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Drugs of Abuse: Chemistry, Pharmacology, Immunology, and AIDS, 96 Drugs of Abuse: Chemistry, Pharmacology, lmmunology, and AIDS U. S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drup Abuse, and Mental Health Administration Drugs of Abuse: Chemistry, Pharmacology, Immunology, and AIDS Editors: Phuong Thi Kim Pham, Ph.D. Research Technology Branch Division of Preclinical Research National Institute on Drug Abuse Kenner Rice, Ph.D. Laboratory of Medicinal Chemistry National Institute of Diabetes and Digestive and Kidney Diseases NIDA Research Monograph 96 1990 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, MD 20857 For sale by the Superintendent of Documents, U.S. Government Printing Office, Washington, DC 20402 Drugs of Abuse: Chemistry, Pharmacology, Immunology, and AIDS ACKNOWLEDGMENT This monograph is based on the papers and discussion from a technical review on “Current Chemical and Pharmacological Advances on Drugs of Abuse Which Alter Immune Function and Their Impact Upon HIV Infec- tion” held on October 31 to November 2, 1988, in Rockville, MD. 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. 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)90-1676 Printed 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 Contents Page Introduction 1 Phuong Thi Kim Pham The Bivalent Ligand Approach in the Design of Highly Selective Opioid Receptor Antagonists 3 Philip S. Portoghese Opium Alkaloids and Affinity Labels 21 Sydney Archer, Jean Bidlack, and G. Keith Mulholland Novel Thebainelike Morphinandienes and Their Diels-Alder Adducts 35 Leendert Maat Opioid Antagonists: Structure Activity Relationships 50 Dennis M. Zimmerman and J. David Leander Effect of Fluorine Substitution on the Anti-HIV Activity of Dideoxynucleosides 61 Victor E. Marquez Opiate Antagonists and Anti-HIV Agents 80 Elliot F. Hahn v Page Classical and Nonclassical Cannabinoids: Mechanism of Action—Brain Binding 100 Allyn C. Hewlett, M. Ross Johnson, and Lawrence S. Melvin Cocaine Receptor-Design of Ligands 112 F.I. Carroll, Abraham Philip, and Anita H. Lewin Structural and Functional Similarities of Opiate Receptors of Neural and Immune Origin 122 Daniel J.J. Carr and J. Edwin Blalock Immunomodulatory Effects of Chronic Morphine Treatment: Pharmacologic and Mechanistic Studies 131 Henry U. Bryant, Edward W. Bernton, and John W. Holaday Morphine-Induced Immune Modulation: Does It Predispose to HIV Infection? 150 Prince Kumar Arora A Murine Retrovitus Model for Studies of the Role of Cofactors and Ethanol in AIDS Development 166 Ronald R. Watson Drug Abuse and AIDS: Causes for the Connection 181 Robert M. Donahoe Immune Function in Heroin Addicts and Former Heroin Addicts in Treatment: Pre- and Post-AIDS Epidemic 192 Mary Jeanne Kreek Opioid Peptides, Receptors, and Immune Function 220 Hemendra N. Bhargava Summary of Recommendations for Future Research 234 Louis Harris List of NIDA Research Monographs 237 vi Introduction Phuong Thi Kim Pham Thousands of pharmaceutical drugs line the shelves of apothecaries across the Nation. They are designed to treat a host of diseases and ailments ranging from heart disease and diabetes to allergies and strep throat. But, of all these drugs, only two (methadone and naltrexone) are available to treat narcotic addiction. The cocaine epidemic of the last few years, coupled with the spread of acquired immunodeficiency syndrome (AIDS) in the drug-abusing population, make the development of effective pharmaco- logical treatments for drug addiction more critical than ever before. While the prevalence of human immunodeficiency virus (HIV) seropositivity in the United States is highest for homosexual males (ranging from 20 per- cent to 70 percent), the incidence of seropositivity among intravenous (IV) drug abusers may be even greater, with prevalence in certain areas reaching 75 percent. Of all seropositives, IV drug abusers are generally regarded as posing the most substantial risk of spreading the disease to heterosexuals, with the risk being greater in urban areas. Also at risk are infants born to parents who are IV drug users. Current statistics suggest that one out of two children born to seropositive