SERIES EDITORS RONALD J. BRADLEY Departmentof Psychiatry, Collegeof Medicine The University of Tennessee Health Science Center Memphis,Tennessee, USA R. ADRON HARRIS Waggoner Centerfor Alcoholand Drug Addiction Research The University of Texas at Austin Austin,Texas, USA PETER JENNER Division of Pharmacologyand Therapeutics GKTSchoolof Biomedical Sciences King’s College, London, UK EDITORIAL BOARD ERIC AAMODT HUDA AKIL PHILIPPE ASCHER MATTHEW J. DURING DONARD S. DWYER DAVID FINK MARTIN GIURFA BARRY HALLIWELL PAUL GREENGARD JON KAAS NOBU HATTORI LEAH KRUBITZER DARCY KELLEY KEVIN MCNAUGHT BEAU LOTTO JOS�E A. OBESO MICAELA MORELLI CATHY J. PRICE JUDITH PRATT SOLOMON H. SNYDER EVAN SNYDER STEPHEN G. WAXMAN JOHN WADDINGTON Pharmacology of 5-HT6 Receptors-Part 1 EDITED BY FRANCO BORSINI Sigma-Tau Industrie Farmaceutiche Riunite S.P.A., Pomezia, Italy AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an imprint of Elsevier Academic Press is an imprint of Elsevier 360 Park Avenue South, New York, NY 10010-1700 525 B Street, Suite 1900, San Diego, California 92101-4495, USA 32 Jamestown Road, London NW1 7BY, UK This book is printed on acid-free paper. Copyright © 2010, Elsevier Inc. All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. 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If no fee code appears on the title page, the copy fee is the same as for current chapters. 0074-7742/2007 $35.00 Permissions may be sought directly from Elsevier’s Science & Technology Rights Department in Oxford, UK: phone: (þ44) 1865 843830, fax: (þ44) 1865 853333, E-mail: [email protected]. You may also complete your request on-line via the Elsevier homepage (http://elsevier.com), by selecting ‘‘Support & Contact’’ then ‘‘Copyright and Permission’’ and then ‘‘Obtaining Permissions.’’ For information on all Elsevier publications visit our website at books.elsevier.com ISBN: 978-0-12-384976-2 PRINTED AND BOUND IN THE UNITED STATES OF AMERICA 10111213 987654321 Working together to grow libraries in developing countries www.elsevier.com | www.bookaid.org | www.sabre.org CONTRIBUTORS Numbers in parentheses indicate the pages on which the authors contributions begin. Paola Bonsi (111), Laboratory of Neurophysiology and Plasticity, I.R.C.C.S. Fondazione Santa Lucia, Rome, Italy Javier Burguen˜o (89), Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain Annamaria Cattaneo (129), Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology, University of Brescia, Brescia, Italy Xavier Codony (89), Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain Massimo Gennarelli (129), Division of Biology and Genetics, Department of Biomedical Sciences and Biotechnology and Head of the Genetics Unit, UniversityofBrescia,IRCCS SanGiovannidiDio,Fatebenefratelli, Brescia, Italy Kevin G. Liu (1), Lundbeck Research USA, Paramus, NJ 07652, USA Angelo Mancinelli (153), Sigma-tau Industrie Farmaceutiche Riunite S.P.A., Pomezia, Rome, Italy Graziella Madeo (111), Department of Neuroscience, University Tor Vergata, Rome, Italy Gloria Oranias Olsina (35), Intellectual Property Department, ESTEVE, Barcelona, Spain Antonio Pisani (111), Laboratory of Neurophysiology and Plasticity, I.R.C.C. S. Fondazione Santa Lucia, Rome, Italy and Department of Neuroscience, University Tor Vergata, Rome, Italy Maria Javier Ram�ırez (89), Pharmacology Department, University of Navarra, Pamplona, Spain Teresa Riccioni (67), Sigma-tau Industrie Riunite S.P.A., Pomezia (Roma), Italy Albert J. Robichaud (1), Lundbeck Research USA, Paramus, NJ 07652, USA Giuseppe Sciamanna (111), Laboratory of Neurophysiology and Plasticity, I. R.C.C.S. Fondazione Santa Lucia, Rome, Italy ix x CONTRIBUTORS Annalisa Tassone (111), Laboratory of Neurophysiology and Plasticity, I.R.C. C.S. Fondazione Santa Lucia, Rome, Italy Jose� Miguel Vela (89), Drug Discovery & Preclinical Development, ESTEVE, Barcelona, Spain Nicolas Vincent Ruiz (35), Intellectual Property Department, ESTEVE, Barcelona, Spain PREFACE The field of 5-HT6 receptors is quite recent story. The number of patents (Ruiz and Oranias, this book) and scientific publications is increasing every year. If one considers the very first indication of the probable presence of 5-HT6 receptors in 1979 (MacDermont et al., 1979), until 1998, only 33 scientific