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Bfm:978-3-0348-8470-9/1.Pdf Milestones in Drug Therapy MDT Series Editors Prof. Dr. Michael J. Pamham Prof. Dr. J. Bruinvels PLIVA INFARM Research Institute Sweelincklaan 75 Prilaz baruna Filipovica 25 NL-3723 JC Bilthoven 10000 Zagreb The Netherlands Croatia Anxiolytics Edited by M. Briley and D. Nutt Springer Basel AG Editors Dr. Mike Briley Professor David Nutt Institut de Recherche Pierre Fabre University of Bristol Parc Industriei de la Chartreuse Psychophannacology Unit 8 I 100 Castres School of Medical Science France University Walk Bristol BS8 ITD UK Library of Congress Cataloging-in-Publication Data Anxiolytics / edited by M. Briley and D. NuU, p. cm - Milestones in drug therapy) lncludes bibliographical references and index. ISBN 978-3-0348-9581-1 ISBN 978-3-0348-8470-9 (eBook) DOI 10.1007/978-3-0348-8470-9 1. Tranquilizing drugs. 1. Briley, M. II. Nutt, David J., 1951- III. Series. RM333 A582 2000 615'.7882--{jc2I 00-033748 Deutsche Bibliothek Cataloging-in-Publication Data Anxiolytics / ed. by M. Briley and D. Nutt. - Basel ; Boston; Berlin: Birkhiiuser, 2000 (Milestones in drug therapy) ISBN 978-3-0348-9581-1 ISBN 978-3-0348-9581-1 The publisher and editor can give no guarantee for the infonnation an drug dosage and administration contained in this publication. The respective user must check its accuracy by consulting other sources of reference in each individual case. The use of registered names, trademarks etc. in this publication, even if not identified as such, does not imply that they are exempt from the relevant protective laws aud regulations or free for general use. This work is subject to copyright. AII rights are reserved, whether the whole or part of the material is concemed, specifically the rights oftranslation, reprinting, re-use ofillustrations, recitation, broadcasting, reproduction an microfilms ar in other ways, and storage in data banks. For any kind ofuse, pennission ofthe copyright owner must be obtained. © 2000 Springer Basei AG Originally published by Birkhiiuser Verlag in 2000 Softcover reprint of the hardcover Ist edition 2000 Printed on acid-free paper produced from chlorine-free pulp. TFC 00 Cover ilJustration: Chemical structures of the selective 5HT2C receptor full agonists Ro 60-0175, Ro 60-0332 ,Org 12962 and Ro 60-0017 (partial agonist) ISBN 978-3-0348-9581-1 987654321 v Contents List of contributors VII Preface IX Caroline McGrath, Graham D. Burrows and Trevor R. Norman The benzodiazepines: a brief review of phannacology and therapeutics ............................................ 1 Darius K. Shayegan and Stephen M. Stahl Buspirone ............................................. 13 Rudolf Hoehn-Saric Tricyclic antidepressants 27 Raimund Buller and Karin M. Jorga Monoamine oxidase inhibitors (including the newer reversible compounds) .................................... 41 David S. Baldwin and Jon Birtwistle Selective serotonin re-uptake inhibitors in anxiety disorders: room for improvement .................................... 55 Guy Griebel, Ghislaine Perrault and David J. Sanger Subtype-selective benzodiazepine receptor ligands 77 Louise R. Levine and William Z. Potter The 5-HT lA receptor: an unkept promise? 95 Chantal Moret 5-HT iBID receptors in anxiety 105 Franrois Jenck, Jean-Luc Moreau, Jiirgen Wichmann, Heinz Stadler, James R. Martin and Michael Bas Brain 5-HT2c receptors: potential role in anxiety disorders 119 Phil Skolnick Glutamate receptor ligands 139 Spilios V. Argyropoulos and David J. Nutt Peptide receptors as targets for anxiolytic drugs 151 Subject index ........................................... 177 VII List of contributors Spilios V. Argyropoulos, Psychopharmacology Unit, School of Medical Sciences, University Walk, Bristol BS8 ITO, England; e-mail: spilios.argyropoulos@bristol.ac.uk David S. Baldwin, Senior Lecturer in Psychiatry, Mental Health Group, Facul­ ty of Medicine, Health and Biological Sciences, University of Southampton, UK; University Department of Psychiatry, Royal South Hants Hospital, Brintons Terrace, Southampton, UK; e-mail: dsb1@soton.ac.uk Jon Birtwistle, Training Fellow, Primary Medical Care Group, Faculty of Medicine, Health and Biological Sciences, University of Southampton, UK; e-mail: jb11@soton.ac.uk Michael Bas, Boehringer Ingelheim, Virology Research Center, Montreal, Canada Raimund Buller, Quintiles, 3-5, rue Maurice Ravel, F-92594 Levallois-Perret, France; e-mail: raimund.buller@quintiles.com Graham D. Burrows, Department of Psychiatry, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia Guy Griebel, Sanofi-Synthelabo, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France; e-mail: guy.griebel@sanofi.synthelabo.com Rudolf Hoehn-Saric, 115 Meyer Building, Johns Hopkins Hospital, Baltimore, MD 21287-7115, USA; e-mail: