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National Institute on Drug Abuse MONOGRAPH SERIES Problems of Drug Dependence 1988 Proceedings of the 50th Annual Scientific Meeting The Committee on Problems of Drug Dependence, Inc. U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service • Alcohol, Drug Abuse, and Mental Health Administration Problems of Drug Dependence, 1988 Proceedings of the 50th Annual Scientific Meeting, The Committee on Problems of Drug Dependence, Inc. Editor: Louis S. Harris, Ph.D. NIDA Research Monograph 90 1988 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICE Public Health Service Alcohol, Drug Abuse, and Mental Health Administration National Institute on Drug Abuse Office of Science 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. Yale University School of Medicine New York, New York New Haven, Connecticut JOSEPH V. BRADY, Ph.D. The Johns Hopkins Unlversity School of Medicine RICHARD RUSSO BaItimore, Maryland New Jersey State Department of Health Trenton, New Jersey THEODORE J. CICERO, Ph.D. Washington Unlversity 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 Foreword In this volume the National Institute on Drug Abuse is publishing once again the scientific presentations from the annual scientific meeting of the Committee on Problems of Drug Dependenre. This 50th annual meeting of the CPDD was held in North Falmouth. Massachusetts, in June 1988. In the typical CPDD meeting, outstanding investigators from many disciplines present their current research on a wide range of topics related to substance abuse. The 1988 meeting was no exception. The topics ranged from the biochemistry of the neuron to the clinical treatment of drug dependent patients. Members of the scientific community and other interested readers of the NIDA Research Monograph series will find this volume to be a valuable "state of the art" summary of research into the many factors involved in drug abuse. John J. Boren, Ph.D. Clinical and Behavioral Pharmacology Branch Division of Clinical Research National Institute on Drug Abuse iii ACKNOWLEDGMENT The Committee on Problems of Drug Dependence, Inc., an independent, nonprofit organization, conducts drug testing and evaluations for academic institutions, government, and industry. This monograph is based upon papers or poster presentations from the 50th Annual Scientific Meeting of the CPDD. held in North Falmouth. Massachu- setts, June 28 - 30. 1988. In the interest of rapid dissemination, it is published by the National Institute on Drug Abuse in its Research Monograph series as reviewed and submitted by the CPDD. Dr. Louis S. Harris, editor of the monograph, is Chairman of the Department of Pharmacology, Medical College of Virginia. COPYRIGHT STATUS The chapter by Drs. D. Novick et al., on pages 169 to 176, is copyrighted by the American Medical Association. Figures 1, 2, and 3 on pages 229 and 230 in the chapter by Drs. S. Deadwyler et al. are copyrighted by the American Society for Pharmacology and Experimental Therapeutics. The National Institute on Drug Abuse has obtained permission to reprint this material. Its further reproduction 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 views and opinions expressed on the following pages 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 number (ADM)89-1605 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 THE COMMlTTEE ON PROBLEMS OF DRUG DEPENDENCE, INC. BOARD OF DIRECTORS William L. Dewey, PhD, Chairman Thomas F. Burks, PhD, Chairman-Elect Mary Jeanne Kreek, MD, Past-Chairman Joseph V. Brady, PhD, Sec/Treasurer Keith F. Killam, PhD, Chair, Advis Council Robert L. Balster, PhD Mitchell B. Balter, PhD William Beaver, MD Richard A. Deitrich, PhD Loretta P. Finnegan, MD Louis S. Harris, PhD Reese T. Jones, MD John Kaplan, LLB Sheppard G. Kellam, MD Herbert D. Kleber, MD Conan Kometsky, PhD Horace H. Loh, PhD Everette L. May, PhD Donald E. McMillan, PhD Nancy K. Mello, PhD Jack H. Mendelson, MD Beny J. Primm, MD Edward C. Senay, MD E. Leong Way, PhD EXECUTIVE SECRETARY Martin W. Adler, PhD v COMMITTEE CHAIRMEN LIAISON Theodore J. Cicero, PhD Harold Kalant, MD, PhD Animal Testing Committee Addiction Research Foundation Marian W. Fischman, PhD (Toronto) Human Testing Committee Howard McClain Charles W. Gorodetzky, MD, PhD Drug Enforcement Administration Rules Committee Charles R. Schuster, PhD Arthur E. Jacobson, PhD National Institute on Drug Abuse Drug Testing Program Boris Tabakoff, PhD National Institute on Alcohol Abuse and Alcoholism Francis J. Vocci, PhD Food and Drug Administration PROGRAM COMMITTEE ARRANGEMENTS COMMITTEE Louis S. Harris, PhD, Chair Conan Kometsky, PhD, Chair Mary Jeanne Kreek, MD Jack H. Mendelson, MD Loretta P. Finnegan, MD Catherine M. Garaffo Horace H. Loh, PhD Everette L. May, PhD CONTRIBUTING FIRMS. 