Opioid Peptides: An Update U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Opioid Peptides: An Update Editors: Rao S. Rapaka, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Bhola N. Dhawan, M.D. Central Drug Research Institute Lucknow, India NIDA Research Monograph 87 1988 U.S. 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 lnstitute 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. MARY L. JACOBSON Temple University School of Medicine National Federation of Parents for Philadelphia, Pennsylvania Drug Free Youth Omaha, Nebraska SYDNEY ARCHER, Ph.D. Rensselaer Polytechnic lnstitute Troy, New York REESE T. JONES, M. D. Langley Porter Neuropsychiatric lnstitute RICHARD E. BELLEVILLE, Ph. D. San Francisco, California NE Associates, Health Sciences RockviIle, Maryland DENISE KANDEL, Ph.D. KARST J. BESTEMAN College of Physicians and Surgeons of Alcohol and Drug Problems Association Columbia University of North America New York, New York Washington, D. C. GILBERT J. BOTVIN, Ph. D. Cornell University Medical College HERBERT KLEBER, M. D. New York, New York Yale University School of Medicine New Haven, Connecticut JOSEPH V. BRADY, Ph. D. The Johns Hopkins Unversity School of Medicine RICHARD RUSSO Baltimore, Maryland New Jersey State Department of Health Trenton, New Jersey THEODORE J. CICERO, Ph. D. Washington University School of Medicine St. Louis, Missouri NIDA Research Monograph Series CHARLES R. SCHUSTER, Ph.D. Director, NIDA THEODORE M. PINKERT, M.D., J.D. Acting Associate Director for Science, NIDA Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Opioid Peptides: An Update ACKNOWLEDGMENT This monograph is based upon papers and discussion from the Indo-U.S. Conference on Recent Progress in the Chemistry and Biology of Biologically Active Peptides With Emphasis on Opioid Peptides, held in Lucknow, India, on February 25-27, 1987. The conference was jointly sponsored by the National Institute on Drug Abuse; the Department of Science and Technology, Government of India; Central Drug Research Institute, Lucknow; and the Indian National Science Academy. COPYRIGHT STATUS The figures on pages 28 and 54 are copyrighted and are reproduced with the permission of the copyright holders. 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 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. 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 essential in the context of the studies reported herein. DHHS publication number (ADM)89-1604 Printed 1988 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 Preface To bring into focus the rapidly expanding areas of research associated with the opioid peptides, an Indo-U.S. Symposium was held in February 1987 at the Central Drug Research Institute (CDRI), Lucknow, India. This symposium was organized by the National Institute on Drug Abuse (NIDA) and the CDRI and was jointly funded by NIDA; CDRI; the Department of Science and Technology, Government of India. and the National Academy of Sciences, New Delhi. A number of individuals were responsible for the success of this conference. We especially acknowledge the help of Dr. Phil Schambra, Science attache, U.S. Embassy (India). Mrs Linda A. Vogel, Associate Director for Management and Program Coordination, Office of International Health; Dr. George V. Coelho, Chief, International Activities Program, ADAMHA; at NIDA, Dr. James C. Cooper, Associate Director for Medical and International Affairs; Dr. Marvin Snyder, Director, Division of Preclinical Research; and Dr. Richard L. Hawks, Chief, Research Technology Branch; and at CDRI, Dr. R. Raghubir and Mr. K.L. Gupta. Selected papers from this symposium have appeared as a research monograph published by the CDRI, entitled Recent Progress in Chemistry and Biology of Centrally Acting Peptides. Other presentations from the symposium, along with contributions from invited authors, comprise the present monograph. We are grateful to all the contributors for their cooperation in preparing this publication. We hope that this volume will serve as a useful reference source on various aspects of the medicinal chemistry, pharmacology, and biochemistry of opioid peptides and will provide new incentives for drug abuse researchers in the opioid peptide field. Rao S. Rapaka Bhola N. Dhawan v Contents Preface . v Neuropeptides, A Personalized History Sidney Udenfriend. 