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Drug Addiction Drug Addiction From Basic Research to Therapy Rao S. Rapaka • Wolfgang Sadée Editors Drug Addiction From Basic Research to Therapy Editors Dr. Rao S. Rapaka Dr. Wolfgang Sadée National Institute on Drug Abuse College of Medicine and Public Health Bethesda, MD Ohio State University USA Columbus, OH USA ISBN: 978-0-387-76677-5 e-ISBN: 978-0-387-76678-2 DOI: 10.1007/978-0-387-76678-2 Library of Congress Control Number: 2008926485 © 2008 American Association of Pharmaceutical Scientists All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York, NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Preface This book affords a comprehensive overview of current research on drug addiction and related disciplines, with topical reviews written by eminent scientists in the field. It was inspired by a joint AAPS–NIDA symposium “Frontiers in Science: Drug Addiction – From Basic Research to Therapies”, held in September 2004, at the NIH campus. Subsequently, we have invited leading scientists to contribute chapters on a broad range of topics, covering basic research (e.g. mechanisms of action of drugs of abuse, development of receptor-specific ligands, animal models), discovery and development of therapies, and other clinical applications. As neuronal circuits involved in drug addiction also impinge upon many other vital functions of the brain and peripheral tissues, we have broadened the scope to include pathophysiologies related to drug abuse/addiction. For example, the complex actions of opioids on pain, addiction liability, and other adverse effects have triggered an intensive search for non-addictive opioid pain medications and for non-opioid analgesics directed against novel targets. Other directions include treatment of stimulant addiction and toxicity, new therapies for gastrointestinal dysfunction, inflammation, cognitive and neurode- generative disorders, and immunological diseases. This book is divided into several portions, each addressing issues of importance in drug addiction or in scientific areas that have naturally evolved as research targets for addiction researchers: 1. General topics 2. Transporters and stimulants and hallucinogens 3. Drug design: nicotine, opioids, and related ligands 4. Opioids: general 5. Cannabinoids The first section starts out with a detailed analysis of a principal addiction path- way involving DARPP32, a key regulator of dopamine signaling, presented by Greengard and colleagues. This is followed by drug discovery from natural sources (Kinghorn), antibodies, endogenous peptides, and small RNAs as drug candidates, and computational analysis of G protein coupled receptors (Reggio). The scope of basic topics further includes pharmacogenetics (Rutter), and addresses the role of chemokines, nicotinic receptors, and PDZ domains as protein–protein interaction modules. v vi Preface The second section addresses issues related to neurotransmitter transporters and their role in mediating the effects of stimulants and hallucinogens. This focuses on monoamine synaptic reuptake transporters and cocaine, among other stimulants. A series of chapters further discuss the interaction of stimulants and hallucinogens with various receptors and their mechanisms of action. The third section “Drug design: nicotine, opioids, and related ligands” critically assesses the molecular biology, physiology, and pharmacology of receptors and other targets for drugs of abuse. Focusing on drug design, several chapters address the basic tools for drug discovery such as crystallography and chemistry, with appli- cations to opioid and nicotinic receptors. This leads to Sect. 4 with opioid ligands and their interaction with target receptors as the focus. Relevant issues include molecular modes of target interactions, opioid receptor regulation and tolerance, the relevance of receptor oligomerization, CNS drug delivery, homology modeling, and the serendipitous discovery of cell-permeable, mitochondrial-targeted peptide anti- oxidants – an example of a distinct application arising from addiction research. The last section deals with cannabinoids, an area of tremendous recent growth because of the role cannabinoids play in multiple physiological systems, including those involved in pain modulation. These diverse disciplines and technologies all converge on a more detailed understanding of addiction and the promise for developing improved treatment strategies for a spectrum of neurological disorders. This volume uniquely brings together seemingly disparate, but nevertheless complementary critical reviews that together paint a rather comprehensive picture of current efforts in drug addiction and its treatment. It also shows how one discipline reaches into many other areas, with the interplay among them yielding the promise for significant advances in understanding and treating drug addiction and related disorders. Columbus, OH Rao S. Rapaka Wolfgang Sadee Contents I General Topics 1 DARPP-32 Mediates the Actions of Multiple Drugs of Abuse . 