1987-1988 The following firms have supported the work of the Committee on Problemsof Drug Dependence, Inc. through contributions during the previous fiscal year. Abbott Labs Marion Labs American Cyanamid (Lederle) McNeil Pharmaceuticals Ayerst, Canada Merck, Sharp & Dohme Research Labs Berlex Labs Merrill Dow Boc-Group, Anaquest Ortho Pharmaceuticals Boehringer-Ingelheim Pfizer Bristol-Myers Reckitt & Colman, Pharm. Div. Buroughs-Wellcome Co. Sandoz, Basle Ciba-Geigy Corp. Sandoz, NJ E. I. DuPont de Nemours Schering Corp. Glaxo, Inc. Searle H. G. Pars Pharmaceuticals Squibb Hoffmann-LaRoche Sterling Drug ICI Americas Syntex Corp. Johnson & Johnson The Upjohn Company Knoll Pharmaceutical Warner-Lambert Lilly Research Wyeth vi Contents AIDS and Intravenous Drug Abuse C. Schuster and R. Pickens 1 Introduction of Nathan B. Eddy Memorial Award E. Way 14 Biodirectional Effects of Opioids in Motivational Processes and the Involvement of D1 Dopamine Receptors A. Herz 17 Effects of 6-Hydroxydopamine Lesions of Nucleus Accumbens on a Concurrent Schedule of Food, Water and Cocaine Self-Administration S. I. Dworkin, G. Guerin, S. M. Dworkin and J. Smith 27 Chronic Cociane Exposure During Gestation Results in Neurobehavioral Deficits Evidient Early in Ontogeny L. Spear, N. Frambes, C. Kirstein, J. Bell, L. Rogers, V. Yoottanasumpun and N. Spear 28 Differential Effects of the Manipulation of Serotonin Systems on Intraveneous Amphetamine and Cocaine Self-Admini- startion in Rats L. Porrino, L. Sharpe, M. Ritz, N. Goodman, S. Goldberg and M. Kuhar 29 Evaluation of Reinforcing Properties of Amantadine and its Effect on Cocaine Self-Injection in Baboons C. Sannerud and R. Griffiths 30 Cocaine-Induced Changes in the Neurotensin Systems of the Basal Ganglia G. Hanson, P. Smiley, L. Bush and J. Gibb 31 Pharmacologic Aspects of Cocaine Rush K. Kumor, M. Sherer, C. Muntaner, J. Jaffe and R. Herning 32 vii Prolactin and Luteinizing Hormone Pulse Frequency Analysis in Cocaine Abusers J. Mendelson, N. Mello, S. Teoh and J. Ellingboe 33 MDMA Biological Disposition in Man: MDA is a Biotransformation Product J. Alrazi and K. Verebey 34 Behavioral and Cardiovascular Effects of Alcohol and d-Amphetamine Combinations in Normal Volunteers S. Higgins, M. Capeless, J. Hughes, W. Bickel and M. Belinson 35 A Pharmacological Analysis of the Discriminative Stimulus Properties od d-Amphetamine in Rhesus Monkeys
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  • Design & Synthesis of Polycyclic Amine Derivatives for Sigma Receptor Activity

    Design & Synthesis of Polycyclic Amine Derivatives for Sigma Receptor Activity

    UNIVERSITY OF THE WESTERN CAPE Design & Synthesis of Polycyclic Amine derivatives for Sigma Receptor Activity Natasha Strydom February 2013 Supervisor: Prof. S.F. Malan Co-Supervisor: Dr. J. Joubert A thesis submitted in partial fulfilment of the requirements for the degree of Magister Scientiae in the Department of Natural Sciences, University of the Western Cape. KEYWORDS Polycyclic amine Pentacycloundecane Amantadine Heterocyclic amines Sigma receptor Neurodegeneration Drug addiction Blood brain permeability Drug Design Ligand based Structure activity relationship i ABSTRACT New therapeutic strategies are needed for a diverse array of poorly understood neurological impairments. These include neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease, and the psychiatric disorders such as depression, anxiety and drug dependence. Popular neuropharmacotherapies have focused on dopamine (DA), serotonin (5HT), γ-aminobutric acid (GABA) and glutamate systems (Jupp & Lawrence, 2010). However recent research points to the sigma receptor (σR) as a possible neuromodulatory system. Due to its multi-receptor action, the σR can trigger several significant biological pathways. This indicates its ideal potential as a drug target to effectively minimise drug dosage and potential side effects. Currently there are a limited number of σR ligands available and few possess the selectivity to significantly show σR’s role in neurological processes. Polycyclic amines have shown notable sigma activity and provide an advantageous scaffold for drug design that can improve pharmacodynamic and pharmacokinetic properties (Banister et al., 2010; Geldenhuys et al., 2005). Aryl-heterocycle amine groups were also shown to improve σR activity (Piergentili et al., 2009). A series of pentacycloundecane compounds were synthesised which aimed at evaluating the inclusion of a amine containing aryl group in the design compared to previous pentacycloundecane structures containing only two lipophilic regions.