1 Synthesis and Biological Activity of Novel Met-enkephalin Analogs Krishna B. Mathur; Balaram J. Dhotre; Shubh D. Sharma; Ram Raghubir; Gyanendra K. Patnaik; and Bhola N. Dhawan . 10 Approaches to Studying Structure-Activity Relationships in Peptide Hormones Through the Expression of Synthetic Genes John W. Taylor. 20 X-Ray Diffraction Studies of Enkephalins and Opiates Jane F. Griffin and G. David Smith . 41 Conformational Analysis of Cyclic Opioid Peptide Analogs Peter W. Schiller and Brian C. Wilkes . 60 Conformational Studies of Dermorphin V. Renugopalakrishnan and Rao S. Rapaka . 74 Use of Molecular Biological Methods to Study Neuropeptides Michael J. Brownstein . 83 Three Technical Approaches for Cloning Opioid Receptors Curtis A. Machida; John Salon; David Grandy; James Bunzow; Paul Albert; Eric Hanneman; and Olivier Civelli . 93 Effects of Opioid Peptides on Human Neuroblastoma Cells Wolfgang Sadee; Victor C. Yu; and Gunther Hochhaus. .111 Analgesia and Neuropeptides David J. Mayer. .118 Mechanism of Development of Tolerance and Dependence to Opioids in Neuroblastoma x Glioma Hybrid Cells and Mice Shail K. Sharma; Madhav Bhatia; and Ranju Ralhan . .157 Development of Spinal Substrate for Nociception in Man Veena Bijlani; Tilat A. Rizvi; and S. Wadhwa. .167 vii Differential Effects of Opioid Peptides Administered Intra- cerebrally in Loci of Self-Stimulation Reward of Lateral Hypothalamus and Ventral Tegmental Area-Substantia Nigra Jitendra Singh and T. Desiraju . .180 Peptides and Thermoregulation R. Shukla and Bhola N. Dhawan. .192 Endogenous Opioids and Immune Responses: An Experimental Study P. K. Mediratta; N. Das; V. S. Gupta; and P. Sen . .209 An Update of Selected Topics in the Biology and Chemistry of Opioid Peptides Rao S. Rapaka; Bhola N. Dhawan; and V. Renugopalakrishnan .217 List of NIDA Research Monographs . .233 viii Opioid Peptides: An Update: NIDA Research Monograph 87 Rao S. Rapaka, Ph.D., and Bhola N. Dhawan, M.D., eds. National Institute on Drug Abuse, 1988 Neuropeptides, A Personalized History Sidney Udenfriend, Ph.D. The full significance of the important roles in neurobiology played by peptides is still emerging. It seems that each day we read of the discovery and characterization of new peptides in extracts of neural tissue. In fact the chemical structures of neuropeptldes are now elucidated before their biological significance becomes apparent. What is responsible for this rapidly growing field are the recent advances in microprotein chemistry and molecular biology. Therefore a brief history of peptide chemistry is important to understand how we have advanced in so relatively short a period of time in our ability to isolate and characterize trace amounts of peptides in biological extracts. In this review, I will not differentiate between small peptides and large peptides (proteins). I will also discuss peptides in the nervous system as well as in the endocrine system because of the interrelationship of these two systems. The earliest neuroactive substances to be characterized were the amlnes and substituted amlnes--first acetylcholine, then adrenaline, noradrenaline, and serotonln. Although dopamine was known for some time, it was considered to be an intermediate rather than a neuroregulator in Its own right until somewhat later. However, in some of the earliest studies (late forties and early fifties) it was recognized that other substances were active in nerve and muscle preparations that were not amlnes and whose activities were destroyed by proteases. In 1950 peptide chemistry was still emerging as a discipline. While synthetic chemists could synthesize small peptides, methods for their purification, even from synthetic mixtures, were not yet very efficient. Sequencing of peptides had not yet been introduced. In fact, there