Opioid Analgesics: Chemistry and Receptors

526 Pages·1986·13.058 MB·English

by  Alan F. Casy, Robert T. Parfitt (auth.)

Opioid Analgesics
Chemistry and Receptors
Opioid Analgesics
Chemistry and Receptors
Alan F. Casy
University of Bath
Bath, United Kingdom
and
Robert T. Parfitt
Canberra College of Advanced Education
Belconnen, ACT, Australia
Formerly, University oj Bath
Bath, United Kingdom
Springer Science+Business Media, LLC
Library of Congress Cataloging in Publication Data
Casy, Alan F.
Opioid analgesics.
Includes bibliographies and index.
1. Opium. 2. Analgesics. 3. Analgesics —Receptors. 4. Narcotics —Receptors. 5. En­
dorphins-Receptors. I. Parfitt, Robert T. II. Title. [DNLM: 1. Endorphins. 2. Nar­
cotics. 3. Receptors, Endorphin. QV 89 C3380]
RM666.06C33 1986 615'.783 86-1520
ISBN 978-1-4899-0587-1
ISBN 978-1-4899-0587-1 ISBN 978-1-4899-0585-7 (eBook)
DOI 10.1007/978-1-4899-0585-7
© Springer Science+Business Media New York 1986
Originally published by Plenum Press, New York in 1986
Softcover reprint of the hardcover 1st edition 1986
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
Foreword
The rapidly burgeoning research of the past two decades on agonist-antagonist
analgesics and opioid receptors makes this exhaustive review of opioid anal
gesics particularly relevant and timely. After an introductory chapter the
additional 12 chapters begin logically with morphine and congeners (4,5-
epoxymorphinans) and end with opioid receptors. All principal chemical types
of centrally acting analgesics (including endogenous opioid-like substances)
and their antagonists as well as the mixed agonist-antagonists are treated
thoroughly, although not always (and for good reason) in historical (chrono
logical) order. A chapter on miscellaneous types (atypical structures for
the most part) includes the benzimidazoles (etonitazene), aminotetralins
(dezocine), tetrahydroisoquinolines (methopholine), and so on. Important
aspects and correlations of chemistry, pharmacology, and biochemistry are
discussed in depth. Literature citations are numerous. For educators, practicing
laboratory scientists, and physicians, this scholarly review by two authors well
versed in the chemistry, pharmacology, and biochemistry of opioid analgesics
will be informative, stimulating, and thought-provoking.
Everette L. May
Medical College of Virginia
Richmond, VA 23298
v
Preface
The history of opium predates the written word, although knowledge of its
constituents dates back less than 200 years. Over the centuries its popularity
for the relief of pain has waxed and waned, until today the opiates are widely
recognized as excellent analgesics but with disadvantages that have impaired
their use seriously. There is a clear need for a potent analgesic with minimal
effects on the respiratory centers and gastrointestinal tract and preferably
devoid of dependence liability. The discovery of endogenous peptides,
although offering a means of understanding some of the actions of opioids at
a molecular level, has not given us desired selective analgesics.
During the past several years ideas regarding the nature of opioid receptors
have evolved rapidly. Multiple receptor hypotheses gained favor and a number
of discrete receptor types have been characterized. This increasingly complex
area has been covered in Chapters 10 and 13. So far we have no evidence for
the chemical nature of opioid receptors or for whether differences between
receptor types are gross or relatively small.
The aim of this book is to afford medicinal scientists an entry into the
chemistry and biological activity of morphine and related compounds.
Although our treatment is not exhaustive we have tried to be comprehensive,
and new researchers in the field should soon discover those areas of opioid
chemistry in need of exploration. In compiling information for the book it
became clear how much more work must be done on the chemistry of com
pounds related to morphine.
To set the scene, the book commences with an introductory chapter that
briefly covers definitions, testing methods, side effects, pharmacokinetics, and
biochemical and bibliographical aspects. The 11 chapters that follow deal with
specific classes of opioid ligand in which emphasis is placed upon chemistry
(especially synthesis and molecular geometry), structure-activity analyses, and
interrelationships within the group itself and in a wider context. It was felt
important to devote a separate chapter to agents that behave as opioid antagon
ists or have dual agonist-antagonist effects and to kappa (K) ligands. Among
these chapters, a full account of opioid peptides is given, together with a
description of how their study has provided evidence for the existence of
vii
viii Preface
subspecies of opioid receptor. In the final chapter, a summary and critique of
progress made toward the isolation and characterization of opioid receptors
is presented and consideration is given to speculations upon receptor scenarios
and ligand-receptor interactions.
