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Opioid Peptides: Molecular Pharmacology, Biosynthesis, and Analysis Opioid Peptides: Molecular Pharmacology, Biosynthesis, and Analysis U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Opioid Peptides: Molecular Pharmacology, Biosynthesis, and Analysis Editors: Rao S. Rapaka, Ph.D. Richard L. Hawks, Ph.D. Division of Preclinical Research National Institute on Drug Abuse NIDA Research Monograph 70 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 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 Institute 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 Institute Alcohol and Drug Problems Association San Francisco, California of North America Washington, D.C. 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 University 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: Molecular Pharmacology, Biosynthesis, and Analysis 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 molecular pharmacology, biosynthesis, and analysis are presented in this volume. Those on the medicinal chemistry of opioid peptides appear in NIDA Research Monograph 69. COPYRIGHT STATUS The diagram on the cover of this volume is reprinted by permission from Camerman et al. Crystal structure of leucine-enkephalin. Nature 306:447-450. Copyright 1983, Macmillan Journals Limited. 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 reprintlng 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. The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this publication are used only because they are considered essentlal in the context of the studies reported herein. DHHS Publication No. (ADM)87-1455 Alcohol, Drug Abuse, and Mental Health Administration Printed 1986 Reprinted 1987 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 discovery of opioid peptides in the mid-seventies came at an opportune time, as all the technologies required for identification and synthesis of opioid peptides were readily available. The identification of opioid genes followed shortly, facilitated by recent advances in recombinant technology. This in turn led to the rapid identification of many more opioid peptides. Concurrently, recognition of opioid receptor heterogeneity brought to the fore questions about the role of the multiple receptors in analgesia and abuse liability. Another area of research which quickly developed following these discoveries was the analysis of opioid peptides in Diofluids, a difficult area which presents unique problems due to the low levels present. Most analytical development has been based on radioimmunoassays, which are quite sensitive but which suffer from variable specificities. Development of chemical methods that are both specific and sensitive has been urgently needed, particularly in anticipation of the development of peptides for clinical trials and the need to have adequate pharmacokinetic analyses of such drugs. This volume is primarily concerned with the molecular pharmacology, biosynthesis, and analysis of the opioid peptides. It is the companion volume to NIDA Research Monograph 69, Opioid Peptides: Medicinal Chemistry. We stand at an exciting point in this rapidly expanding field. It is hoped that this volume and the preceding one will serve as useful reference sources for researchers and will provide new incentives for drug abuse research in the opioid peptide field. 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 Folding and Enzymatic Processing of Precursors of Biologically Active Peptides and Proteins Irwin M. Chaiken; Tatsuhiko Kanmera; and Reginald P. Sequeira . 3 Biosynthesis of Opioid Peptides Olivier Civelli; Jim Douglass; Haim Rosen; Gerard Martens; and Edward Herbert . 21 Proenkephalin Biosynthesis in the Rat Richard D. Howells . 43 Enzymes in the Metabolism of Opioid Peptides: Isolation, Assay, and Specificity Neville Marks; Myron Benuck; and Martin J. Berg . 66 Isolation and Identification of Opioid Peptides Hisayuki Matsuo . 92 B-Endorphin: Naturally Occurring or Synthetic Agonists and Antagonists Choh Hao Li . .109 Enkephalin Degrading Enzyme Inhibitors: A Physiological Way to New Analgesics and Psychoactive Agents Bernard P. Roques and Marie-Claude Fournie-Zaluski . 128 Progress in the Characterization of the Opioid Receptor Subtypes: Peptides as Probes. Future Directions Eric J. Simon. 155 Regulation of Agonist Binding to Opioid Receptor Types by Sodium and GTP: Relevance to Receptor Function Brian M. Cox; Linda L. Werling; and Gary Zarr . 175 Opioid Receptors for the Dynorphin Peptides Iaian F. James . , . 192 vii Computer Analysis of Radioligand Data: Advantages, Problems, and Pitfalls David Rodbard; Rudolph A. Lutz; Ricardo A. Cruciani; Vincenzo Guardabasso; Guido 0. Pesce; and Peter J. Munson . 209 Recent Developments in Bioassay Using Selective Ligands and Selective In Vitro Preparations Hans W. Kosterlitz; Alistair D. Corbett; Maureen G. C. Gillan; Alexander T. McKnight; Stewart J. Paterson; and Linda E. Robson . 223 Endorphins and Memory Regulation Ivan Izquierdo; Carlos A. Netto; and Renato D. Dias . 237 Current Status of RIA Methods for the Analysis of Enkephalins and Endorphins R. Wayne Hendren. 255 The Analysis of Endogenous Opioid Peptides With HPLC, Radioreceptor Assay, Radioimunoassay, and Mass Spectrometry Dominic M. Desiderio; Hisayoshi Takeshita; Hiroshi Onishi; Genevieve Fridland; Francis S. Tanzer; Claire Wakelyn; and Chhabil Dass. 304 Reverse Phase HPLC of Peptides: Application to the Opioid Peptides Tatsuhiko Kanmera and Reginald P. Sequeira . 319 Peptides as Drugs in the Treatment of Opiate Addiction Hemendra N. Bhargava . 337 Progress in the Potential Use of Enkephalin Analogs Robert C. A. Frederickson. 367 Opioid Peptides as Drug Products: FDA Regulatory Requirements Charles P. Hoiberg and Rao S. Rapaka . 385 A Few Thoughts on the Development and Regulation of Neuropeptides John L. Gueriguian and Yuan-Yuan H. Chiu. 405 viii Introduction Rao S. Rapaka, Ph.D. In order to bring into focus the rapidly expanding areas of research associated with the opioid peptides, the National Institute on Drug Abuse sponsored a technical review in September 1984 on the medicinal chemistry and molecular pharmacology of opioid peptides and the opiates. As stated in the introduction to NIDA Research Monograph 69, a companion volume to NIDA Research Monograph 70, this is an area of major interest for both the short-term and long-term goals of the Institute because of its potential usefulness in further research and in treatment applications. This monograph presents contributions both from the symposium speakers and from other invited
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