women develop and almost certainly die of AIDS before the age of 5. Therefore, does the high rate of seropreva- lence among drug abusers reflect some factor predisposing them to AIDS? Both clinical and preclinical studies suggest that chronic morphine treatment depresses the immune function, predisposing an individual to higher inci- dence of infections. By altering immunocompetence, abused drugs, such as morphine, heroin, and possibly cocaine, represent a potential source of immunodeficiency independent of HIV infection, thus making the addicts susceptible to HIV and the development of AIDS. The first direct evidence that heroin addiction may influence the immune system came from the observation that lymphocyte mitogenesis was de- pressed in heroin addicts. Opiate addiction produced a significant depres- sion in the absolute number of T lymphocytes in peripheral blood. The immune modulatory capacity of the opioid receptor agonist morphine led in- vestigators to hypothesize the existence of opioid receptors on cells of the 1 immune system. Recent studies have now identified such receptors. Bind- ing sites for both classical opioids, i.e., naloxone-reversible agonists, and nonclassical opioids, insensitive to naloxone reversibility, have been detected on lymphocytes. In addition, recent observations describing the production of opioid peptides by cells of the immune system have led to the hypothesis of bidirectional pathways shared between the immune and neurcendocrine systems based on the commonality of ligands and receptors. The intention of this technical review was to bring together a group of internationally recognized medicinal chemists, pharmacologists, and immu- nologists working on both drug addiction and AIDS to discuss recent advances. Researchers from areas of pharmacology, medicinal chemistry, and immunology presented their work, interacted, and discussed several new ideas as well as areas of emphasis for future research. It is hoped that investigations of the effects of drug abuse on the immune system may facilitate our understanding of the basic mechanisms underlying the AIDS syndrome. This in turn will help us to determine the feasibility of treatment modalities for AIDS and AIDS-related syndromes. ACKNOWLEDGMENT The author wishes to thank Richard Weber, Ph.D., of the National Institute of Diabetes and Digestive and Kidney Diseases for providing advice and guidance in the preparation of the technical review meeting and the monograph. AUTHOR Phuong Thi Kim Pham, Ph.D. Program Manager and Organic Chemist Research Technology Branch Division of Preclinical Research National Institute on Drug Abuse Parklawn Building, Room 10A-13 5600 Fishers Lane Rockville, MD 20857 2 The Bivalent Ligand Approach in the Design of Highly Selective Opioid Receptor Antagonists Philip S. Portoghese INTRODUCTION Significant advances in opioid research rely heavily on the use of selective ligands as tools. Although the opioid antagonists naloxone 1 and naltrexone 2 have been employed extensively for this purpose (Sawynok et al. 1979; Gold et al. 1982) their usefulness in sorting out the effects mediated by different opioid receptor types is limited because they are not highly selec- tive. The multiplicity of opioid receptors, their varied distribution in neural tissue, and the array of physiologic and pharmacologic effects produced by endogenous and exogenous opioid ligands have created a need for highly selective antagonists for use as research tools (Herz 1987). In this regard, the opioid antagonist should be potent, highly selective, and be useful both in vitro and in vivo for optimal utility as receptor probes. Also, such an- tagonists should be relatively stable to enzymatic degradation and be capable of penetrating the central nervous system (CNS). All of these properties are desirable in the same molecule so that the in vivo pharmacology can be more reliably correlated with in vitro studies. This chapter reviews two convergent variations of the bivalent ligand approach (Portoghese 1987) that have been employed in the design of highly selective opioid antagonists. DESIGN CONSIDERATIONS AND STRUCTURE-ACTIVITY RELATIONSHIP
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