Although this book has been written with the needs in mind of those
actively engaged in research upon central analgesics, whether in academia or
in pharmaceutical industry, it should also serve as a background and source
book to postgraduate and senior undergraduate students of chemistry,
medicinal chemistry, biochemistry, and pharmacology and their teachers.
Our colleagues in the field of central analgesics have been most helpful
and forthcoming in the provision of valuable information and comment and
are too numerous to list. We should, however, like to express our special
appreciation to Bernard Belleau, George Dewar, Mark Froimowitz, Arthur
Jacobson, Hans Kosterlitz, Everette May, Philip Portoghese, and Jan
Tollenaere. We also thank Shirley Hancock, Eve Gonty, and Dawn Hodges
for their careful and patient work on typing the manuscript.
Contents
1. INTRODUCTION....................................... 1
References ........ .. . .. . .. . .. .. . . . . .. . . .. . .. . .. . . .. . . . .. . 7
2. 4,S-EPOXYMORPHINANS
2.1. Introduction........................................ 9
2.2. Pharmacological and Clinical Considerations. .. . . . . . . . . . 10
2.3. Synthesis........................................... 14
2.4. Interconversions in the Morphine Series .. . . . . . . . . . . . . . . 22
2.5. Substituted 4,S-Epoxymorphinans. .. . . . . . . . . . . . . . . . . . . . 29
2.6. Diels-Alder Adducts of Thebaine. .. . . . . . . . . . . . . . . . . . . . 69
2.7. Spectroscopy and Other Physical Measurements .. . . . . . . . 84
2.8. Metabolism of 4,S-Epoxymorphinans. .. . . . . . . . . . . . . . . . . 87
2.9. Summary of Structure-Activity Relationships. .. . . . . . . . . . 91
References .. . .. . . . .. . . .. .. . .. .. . . .. . .. . . . .. . . .. . . .. . .. . . . 94
3. MORPHINANS
3.1. Introduction........................................ 105
3.2. Synthesis........................................... 105
3.3. Stereochemistry..................................... 113
3.4. Substituted Morphinans .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
3.5. Structure-Activity Relationships. .. . . . . . . . . . . . . . . . . . . . . 146
References. . .. . .. . . . .. . .. . .. .. .. . . . .. . . . .. . . .. . .. . . .. . . .. 147
4. BENZOMORPHANS
4.1. Introduction........................................ 153
4.2. Synthesis........................................... 155
4.3. Substituted Benzomorphans. .. . . . . . .. .. . . . . . . . . . . . . . . . 176
4.4. Spectroscopy........................................ 196
4.5. X-Ray Studies ...................................... 205
4.6. Structure-Activity Relationships. .. . . . . . . . . . . . . . . . . . . . . 205
References . . .. . . . .. . . . .. . .. .. .. . . . . .. . . . .. . . .. . .. . . .. . . . . 208
ix
x Contents
5. ARYLMORPHANS AND RELATED COMPOUNDS
5.1. Introduction........................................ 215
5.2. Synthesis of 5-Arylmorphans .. . . . . . . . . . . . . . . . . . . . . . . . . 215
5.3. Pharmacological Activity and Stereochemistry. .. . . . . . . . . 216
5.4. Substituted 5-Arylmorphans. .. . . . . . . . . . . . . . . . . . . . . . . . . 218
5.5. Azabicyclo[3.2.1.]octanes............................. 222
5.6. Other Analogs ...................................... 225
5.7. Summary........................................... 226
References . .. . .. . . . . . .. . .. . .. . .. . . . .. . . . .. . . .. .. . . .. . . .. . 226
6. PETHIDINE AND RELATED 4-PHENYLPIPERIDINE
ANALGESICS
6.1. Introduction........................................ 229
6.2. N -Substituted Norpethidines. .. . . . . . . . . . . . . . . . . . . . . . . . 231
6.3. Variation of the Oxygen Function at C-4 of the Piperidine
Ring.... ...... ......... .... .......... ......... ..... 236
6.4. Variation of the 4-Aryl Group. .. . . . . . . . . . . . . . . . . . . . . . . 240
6.5. Analogs with C-methyl (and Other Hydrocarbon) Sub-