communications were published in this 19-year period, mainly focused on distribution, structure, and gross function of the receptor. Pharmaceutical companies found potentially interesting the interference with the function of this receptor and started to synthesize various 5-HT6 receptor ligands (Liu and Robichaud, this book). Between 1999 and 2004, in 5 years, the number of publications raised to 79. After the first period, with the advent of several 5-HT6 ligands, the number of publications increased even more and, between 2005 and mid-2010, reached 154. With the rise of the number of researchers working in this field and then with the increase of different experimental settings, the information on 5-HT6 recep­ tors started to appear inconsistent. In fact, the definition of 5-HT6 receptor agonist or antagonist may be test dependent (Codony et al., this book), and this may explain why both agonists and antagonists may exert similar pharmacolo­ gical effects (part two of this book). Also the first enthusiasm in going to clinical phase with 5-HT6 ligands (part two of this book), as antiobese or anti-amnesic agents, was attenuated by the unsatisfactory clinical results. Also the first idea to use 5-HT6 ligands against cognitive impairment associated with schizophrenia seems destined to be unsuccesful (part two of this book). However, so far, no genetic modification has clearly been associated with any pathology (Gennarelli and Cattaneo, this book). In the field of 5-HT6 receptors, neurochemical (part two of this book) and electrophysiological (Tassone et al., this book) properties of the receptor are also far to be clearly understood. Therefore, it is difficult to ascertain 5-HT6 receptor pharmacological effects, since many pieces of information are unsatisfactory, such as pharmacokinetics/metabolism of the 5-HT6 ligands (Mancinelli, this book), or how radioligands bind to the receptor (Riccioni, this book) (Figure 1). This book was thought to summarize all the data so far obtained in order to put forward some hypothesis for the inconsistencies in the 5-HT6 field. One is that 5-HT6 receptors might exist in different conformational states, according to the G protein with which the 5-HT6 receptor interacts. Since the coupling with the various G proteins may depend on cellular environment, which is differently xi xii PREFACE 180 160 140 120 100 80 60 40 20 Number of scientific communications 0 1979–1998 1999–2004 2005–2010 Years FIG. 1. Number of scientific publications in the field of 5-HT6 receptors since the first possible publication. sensitive to various stressors, the final output (agonist versus antagonist) might depend on cellular state itself. If one assumes that the various 5-HT6 receptor ligands might bind to different receptor sites, it might become clearer why similar pharmacological properties are shared by alleged agonists and antagonists. If this hypothesis is confirmed, 5-HT6 receptor might be a type of receptor that is cell- state sensitive. However, there is no clear explanation for the inconsistencies in the 5-HT6 field. This book wants to evidence the state of the art in the field of 5-HT6 receptor physiology and pharmacology. We hope that this book may represent a reference information for all researchers who work in the field of 5-HT6 receptors. The book on “Pharmacology of 5-HT6 receptors” is published in two parts. The first part deals with in-vitro results and pharmakinetics of 5-HT6 receptor ligands, and the second part with in-vivo findings. Reference MacDermont, J., Higashida, H., Wilson, S.P., Matsuzawa, H., Minna, J., and Nirenberg, M. (1979). Adenylate cyclase and acetylcholine release regulated by separate serotonin receptors of somatic cell hybrids. Proc. Natl. Acad. Sci. U. S. A. 76, 1135–1139. FRANCO BORSINI 5-HT6 MEDICINAL CHEMISTRY Kevin G. Liu and Albert J. Robichaud Lundbeck Research USA, Paramus, NJ 07652, USA I. Introduction II. 5-HT6 Antagonists A. Bisaryl Sulfonamides and Sulfones B. Piperazinylbenzenesulfonamides C. Indoles D. Indazoles E. Azaindoles and Azaindazoles F. Benzofuran, Benzothiaphenes, Benzimidazoles, Thienopyrroles, and Pyrazolotriazines G. Quinolines, Isoquinolines, and Naphthalenes H. Benzene and Its Fused Carbocyclic Derivatives I. Miscellaneous Derivatives Lacking