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Emerging Technologies and New Directions in Drug Abuse Research National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Emerging Technologies and New Directions in Drug Abuse Research U.S. Department of Health and Human Services1 • Public1 Health Service2 • National Institutes of Health Emerging Technologies and New Directions in Drug Abuse Research Editors: Rao S. Rapaka, Ph.D. Alexandros Makriyannis, Ph.D. Michael J. Kuhar. Ph.D. Research Monograph 112 1991 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 ACKNOWLEDGMENT This monograph is based on the papers and discussion from a technical review on “Emerging Technologies for Drug Abuse Research,” held on October 12-13, 1989, in Rockville, MD. The review meeting was sponsored by the 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. 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. DHHS publication number (ADM)91-1812 Printed 1991 ii Foreword In October 1989 the National Institute on Drug Abuse (NIDA) organized a conference titled “Emerging Technologies for Drug Abuse Research” to discuss the impact of new technological advances on drug abuse research. The conference set as its principal goal the discussion of novel methodologies with an emphasis on the important current and future directions in research related to drugs of abuse. In the past two decades we have witnessed not only the emergence of many scientific discoveries but also an explosive growth in the development of new methods that greatly enhance the quality and productivity of research. These include the application of solid-phase peptide synthesis methods in the design of novel peptide analogs, cDNA and cloning techniques in biological research, spectroscopic methods in biochemical and biophysical research, novel imaging techniques in biological research, high-performance, liquid chromatographic methods in analysis and purification of biomolecules, and, importantly, the application of computer technology across all scientific fields of research, including the area of computer-aided drug design (CADD). Hence, NIDA believed that it was timely to call together experts in these areas and seek new directions and applications for NIDA-related research. Discussions at this conference were centered on CADD of benzodiazepine drugs, 3D-searching methodologies for drug design, design of selective agonists for 5-HT receptors, application of spectroscopic techniques such as 2D and 3D nuclear magnetic resonance (NMR), solid-state NMR, small-angle x-ray diffraction, differential scanning calorimetry, positron emission tomography (PET) and its application for studies on cocaine, autoradiographic and PET studies of the cannabinoid receptor, cocaine antagonists, and modified solid- phase peptide synthesis methods. It was clear from the discussions that these techniques hold great promise in such areas as understanding the mechanisms iii of action of drugs, understanding the molecular determinants for interaction at receptor types, understanding addictive behavior, and, finally, design of new pharmacotherapies. Marvin Snyder, Ph.D. Director Office of Policy and External Affairs National Institute on Drug Abuse For sale by the U.S. Government Printing Office Superintendent of Documents, Mail Stop: SSOP, Washington, DC 20402-9328 ISBN 0-16-035851-5 iv Contents Page Foreword iii Emerging Technologies and New Directions in Drug Abuse Research: An Overview 1 Rao S. Rapaka, Alexandros Makriyannis, and Michael J. Kuhar Voronoi Binding Site Models 7 Gordon M. Crippen A Mechanistic Basis for Design of Selective Agonists for 5-HT Receptors 21 Roman Osman and Harel Weinstein Computer-Aided Drug Design for the Benzodiazepine Receptor Site 43 Gilda H. Loew, Hugo O. Villar, Waymond Jung, and M. Frances Davies 3D-Searching: An Overview of a New Technique for Computer-Assisted Molecular Design 62 Robert S. Pearlman Protein Structure Determination in Solution Using Nuclear Magnetic Resonance Spectroscopy 76 Angela M. Gronenborn and G. Marius Clore v Combined Use of Solid-State Nuclear Magnetic Resonance Spectroscopy, Small-Angle X-Ray Diffraction, and Differential Scanning Calorimetry in Studies of Cannabinoid: Membrane Interactions 106 Alexandros Makriyannis, De-Ping Yang, and Thomas Mavromoustakos Characterization and Localization of Cannabinoid Receptors in Brain: An In Vitro Technique Using Slide-Mounted Tissue Sections 129 Miles Herkenham New Developments in Radiotracers for Positron Emission Tomography 146 Joanna S. Fowler and Alfred P. Wolf Use of Positron Emission Tomography To Study Cocaine in the Human Brain 166 Nora D. Volkow, Joanna S. Fowler, and Alfred P. Wolf Development of Opioid Peptide Analogs as Pharmacologic Tools and as Potential Drugs: Current Status and Future Directions 180 Peter W. Schiller Conformational Analysis of Opioid Receptor-Selective Peptides Using Nuclear Magnetic Resonance and Theoretical Calculations 198 Victor J. Hruby, Om Prakash, Wieslaw Kazmierski, Catherine Gehrig, and Terry O. Matsunaga Peptidomimetic Opioids—Synthesis, Spectroscopy, and Computer Simulations 218 Murray Goodman, Odile E. Said-Nejad, Eduard Felder, Dale F. Mierke, Toshimasa Yamazaki, and Peter W. Schiller Modified Solid-Phase Methods for the Rapid Synthesis of Opioid Peptides 239 Richard A. Houghten, John M. Ostresh, and Suzanne M. Pratt vi Irreversible Ligands as Probes for Drug Receptors 256 Amy Hauck Newman Important Compounds in the Cocaine Class: A Synthesis Overview 284 F.I. Carroll and Anita H. Lewin lmmunomodulatory Effects of Drugs of Abuse and the Importance of Structure-lmmunomodulatory Activity Studies 300 Rao S. Rapaka and Charles P. Hoiberg FDA Regulatory Requirements for Investigational New Drugs and New Drug Applications: An Update 313 Charles P. Hoiberg and Rao S. Rapaka List of NIDA Research Monographs 326 vii Emerging Technologies and New Directions in Drug Abuse Research: An Overview Rao S. Rapaka, Alexandros Makriyannis, and Michael J. Kuhar During the past decade, many important advances in physicochemical methodologies have been adopted successfully in drug research. The concerted use of these methods coupled with computer-aided approaches for drug design have produced a new era in drug discovery and in the understanding of the molecular mechanisms of drug action. In October 1989, the National Institute on Drug Abuse organized a conference to discuss these advances as they apply to research on drugs of abuse. This volume draws to a large extent from this event, and a summary of these contributions follows. Of the 17 chapters included in this volume, 4 are dedicated to the use of computer technology in drug research. Dr. Crippen discusses methods for gaining information on receptor structure and the energetics involved in drug- receptor interactions. Calculations are based on observing the binding constants of small ligands with several receptor preparations. The approach consists of developing simple binding site models and, through computational methods, exploring their interactions with drug molecules. In the second chapter, Drs. Osman and Weinstein add an extra level of complexity in the theoretical model of ligand-receptor interactions. Again, using biochemical and pharmacological data as a starting point, the authors undertake computational slmulations to develop a mechanism by which ligands can activate the 5-HT1A receptor. This molecular model for receptor activation can differentiate between agonist and antagonist response. Dr. Loew and coworkers discuss a further expansion of this approach in describing a computer-aided approach for drug design aimed at the benzodiazepine receptor site. As with other computational approaches, receptor-binding and pharmacological data for a series of analogs are used to identify and characterize the stereoelectronic properties associated with agonist and antagonist activities, These stereoelectronic criteria are used in turn in a three-dimensional search of databases of known compounds. Finally, using stereoelectronic criteria complementary to those developed for the ligands, the entire set of data is used to characterize the receptor-binding site. 1 The information developed in this manner can be used to characterize regions
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