Opioid Peptides: Medicinal Chemistry DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Opioid Peptides: Medicinal Chemistry Editors: Rao S. Rapaka, Ph.D. Gene Barnett, Ph.D. Richard L. Hawks, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 69 1986 DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse 5600 Fishers Lane Rockville, Maryland 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office Washington, D.C. 20402 NIDA Research Monographs are prepared by the research divisions of the National Institute on Drug Abuse and published by its Office of Science. The primary objective of the series is to provide critical reviews of research problem areas and techniques, the content of state-of-the-art conferences, and integrative research reviews. Its dual publication emphasis is rapid and targeted dissemination to the scientific and professional community. Editorial Advisors MARTIN W. ADLER, Ph.D. SIDNEY COHEN, M.D. Temple University School of Medicine Los Angeles, California Philadelphia, Pennsylvania SYDNEY ARCHER, Ph.D. MARY L. JACOBSON Rensselaer Polytechnic lnstitute National Federation of Parents for Troy, New York Drug Free Youth RICHARD E. BELLEVILLE, Ph.D. Omaha, Nebraska NB Associates, Health Sciences Rockville, Maryland REESE T. JONES, M.D. KARST J. BESTEMAN Langley Porter Neuropsychiatric lnstitute San Francisco, California Alcohol and Drug Problems Association of North America WashIngton, DC DENISE KANDEL, Ph.D. GILBERT J. BOTVIN, Ph.D. College of Physicians and Surgeons of Cornell University Medical College Columbia University New York, New York New York, New York JOSEPH V. BRADY, Ph.D. The Johns Hopkins University School of HERBERT KLEBER, M.D. Medicine Yale University School of Medicine Baltimore, Maryland New Haven, Connecticut THEODORE J. CICERO, Ph.D. Washington Universitv School of RICHARD RUSSO Medicine New Jersey State Department of Health St Louis, Missouri Trenton, New Jersey NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director. NIDA JEAN PAUL SMITH, Ph.D. Acting Associate Director for Science, NIDA Acting Editor Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Opioid Peptides: Medicinal Chemistry ACKNOWLEDGMENT This monograph is based upon papers and discussion from the technical review on the medicinal chemistry and molecular pharmacology of opioid peptides and the opiates which took place on September 4 - 6, 1984. at Bethesda. Maryland. The meeting was sponsored by the Office of Science and the Division of Preclinical Research, National Institute on Drug Abuse. The papers on medicinal chemistry are presented in this volume; those on the molecular pharmacology, biosynthesis, and analysis of opioid peptides appear in NIDA Research Monograph 70. COPYRIGHT STATUS The diagram on the cover of this volume is reprinted by permission from Science, Vol. 199. p. 1214, copyright 1978, The American Association for the Advancement of Science. The National Institute on Drug Abuse has also obtained permission from the copyright holders to reproduce certain previously published material as noted in the text. Further reproduction of this copyrighted material is permitted only as part of a reprinting of the entire publication or chapter. For any other use, the copyright holder's permission is required. All other material in this volume except quoted passages from copyrighted sources is in the public domain and may be used or reproduced without permission from the Institute or the authors. Citation of the source is appreciated. Opinions expressed in this volume are those of the authors and do not necessarily reflect the opinions or official policy of the National Institute on Drug Abuse or any other part of the U.S. Department of Health and Human Services. DHHS Publication No. (ADM)90-1454 Alcohol, Drug Abuse, and Mental Health Administration Printed 1986, Reprinted 1987, 1990 NIDA Research Monographs are indexed in the Index Medicus They are selectively included in the coverage of American Statistics Index, BioSciences Information Service, Chemical Abstracts, Current Contents, Psychological Abstracts, and Psychopharmacology Abstracts. iv Foreword The search for the molecular basis of drug addiction led, in the mid-seventies, to the exciting discovery of opioid receptors and a variety of endogenous and exogenous ligands. The fact that thousands of publications have appeared already is astounding and attests to the attention attracted by this area. The discovery of multiple opioid receptors brings an additional dimension to research in this area, and medicinal chemists have already succeeded in synthesizing many highly specific ligands to these receptor subtypes. The