stituents in the Piperidine Ring. .. . . . . . . . . . . . . . . . . . . . . . 243
6.6. Miscellaneous Variations. .. . . . . . . . . . . . . . . . . . . . . . . . . . . 243
References. . .. . . . .. . . .. . . .. .. . .. . . . .. . . . . .. . .. .. . . .. . . . .. 247
7. FURTHER ANALGESICS BASED ON PIPERIDINE AND
RELATED AZACYCLOALKANES: PRODINES, PROMEDOLS,
PROFADOL, AND THEIR DERIVATIVES
7.1. Introduction........................................ 251
7.2. Stereochemical Structure-Activity Relationships. .. . . . . . . 253
7.3. Synthetic and Stereochemical Methodology. .. . . . . . . . . . . 266
7.4. Concluding Remarks. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273
7.5. Phenolic Piperidines and Pyrrolidines .. . . . . . . . . . . . . . . . . 276
References .. . . .. . . . . .. . .. . .. .. . . . .. . . . .. . . . .. . .. . .. . . .. . . 283
8. FENTANYL AND THE 4-ANILINOPIPERIDINE GROUP OF
ANALGESICS
8.1. Introduction........................................ 287
8.2. Synthetic Methods and SAR Data .. .. . . . . . . . . . . . . . . . . . 288
References .. . .. . . . . .. . .. . .. . .. . . . .. . .. . . .. . . .. . .. . . .. . . . . 299
9. METHADONE AND RELATED
3,3-DIPHENYLPROPYLAMINES
9.1. Introduction........................................ 303
9.2. Synthetic Methods. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305
Contents xi
9.3. Structure-Activity Relationships. .. . . . . . . . . . . . . . . . . . . . . 306
9.4. Stereochemistry..................................... 313
References. .. . . . . . . . .. .. . . ... . .. . . . . ... .. .. .. .. .. .. .. ... . 329
10. ENKEPHALINS, ENDORPHINS, AND OTHER OPIOID
PEPTIDES
10.1. Introduction....................................... 333
10.2. Enzymatic Degradation ............................. 336
10.3. Synthetic Methods. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338
10.4. Structure-Activity Relationships ...................... 342
10.5. Receptor Multiplicity ............................... 353
10.6. Endorphins and Other Natural Peptides with Opioid
Properties. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359
10.7. Conformational Studies of Opioid Peptides .. . . . . . . . . . . 364
10.8. Conformationally Restrained Analogs. .. . . . . . . . . . . . . . . 371
References.. . ... . ... . .. . ... .. . .. . .. .. .. . .. . ... .. .. .. . . . .. 377
11. MISCELLANEOUS GROUPS OF ANALGESICS
11.1. Benzimidazole Derivatives. .. . . . . . . . . . . . . . . . . . . . . . . . . 385
11.2. Tetrahydroisoquinoline Derivatives ................... 389
11.3. Cyclohexane Derivatives ............................ 390
11.4. Aminotetralins..................................... 396
11.5. 4-Piperidinols...................................... 398
11.6. (l,2-Diphenylethyl)piperazines and Other Piperazines .. . 399
11. 7. Viminol........................................... 400
References ............ , .. , ... " ............. '" . ... . .. .. . 401
12. ANTAGONISTS, DUALISTS, AND KAPPA AGONISTS
12.1. Introduction....................................... 405
12.2. Structural Classes of Antagonist. .. . . . . . . . . . . . . . . . . . . . 409
12.3. Morphine Derivatives .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 409
12.4. Morphinans....................................... 416
12.5. Benzomorphans.................................... 420
12.6. Basic Nitrogen and C-14 Substituents .. . . . . . . . . . . . . . . . 424
12.7. Nonmorphine-based Antagonists. .. .. .. . .. .. .. .. .. .. . 431
12.8. Kappa-Agonists and Antagonists ..................... 434
References .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . 439
13. OPIOID RECEPTORS: FACTS AND SPECULATIONS
13.1. Introduction....................................... 445
13.2. Localization of Receptors. .. . . . . . . . . . . . . . . . . . . . . . . . . . 446
13.3. Isolation of Receptors. .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447