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

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 xii Contents

13.4. Receptor Scenarios ...... 455 13.5. Overall Structure-Activity Relationships of Opioid Ligands...... 459 13.6. Basic Natur~ ...... 460 13.7. N-Substituent Structure...... 467 13.8. Aromatic Features...... 469 13.9. Oxygen Functions...... 470 13.10. Stereochemical Features...... 472 13.11. Receptor Models...... 473 13.12. Some Aspects of ~-Receptors ...... 490 13.13. Computational Approach...... 495 13.14. Postscript...... 496 References ...... " ...... 498

INDEX...... 503 Abbreviations

ADso antagonist dose effective in 50% of a population (usually expressed in mg/kg) amino acids IUPAC abbreviations are employed; those for less com• mon residues such as 4-hydroxyproline (Hyp) are included in the text Boc t-butyloxycarbonyl Bu butyl Bz benzyl cAMP cyclic adenosine monophosphate CD circular dichroism CNA chlomaltrexamine CNS central nervous system COA N-methyl analog of CNA CBM cyclobutylmethyl CPM cyclopropylmethyl CSF cerebrospinal fluid DADL Tyr-o-Ala-Gly-Phe-o-Leu DALAMID amide of DADL DAGO Tyr-o-Ala-Gly-MePhe-Gly-ol DCCI dicyclohexylcarbodiimide DMF dimethylformamide DMSO dimethylsulfoxide DSLT Tyr-o-Ser-Gly-Phe-Leu-Thr EDso agonist dose effective in 50% of a population (usually expressed in mg/kg) EKC ethylketazocine Et ethyl FNA funaltrexamine FOA N-methyl analog of FNA gc gas chromatography gcl ms combined gas chromatographyI mass spectrometry GIT gastrointestinal tract xiii xiv Abbreviations

GPI guinea pig ileum GTP guanosine triphosphate hplc high-performance liquid chromatography ICso (or IDso) concentration of drug that displaces 50% of a radio• active ligand (binding assay) or causes 50% depression of the twitch induced by coaxial stimulation of smooth muscle (GPI, MVD assays) im intramuscular ip intraperitoneal ir infrared iv intravenous ivent intraventricular 2J,3J coupling constant (in Hz) over two or three bonds, respectively (in nmr) Ke equilibrium constant of antagonists obtained from the expression Ke = a/DR-l where a is the molar con• centration of antagonist and DR the ratio of the con• centration of agonist required to depress the muscular twitch to the same extent in the presence and absence of a given concentration of antagonist LAH lithium aluminum hydride J3-LPT J3-lipotropin Me methyl MHP mouse hot-plate assay MID multiple ion detection (in ms) ms mass spectrometry MST mouse Straub tail MVD mouse vas deferens MW (MWR) mouse writhing assay (chemical writhing agent may be appended, e.g., MWQ (benzoquinone-induced» NIH National Institutes of Health (Bethesda, Md.) NBA N-bromoacetamide NBS N -bromosuccinimide NCS N -chlorosuccinimide nnir nuclear magnetic resonance NOE nuclear Overhauser effect (in nmr) ORD optical rotatory dispersion pA2 negative logarithm of dose of antagonist that converts response to a double dose of agonist to that of a single dose PDC physical dependence capacity po per os (by mouth) Ph phenyl Abbreviations xv

PPA polyphosphoric acid Pr propyl Py pyridine QSAR quantitative structure-activity relationships R(S) Rectus (Sinister) configurational symbols of the Cahn• Ingold-Prelog protocol RTC rat tail clip assay RTF rat tail-flick assay RTA/ A rat tail-tlick antagonist assay RTP rat tail pressure assay SAR structure-activity relationships sc subcutaneous SSB stereospecific binding TFA tritluoroacetic acid Ts tosyl(p-tolylsulfonyl) THF tetrahydrofuran tic thin layer chromatography uv ultraviolet WK Wolff-Kishner reduction Z benzyloxycarbonyl