Restraints ................................... 114 4.15. Binding Experiments and Influence of Adrenoeeptor Ligands
on Adenylate Cyclase ....................................... 119 Appendix: Reserpine ............................................. 121 References ...................................................... 122
CONTENTS xvii
5. Adrenoceptor Antagonists 129
5.1. Introduction ............................................... 129 5.2. a-Antagonists.............................................. 129 5.3. Benzodioxans.............................................. 129 5.4. Yohimbine and Its Stereoisomers and Analogues ................ 133 5.5. Stereochemistry of Yohimbine and its Stereo isomers ............. 135 5.6. Miscellaneous Agents ....................................... 138 5.7. ß-Antagonists.............................................. 139 5.8. Second-Generation ß-Blockers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 141 5.9. Pharmacokinetics of Propranolol and Its Analogues ............. 143 5.10. Stereoselective Synthesis ..................................... 149 5.11. Timolol ................................................... 151 5.12. Oxime Class ............................................... 154 5.13. Further Analogues Including a-Methyl Derivatives .............. 157 5.14. Conformational Aspects ..................................... 159 References ...................................................... 160
6. Dopamine and Dopaminergic Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 165
6.1. Introduction............................................... 165 6.2. Conformational Studies ..................................... 166 6.3. Methylated and Small-Ring Analogues of Dopamine . . . . . . . . . . . .. 167
6.3.1. ß-Hydroxy Analogues ................................. 168 6.3.2. Small-Ring Analogues ................................. 169
6.4. Aporphines................................................ 169 6.5. 2-Aminotetralins ........................................... 174 6.6. 3-Phenylpiperidines......................................... 183 6.7. Ergot Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 185 6.8. Octahydrobenzo[f]quinolines................................ 188 6.9. Octahydrobenzo[g]quinolines................................. 191 6.10. Miscellaneous Agonists Including Benzazepines ................. 193 6.11. Models.................................................... 197 6.12. Cocaine and Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 202 References ...................................................... 203
7. Dopamine Antagonists ............................................ 209
7.1. Introduction............................................... 209 7.2. Thioxanthenes ............................................. 209 7.3. Butaclamol and Re1ated Benzocycloheptapyridoisoquinolines ..... 212 7.4. Dibenzo[b,J]thiepins and Related Compounds . ... ... . ... ..... .. 217 7.5. Benzamides................................................ 219 7.6. Halogenated Benzazepines ................................... 223 7.7. Miscellaneous Antagonists ................................... 225 References ...................................................... 228
8. Cholinergic Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 231
8.1. Introduction ............................................... 231 8.2. Methylated Analogues of Acetylcholine ........................ 231
XVlll CONTENTS
8.3. Muscarine and Its Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 236 8.4. Muscarone Analogues and Cyc10pentane Derivatives ............ 240
8.4.1. Muscarine Analogues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 240 8.4.2. Cyc10pentane Derivatives .............................. 248
8.5. Conformational Studies ..................................... 249 8.6. NMR (Chiefly IH) Studies of Conformation ..... . . . . . . . . . . . . . .. 252
8.6.1. Methylacetylcholines .................................. 255 8.7. Molecular Orbital (MO) Calculations of Conformation . . . . . . . . . .. 257 8.8. Conformationally Restrained Analogues of Muscarinie Agonists . .. 258
8.8.1. Analogues of ACh .................................... 259 8.9. Derivatives of Quinuc1idine and Related Bicyc1ic Agonists ........ 270 8.10. Piperidine and Thiane Analogues ............................. 275 8.11. Metabolie Inactivation of ACh and AChE Inhibitors. . . . . . . . . . . .. 278 8.12. Storages and Release of ACh. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 280 References ...................................................... 281
9. Muscarinic Antagonists ........................................... 287
9.1. Introduction: Tropane Alkaloids. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 287 9.2. Orientation of the Acyloxy Function in Relation to the Basic
Nitrogen of Tropane and Piperidyl Anticholinergics ............. 290 9.3. Choline Derivatives ......................................... 295 9.4. Dioxolane and 1,3-0xathiolane Derivatives. . . . . . . . . . . . . . . . . . . .. 297 9.5. Quinuc1idines.............................................. 304 9.6. Procyc1idine, Benzhexol, and Miscellaneous Anticholinergics ...... 307 9.7. Chiral Oxotremorine Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 314 9.8. Chiral Analogues ofPirenzepine .............................. 319 References ...................................................... 322
10. Ligands of Nicotinie Cholinergic Receptors (nAChR) Including Neuromuscular Blocking Agents .................................... 327
10.1. Introduction.............................................. 327 10.2. Nicotine.................................................. 328 10.3. Cytisine and Other Agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 330 10.4. Stereo-SAR Ana1yses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 331 10.5. Nicotinic Receptor Antagonists: Neuromuscular Blocking (NMB)