3 Per Svenningsson, Angus C. Nairn, and Paul Greengard 2 Drug Discovery From Natural Sources . 17 Young-Won Chin, Marcy J. Balunas, Hee Byung Chai, and A. Douglas Kinghorn 3 Computational Methods in Drug Design: Modeling G Protein-Coupled Receptor Monomers, Dimers, and Oligomers. 41 Patricia H. Reggio 4 Symbiotic Relationship of Pharmacogenetics and Drugs of Abuse. 69 Joni L. Rutter 5 Monoclonal Antibody Form and Function: Manufacturing the Right Antibodies for Treating Drug Abuse. 87 Eric Peterson, S. Michael Owens, and Ralph L. Henry 6 Cocaine- and Amphetamine-Regulated Transcript Peptides Play a Role in Drug Abuse and Are Potential Therapeutic Targets. 101 Michael J. Kuhar, Jason N. Jaworski, George W. Hubert, Kelly B. Philpot, and Geraldina Dominguez 7 RNAi-Directed Inhibition of DC-SIGN by Dendritic Cells: Prospects for HIV-1 Therapy . 113 Madhavan P.N. Nair, Jessica L. Reynolds, Supriya D. Mahajan, Stanley A. Schwartz, Ravikumar Aalinkeel, B. Bindukumar, and Don Sykes vii viii Contents 8 Viewing Chemokines as a Third Major System of Communication in the Brain . 127 Martin W. Adler, Ellen B. Geller, Xiaohong Chen, and Thomas J. Rogers 9 Targeting the PDZ Domains of Molecular Scaffolds of Transmembrane Ion Channels. 139 Andrea Piserchio, Mark Spaller, and Dale F. Mierke 10 Neuronal Nicotinic Acetylcholine Receptor Expression and Function on Nonneuronal Cells . 149 Lorise C. Gahring and Scott W. Rogers II Transporters & Stimulants & Hallucinogens 11 Role of Monoamine Transporters in Mediating Psychostimulant Effects . 169 Evan L. Riddle, Annette E. Fleckenstein, and Glen R. Hanson 12 Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse . 179 F. Ivy Carroll, James L. Howard, Leonard L. Howell, Barbara S. Fox, and Michael J. Kuhar 13 Serotonin Transporters: Implications for Antidepressant Drug Development . 193 Kellie J. White, Crystal C. Walline, and Eric L. Barker 14 Recent Advances for the Treatment of Cocaine Abuse: Central Nervous System Immunopharmacotherapy . 217 Tobin J. Dickerson and Kim D. Janda 15 k Opioids as Potential Treatments for Stimulant Dependence . 231 Thomas E. Prisinzano, Kevin Tidgewell, and Wayne W. Harding 16 Regulation of Monoamine Transporters: Influence of Psychostimulants and Therapeutic Antidepressants . 247 Lankupalle D. Jayanthi and Sammanda Ramamoorthy 17 Hallucinogen Actions on 5-HT Receptors Reveal Distinct Mechanisms of Activation and Signaling by G Protein-Coupled Receptors. 265 Harel Weinstein Contents ix 18 Recognition of Psychostimulants, Antidepressants, and Other Inhibitors of Synaptic Neurotransmitter Uptake by the Plasma Membrane Monoamine Transporters . 287 Christopher K. Surratt, Okechukwu T. Ukairo, and Suneetha Ramanujapuram 19 Dual Dopamine/Serotonin Releasers as Potential Medications for Stimulant and Alcohol Addictions . 311 Richard B. Rothman, Bruce E. Blough, and Michael H. Baumann 20 Receptors of Mammalian Trace Amines . 327 Anita H. Lewin III Drug Design: Nicotine, Opioids and Related Ligands 21 The Role of Crystallography in Drug Design . 343 Jeffrey R. Deschamps 22 Opioid Peptide-Derived Analgesics . 357 Peter W. Schiller 23 Opioid Ligands with Mixed µ/d Opioid Receptor Interactions: An Emerging Approach to Novel Analgesics . 367 Subramaniam Ananthan 24 Small-Molecule Agonists and Antagonists of the Opioid Receptor-Like Receptor (ORL1, NOP): Ligand-Based Analysis of Structural Factors Influencing Intrinsic Activity at NOP . 381 Nurulain Zaveri, Faming Jiang, Cris Olsen, Willma Polgar, and Lawrence Toll 25 Kappa Opioid Antagonists: Past Successes and Future Prospects. 395 Matthew D. Metcalf and Andrew Coop 26 In Vitro and Direct In Vivo Testing of Mixture-Based Combinatorial Libraries for the Identification of Highly Active and Specific Opiate Ligands . 433 Richard A. Houghten, Colette T. Dooley, and Jon R. Appel 27 Current Status of Immunologic
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