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Structure-Activity Relationships of the Cannabinoids

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Structure-Activity Relationships of the Cannabinoids RESEARCH ANALYSIS and UTILIZATION SYSTEM Structure-Activity Relationships of the Cannabinoids DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Alcohol, Drug Abuse, and Mental Health Administration Structure-Activity Relationships of the Cannabinoids Editors: Rao S. Rapaka, Ph.D. Division of Preclinical Research National Institute on Drug Abuse Alexandros Makriyannis, Ph.D. School of Pharmacy and Institute of Materials Science University of Connecticut and F. Bitter National Magnet Laboratory Massachusetts Institute of Technology NIDA Research Monograph 79 A RAUS Review Report 1987 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, DC 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. 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 Institute RICHARD E. BELLEVILLE, Ph.D. San Francisco, California NB Associates. Health Sciences Rockville, 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 University 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 JEAN PAUL SMITH, Ph.D. Acting Associate Director for Science, NIDA Acting Editor Parklawn Building, 5600 Fishers Lane, Rockville, Maryland 20857 Structure-Activity Relationships of the Cannabinoids ACKNOWLEDGMENT This monograph is based upon papers and discussion from the RAUS review on structure-activity relationships of the cannabinoids which took place on October 30 and 31, 1986, at Bethesda, Maryland. The review meeting was sponsored by the Office of Science and the Division of Preclinical Research, National Institute on Drug Abuse. COPYRIGHT STATUS The National Institute on Drug Abuse has 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. 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 No. (ADM)90-1534 Alcohol, Drug Abuse, and Mental Health Administration Printed 1987, Reprinted 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 Preface The Research Analysis and Utilization System (RAUS) is designed to serve four functions: Collect and systematically classify the findings of all intramural and extramural research supported by the National Institute on Drug Abuse (NIDA); Evaluate the findings in selected areas of particular interest and formulate a state-of-the-art review by a panel of scientific peers; Disseminate findings to researchers in the field and to administrators, planners, instructors, and other interested persons; Provide a feedback mechanism to NIDA staff and planners so that the administration and monitoring of the NIDA research program reflect the very latest knowledge gleaned from research in the field. Since the number of research topics that can be intensively reviewed annually is limited, four subject areas are chosen each year to undergo a thorough examination. Distinguished scientists are invited to participate. Each scientist is provided reports from NIDA-funded research and asked to add information derived from the literature and his or her own research and to prepare a comprehensive, state-of-the-art review paper on an assigned topic. These papers, together with a summary of the discussions which take place at the review meeting, make up a RAUS Review Report in the NIDA Research Monograph series. In recent years a large number of reviews and books have appeared summarizing research advances in the chemistry, pharmacology, toxicology, metabolism, and distribution of cannabinoids and their synthetic analogs. Yet the volume of research on structure-activity relationships of cannabinoids appears to have decreased. In order to evaluate NIDA's current research program on cannabinoids, to rekindle interest in this critical area, and to focus attention on profitable avenues for future research, NIDA found it timely to bring together experts on the structure-activity relationships of cannabinoids for a comprehensive review. v Many cannabinoid analogs have been designed. Some have served as excellent probes for understanding the mechanism of action of cannabinoids and have generated optimism that in the near future potent therapeutic drugs that lack "cannabimimetic" activity can be developed. In this monograph, while emphasis is placed on structure-activity relationships and molecular mechanisms of action of cannabinoids. chapters added to broaden the subject area will increase the usefulness of this volume as a reference text for researchers in the chemistry and biology of the cannabinoids. Drs. Rao S. Rapaka, Alexandros Makriyannis, and Sumner Burstein served as the scientific moderators of the RAUS review meeting. The introduction and the concluding overview chapter, by Drs. Makriyannis and Rapaka, provide a brief summary of the presentations and the discussions. Jacqueline P. Ludford, Chief, Research Analysis Branch, Office of Science, is the RAUS coordinator for NIDA. vi Contents Preface V Introduction Rao S. Rapaka and Alexandros Makriyannis 1 Structure-Activity Relationships in Cannabinoids: An Overview Raj K. Razdan 3 Stereochemical Requirements for Cannabimimetic Activity Raphael Mechoulam; Naphtali Lander; Morris Srebnik; Aviva Breuer; Mark Segal; Jeffery J. Feigenbaum; Tobjorn U. C. Jarbe; and Paul Consroe 15 Structure-Activity Relationships of Tricyclic and Nonclassical Bicyclic Cannabinoids Larry S. Melvin and M. Ross Johnson 31 Structure-Anticonvulsant Activity Relationships of Cannabidiol Analogs Arnold R. Martin; Paul Consroe; Vinayak V. Kane; Vibhakar Shah; Vishwakarma Singh; Naftali Lander; Raphael Mechoulam; and Morris Srebnik 48 Anticonvulsant and Neurotoxic Effects of Tetrahydrocannabinol Stereoisomers Paul Consroe and Raphael Mechoulam 59 Different Cannabinoids Exhibit Different Electrophysiological Properties Stuart A. Turkanis and Ralph Karler 67 Molecular Determinants for Cannabinoid Activity: Refinement of a Molecular Reactivity Template Patricia H. Reggio 82 Different Cannabinoids Exhibit Different Pharmacological and Toxicological Properties Ralph Karler and Stuart A. Turkanis 96 Pharmacological Evaluation of Agonistic and Antagonistic Activity of Cannabinoids Billy R. Martin; David R. Compton; Patrick J. Little; Thomas J. Martin ; and Patrick M. Beardsley 108 vii Interactions of Cannabinoids With Membranes. The Role of Cannabinoid Stereochemistry and Absolute Configuration and the Orientation of Delta-9-THC in the Membrane Bilayer Alexandros Makriyannis; Ali Banijamali; Cornelis Van Der Schyf; and Harold Jarrell 123 The High Affinity Cannabinoid Binding Site in Brain: Regulation by Guanine Nucleotides and Isolation of an Endogenous Inhibitor Jeffrey S. Nye and Solomon H. Snyder 134 Regulation of Adenylate Cyclase in a Cultured Neuronal Cell Line by Marijuana Constituents, Metabolites of Delta-9-tetrahydrocannabinol, and Synthetic Analogs Having Psychoactivity Allyn C. Howlett 148 Inhibitory and Stimulatory Effects of Cannabinoids on Eicosanoid Synthesis Sumner H. Burstein 158 Pharmacokinetics and Disposition of Cannabinoids C. Nora Chiang and Rao S. Rapaka 173 Drug Abuse in India: Progress in Research B. N. Dhawan 189 The Medicinal
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