Agents ................................................... 333 10.5.1. Nondepolarizing Agents ............................. 334 10.5.2. Depolarizing Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 334
10.6. Stereochemistry in Nondepolarizing NMB Agents .............. 335 10.6.1. Tubocurarine and Closely Related Substances . . . . . . . . . .. 335 10.6.2. Synthetic, Symmetrical1-Benzylisoquinolinium Agents ... 338 10.6.3. Alkaloids of Calabash Curare (Strychnos) .............. 344 10.6.4. Steroidal Neuromuscular Blocking Agents .............. 348 10.6.5. Miscellaneous NMB Agents .......................... 354
10.7. Stereochemistry in Depolarizing Agents . . . . . . . . . . . . . . . . . . . . . .. 359 10.8. Snake Neurotoxins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 360 10.9. Other Toxins. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 360 References ...................................................... 361
CONTENTS xix
11. Histamine Receptors: Agonists and Antagonists 367
11.1. Histamine: Biogenesis and Metabolism. . . . . . . . . . . . . . . . . . . . . . .. 367 11.2. Reeeptor Subtypes and Agonist Conformation ................. 368 11.3. Chiral and Restrained Analogues of Histamine and Impromidine 371 11.4. Antagonists of H [-Reeeptors: Testing Methods . . . . . . . . . . . . . . . .. 376 11.5. Tertiary Aminoalkyl Ethers ................................. 377 11.6. 3-Amino-l-aryl-l-(2-pyridyl)propanes (Pheniramines) ........... 382 11. 7. Trieyclie Antihistamines .................................... 387 11.8. Miseellaneous Antihistamines ............................... 387 11.9. Geometrieal Isomers ....................................... 391
11.9.1. Configurational Studies .............................. 393 11.9.2. Pyrrobutamine and Related 1,2-Diaryl-4-aminobutenes ... 396
11.10. Conformational Analysis of Antihistamines . . . . . . . . . . . . . . . . . . .. 397 11.11. General Remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 400
11.11.1. Isomerie Poteney and Affinity Ratios . . . . . . . . . . . . . . . . .. 402 11.12. Conformationally Restrained Antihistamines of Cyclic Nature. . .. 403 11.13. Central Effeets ............................................ 405 References ...................................................... 405
12. 5-Hydroxytryptamine Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 409
12.1. Introduetion.............................................. 409 12.2. Uptake Inhibition ......................................... 411 12.3. Chiral Ligands ............................................ 414 12.4. 8-Hydroxy-DPAT......................................... 416
12.4.1. I-Methyl Analogues ................................. 417 12.4.2. 3-Methyl Analogues ................................. 418
12.5. Phenalkylamines........................................... 420 12.6. Chiral 5-HT Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 422 12.7. 5-HT3 Ligands ............................................ 424 12.8. Mapping of Agonist Sites ................................... 425 References ...................................................... 427
13. Opioid Ligands: Part 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 429
13.1. Introduetion.............................................. 429 13.2. Morphine and Congeners Derived from Opium Alkaloids ...... " 429
13.2.1. B/C trans-Morphine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 433 13.2.2. Ring C Diastereoisomers . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 435 13.2.3. 6-Amino Derivatives: Affinity Ligands ................. 436 13.2.4. Bivalent Ligands . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 441 13.2.5. Substituents at C-14 ................................. 442 13.2.6. Quaternary Salts .................................. " 443 13.2.7. Thebaine-Derived Opiates: Etorphine and Hs Relatives ... 444
13.3. Morphinans .............................................. 448 13.3.1. B/C trans Series: Isomorphinans and Other Analogues . . .. 451
13.4. 6,7-Benzomorphans........................................ 456 13.4.1. 9-Hydroxy Derivatives. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 463
13.5. 4-Arylpiperidines.......................................... 465
xx CONTENTS
13.6. Arylmorphans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 474 13.7. 3-Arylpiperidines.......................................... 476 13.8. 4-Phenylpiperidines with C-4 Oxygen Substituents .............. 478
13.8.1. u- and ß-Prodine and Related Compounds . . . . . . . . . . . . .. 478 13.8.2. Analysis of Stereostructure-Activity Relationships in
4-Phenylpiperidine Reversed Esters .................... 484 13.8.3. Stereochemical Methods ............................. 489 13.8.4. Receptor Speculations ............................... 491
References ...................................................... 495
14. Opioid Ligands: Part 2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 503
14.1. Introduction.............................................. 503 14.2. Fentanyl Group ........................................... 503 14.3. Methadone and Related 3,3-Diphenylpropylamines . . . . . . . . . . . .. 510 14.4. Opioid Peptides ........................................... 524
14.4.1. Nonalkenie Cyc1ic Analogues ......................... 526 14.5. Miscellaneous Opioids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 528
14.5.1. Tetrahydroisoquinolines ............................. 528 14.5.2. Cyc10hexane Derivatives ............................. 528 14.5.3. Kappa (K) Agonists: U-50488 and its Relatives .......... 531 14.5.4. Aminotetralins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 542 14.5.5. Viminol ........................................... 543
References ...................................................... 544
Appendix and Postscript .............................................. 549
References ...................................................... 551
Index.. ..... ... .. . . .. . .. . ...... . ... ...... .... ... . ... ... . ... ... . .. .. 553