rhoehn@welchlink.welch.jhu.edu Fran<;ois Jenck, Roche Pharma Division, Preclinical CNS Research, CHA070 Basel, Switzerland; e-mail: francois.jenck@roche.com Karin M. Jorga, F. Hoffmann-La Roche, Dept. of Clinical Pharmacology, Grenz­ achstrasse 124, CHA070 Basel, Switzerland; e-mail: karin.jorga@roche.com Louise R. Levine, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 1730, Indianapolis, IN 46285, USA; e-mail: lulu@lilly.com Caroline McGrath, Department of Psychiatry, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia; e-mail: c.mcgrath@medicine.unimelb.edu.au James R. Martin, F. Hoffmann-La Roche, Preclinical CNS Research, Grenzachstrasse 124, CH-4070 Basel, Switzerland Jean-Luc Moreau, F. Hoffmann-La Roche, Preclinical CNS Research, Grenzachstrasse 124, CH-4070 Basel, Switzerland Chantal Moret, Les Grezes, La Verdarie, 81100 Castres, France; e-mail: chantal.moret@neurobiz.com Trevor R. Norman, Department of Psychiatry, University of Melbourne, Austin VIII List of contributors & Repatriation Medical Centre, Heidelberg 3084, Victoria, Australia; e-mail: trevor@austin.unimelb.edu.au David J. Nutt, Psychopharmacology Unit, School of Medical Sciences, Univer­ sity Walk, Bristol BS8 1TO, England; e-mail: David.J.Nutt@bristol.ac.uk Ghislaine Perrault, Sanofi-Synthelabo, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France William Z. Potter, Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center DC 1730, Indianapolis, IN 46285, USA; e-mail: wzp@lilly.com David J. Sanger, Sanofi-Synthelabo, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France Darius K. Shayegan, Clinical Neuroscience Research Center, 8899 University Center Lane, Suite l30, San Diego, California 92122, USA Phil Skolnick, Neuroscience Discovery, Lilly Research Laboratories, Lilly Corporate Center, Drop Code 0510, Indianapolis, IN 46285, USA; e-mail: SKOLNICK]HIL@LILLY.COM Heinz Stadler, F. Hoffmann-La Roche, Preclinical CNS Research, Grenzachstrasse 124, CH-4070 Basel, Switzerland Stephen M. Stahl, Department of Psychiatry, University of California, San Diego, USA Jtirgen Wichmann, F. Hoffmann-La Roche, Preclinical CNS Research, Grenzachstrasse 124, CH-4070 Basel, Switzerland IX Preface For over thirty years the benzodiazepines monopolised not only the anxiolytic market but also clinical and animal research in anxiety. Indeed many animal tests developed since the 1960s have been optimised for the benzodiazepines and some programmes have even screened candidates as potential anxiolytics on their benzodiazepine-like side-effects rather than their anxiolytic activity. With the realisation of the drawbacks of the benzodiazepines, namely their potential for tolerance and dependency, there has been a renewed interest in alternative anxiolytics both from existing drugs such as the tricyclic and monoamine oxidase antidepressants and from newer agents such as buspirone. In addition anxiety is no longer considered to be a unique entity but rather an umbrella term for a series of specific anxiety disorders such as panic disorder without or with agoraphobia, generalised anxiety disorder (GAD), specific phobias, social phobias and post-traumatic stress disorder (PTSD). These new clinical categories have opened another dimension in the therapy of anxiety requiring the optimisation of treatments for different syndromes. This book is a critical review of today's anxiolytics and those that may become the anxiolytics of tomorrow. What is clear is that currently there are few clinically satisfactory alternatives to the benzodiazepines for the treatment of acute anxiety. For chronic anxiety, it is generally agreed that benzodi­ azepines are not the treatment of first choice. The tricyclic and monoamine oxidase antidepressants, the serotonin reuptake inhibitors and buspirone offer better solutions for chronic anxiety but they are still far from being ideal. The challenge for tomorrow is not only to find more efficacious treatments with a more rapid onset of action and an acceptable side-effect profile but to define more precisely which agents may treat the different anxiety disorders. Serotonin is a major target, particularly through the 5-HTlA, 5-HTlB and 5-HT2 receptors. The amino acid receptors, the glutamate complex in particu­ lar, is being intensively investigated as a potential target for anxiolytics. Finally the involvement of a number of neuropeptides in the control of stress and anxious reactions is becoming increasingly clear and new chemical agents are being developed to probe these potential anxiolytic targets. This intense research activity suggests that we may soon have a whole new range of options for the treatment of anxiety disorders and so be able to final­ ly leave behind us "the age of anxiety". Mike Briley David Nutt .
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