Drugs of Abuse: Chemistry, Pharmacology, Immunology, and AIDS

251 Pages·2002·2.49 MB·English

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 (SAR) STUDIES
The rationale employed to design selective opioid antagonists emanated from
two different concepts that bear certain elements of similarity. In the first
approach, there was a possibility of bridging two vicinal opioid receptors by
means of ligands that contain two opioid antagonist pharmacophores linked
through a spacer (Portoghese 1987). The second approach (Portoghese
et al. 1988a) utilized the “message-address” concept (Schwyzer 1977) that
involved the linkage of an opioid antagonist pharmacophore (the “message”)
3