interest in this area is not only to develop nonaddictive peptide analgetic substitutes for morphine, but also to understand the role of these endogenous peptides in health and in disease. Although several thousand analogs of enkephalins and other opioid peptides have been synthesized, including some that are stable and can be taken orally, a nonaddicting opioid has yet to be synthesized. Hence, the National Institute on Drug Abuse felt that it was timely to call together experts in the area to evaluate current research on the development of new opioid peptides with potential value for basic research and therapeutics. In this monograph, emphasis is placed on structure-activity relationships, conformational analysis using various spectroscopies, computer assisted drug design, and molecular mechanics. It is hoped that the discussions of current research by various experts presented here will helpful in establishing future goals for development of new molecular entities with desired biological activity or receptor specificity. An effort has been made to cover all aspects of medicinal chemistry pertaining to opioid peptides, so that the volume can serve as a broadly useful reference text. Marvin Snyder, Ph.D., Director Division of Preclinical Research National Institute on Drug Abuse v Contents Foreword Marvin Snyder v Introduction Rao S. Rapaka 1 Frontiers of Research in the Medicinal Chemistry and Molecular Pharmacology of Opioid Peptides Rao S. Rapaka 3 Synthesis of Opioid Peptide Analogs John M. Stewart 21 Structure-Activity Relationships of Opioid Peptides J. S. Morley and A. S. Dutta 42 Design Principles: Enkephalins With Predictable Mu/Delta Receptor Specificity Yasuyuki Shimohigashi 65 Structure-Activity Relationship and Pharmacology of the Highly Selective µ-Opioid Agonist, Morphiceptin Kwen-Jen Chang 1O1 Dermorphin: Autonomic Pharmacology and Structure-Activity Relationships Giora Feuerstein 112 Design of Conformationally Constrained Cyclic Peptides With High Delta and Mu Opioid Receptor Specificities Victor J. Hruby 128 Dehydro and Cyclopropyl Amino Acids and Peptides Charles H. Stammer 148 Affinity Labels as Probes for Opioid Receptor Types and Subtypes Phillip S. Portoghese and A. E. Takemori 157 Peptide Conformation and Biological Activity: A General Review with Examples of Approaches Relevant to Opioid Peptide Function Dan W. Urry 169 vii Opioid Peptides: Analysis of Specificity and Multiple Binding Modes Through Computer-Aided Drug Design and Structure-Activity Studies Raoul D. Nelson; David I. Gottlieb; T. M. Balasubramanian; and Garland R. Marshall 204 Mechanistic Structure-Activity Studies of Peptide and Nonpeptide Flexible Opioids: An Interdisciplinary Approach Gilda H. Loew; Lawrence Toll; Edward Uyeno; Alice Cheng; Amrit Judd; John Lawson; Christopher Keys; Peter Amsterdam; and Wilma Polgar 231 Conformations of Opioid Peptides as Determined by Nuclear Magnetic Resonance and Related Spectroscopies M. Abu Khaled 266 Conformational Analysis of Opioid Peptides and the Use of Conformational Restriction in the Design of Selective Analogs Peter W. Schiller 291 Stereochemically Constrained Enkephalin Analogs Containing X-Aminoisobutyric Acid and 1-Amino-Cyclopentane-l-Carbolylic Acid Raghuvansh Kishore and Patinabhan Balaram 312 Enkephalin Conformation in Solution: A Perspective From Vibrational Spectroscopic Studies V. Renugopalakrishnan; T. W. Collette; L. A. Carreira; and R. S. Rapaka 332 Conformational Features of the Opioid Peptides in the Solid State: A Review of X-Ray Crystallographic Research Arthur Camerman and Norman Camerman 351 The Search for Nonaddicting Strong Analgesics: Hopes and Frustrations Sydney Archer 364 viii Introduction Rao S. Rapaka, Ph.D. The discovery of opioid peptides has opened up new scientific area and posed questions which are still at an early stage of exploration. This area is of major interest to the immediate and long-range goals of the National Institute on Drug Abuse, and in order better to focus the rapidly expanding research areas associated with peptide chemistry and its potential application to drug abuse research and therapeutic treatment, the Institute sponsored a technical review in September 1984. This monograph presents contributions both from the symposium speakers and from other invited authors in the various aspects of the medicinal chemistry of the opioid peptides and the opiates. Highlights of these reviews are presented here. Biosynthetic, analytical, and molecular pharmacology aspects are presented in NIDA Research Monograph 70. A number of presentations are on structure-activity relationships (SAR) of the opioid peptides--Drs. Morley