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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

SYDNEY ARCHER, Ph.D.

Omaha, Nebraska

 

Rensselaer Polytechnic lnstitute

REESE T. JONES, M.D.

Troy, New York

RICHARD E. BELLEVILLE, Ph.D.

Langley Porter Neuropsychiatric Institute

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.

HERBERT KLEBER, M.D.

Cornell University Medical College

Yale University School of Medicine

New York, New York

New Haven, Connecticut

JOSEPH V. BRADY, Ph.D.

 

The Johns Hopkins University School of

RICHARD RUSSO

Medicine

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

 

1

Rao S. Rapaka and Alexandros Makriyannis

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;

15

Tobjorn U. C. Jarbe; and Paul Consroe

Structure-Activity Relationships of Tricyclic and

 

Nonclassical Bicyclic Cannabinoids

31

Larry S. Melvin and M. Ross Johnson

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

96

Ralph Karler and Stuart A. Turkanis

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 Chemistry of Cannabinoids: An Overview

 

Alexandros Makriyannis and Rao S. Rapaka

204

List of NIDA Research Monographs

211

viii