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1 Trp Channels and Human Diseases VANILLOID RECEPTOR TRPV1 IN DRUG DISCOVERY VANILLOID RECEPTOR TRPV1 IN DRUG DISCOVERY Targeting Pain and Other Pathological Disorders Edited by ARTHUR GOMTSYAN CONNIE R. FALTYNEK Abbott Laboratories A JOHN WILEY & SONS, INC., PUBLICATION Copyright © 2010 by John Wiley & Sons, Inc. All rights reserved Published by John Wiley & Sons, Inc., Hoboken, New Jersey Published simultaneously in Canada 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, scanning, or otherwise, except as permitted under Section 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, (978) 750-8400, fax (978) 750-4470, or on the web at www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, (201) 748-6011, fax (201) 748-6008, or online at http://www.wiley.com/go/permission. Limit of Liability/Disclaimer of Warranty: While the publisher and author have used their best efforts in preparing this book, they make no representations or warranties with respect to the accuracy or completeness of the contents of this book and specifi cally disclaim any implied warranties of merchantability or fi tness for a particular purpose. No warranty may be created or extended by sales representatives or written sales materials. The advice and strategies contained herein may not be suitable for your situation. You should consult with a professional where appropriate. Neither the publisher nor author shall be liable for any loss of profi t or any other commercial damages, including but not limited to special, incidental, consequential, or other damages. For general information on our other products and services or for technical support, please contact our Customer Care Department within the United States at (800) 762-2974, outside the United States at (317) 572-3993 or fax (317) 572-4002. Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic formats. For more information about Wiley products, visit our web site at www.wiley.com. Library of Congress Cataloging-in-Publication Data ISBN: 978-0-470-17557-6 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 Arthur wishes to dedicate this book to his wife Natalia, daughters Anahit, Lusine, Ani, and parents, especially father, with love and gratitude. Connie dedicates this book with love to her husband Robert, who is her lifelong dearest friend and soul mate. CONTENTS PREFACE AND ACKNOWLEDGMENTS ix FOREWORD xiii CONTRIBUTORS xv PART I INTRODUCTION TO THE TRP CHANNELS 1 1 TRP Channels and Human Diseases 3 Bernd Nilius and Rudi Vennekens 2 Role of TRP Channels in Pain: An Overview 68 Arpad Szallasi 3 Biochemical Pharmacology of TRPV1: Molecular Integrator of Pain Signals 101 Carol S. Surowy, Philip R. Kym, and Regina M. Reilly 4 TRPV1 Genetics 134 Ruslan Dorfman, Hubert Tsui, Michael W. Salter, and H.-Michael Dosch PART II ROLE FOR TRPV1 IN PAIN STATES 151 5 TRPV1 and Infl ammatory Pain 153 Anindya Bhattacharya, Sonya G. Lehto, and Narender R. Gavva 6 Role of TRPV1 Receptors in Osteoarthritic Pain 175 Shailen K. Joshi and Prisca Honore 7 TRPV1 and Bone Cancer Pain 191 Juan Miguel Jimenez-Andrade and Patrick Mantyh 8 TRPV1 in Visceral Pain and Other Visceral Disorders 206 António Avelino and Francisco Cruz vii viii CONTENTS 9 TRPV1 Receptors and Migraine 239 Philip R. Holland and Peter J. Goadsby 10 TRPV1 in Neuropathic Pain and Neurological and Neuropsychiatric Disorders 260 Enza Palazzo, Katarzyna Starowicz, Sabatino Maione, and Vincenzo Di Marzo PART III TRPV1 ANTAGONISTS AND AGONISTS AS NOVEL ANALGESIC DRUGS 293 11 Aryl-Urea Class and Related TRPV1 Antagonists 295 Arthur Gomtsyan 12 2-Pyridinylpiperazine Carboxamide Class and Related TRPV1 Antagonists 311 Natalie A. Hawryluk and Nicholas I. Carruthers 13 TRPV1 Agonist Approaches for Pain Management 325 Keith R. Bley PART IV ROLE FOR TRPV1 IN OTHER PHYSIOLOGICAL PROCESSES BESIDES PAIN TRANSMISSION 349 14 The TRPV1 Channel in Normal Thermoregulation: What Have We Learned from Experiments Using Different Tools? 351 Andras Garami, Maria C. Almeida, Tatiane B. Nucci, Tamara Hew-Butler, Renato N. Soriano, Eszter Pakai, Kazuhiro Nakamura, Shaun F. Morrison, and Andrej A. Romanovsky 15 The Role of TRPV1 in Respiratory Diseases 403 Serena Materazzi, Alain Tchoimou, Romina Nassini, Marcello Trevisani, and Pierangelo Geppetti 16 The Role of TRPV1 in Diabetes 423 Hubert Tsui, Ruslan Dorfman, Michael W. Salter, and H.-Michael Dosch AFTERWORD 449 INDEX 451 PREFACE AND ACKNOWLEDGMENTS The intended purpose of this book is to summarize available data related to the therapeutic utility for transient receptor potential vanilloid 1 (TRPV1) ligands. Many of the world ’ s leading experts on TRPV1 contributed to this book, not only by reviewing the most relevant information on the subject but also by providing personal opinions on the critical issues. The history of the TRPV1 receptor is, for the most part, the history of chili pepper, a popular hot spice that has been cultivated in South America for over 6000 years and in the rest of the world since the sixteenth century. However, food fl avoring has not been the only benefi t chili peppers have offered. Chili preparations have been used as treatments for ulcers, backaches, and coughs, among other maladies. The ingredient that is responsible for the initial burning effect of chili pepper, as well as for its medicinal properties, is a compound called capsaicin, which constitutes approximately 0.14% w/w of chili peppers. Capsaicin was isolated in 1876, and its structure was determined shortly there- after. The homovanillyl fragment in the structure of capsaicin was the basis for naming the putative cell surface receptor vanilloid receptor 1 (VR1). An amazing breakthrough occurred in 1997, when VR1 was molecularly cloned by David Julius ’ team. VR1 later was renamed the TRPV1 to under- score its membership in a larger family of transient receptor potential (TRP) ion channels. The Foreword by Professor Julius presents an illuminating per- spective on the entire fi eld. The two introductory chapters in this volume (Nilius and Vennekens; Szallasi) are designed to familiarize the reader with the multifunctional TRP family of ion channels and, at the same time, to lay the foundation for the remaining chapters, which focus on one member of that family, TRPV1. Members of the TRP superfamily have been shown to be polymodal molecular ix x PREFACE AND ACKNOWLEDGMENTS sensors, with the important roles of detecting a variety of thermal, mechanical, and chemical stimuli. These ion channels have been shown to contribute to sensory processes such as pain transmission, vision, taste, and hearing. The complex nature of TRPV1 modulation is described in the chapter by Surowy et al., which provides basic information about the structure of the receptor, numerous regulators (activators and sensitizers), and their modes and sites of action. The chapter on TRPV1 genetics (Dorfman et al.) reviews the impact of TRPV1 genetic variability on the pharmacological properties of TRPV1 in different species and summarizes available data on identifi cation of the binding sites for biological substrates. Several key studies with TRPV1 knockout mice and with TRPV1 antago- nists, support the conclusion that TRPV1 plays an important role in pain pathways. Indeed, most of the advances with TRPV1 as a new molecular target for novel medications have been in the development of new analgesics. The next chapters discuss in detail the connection between TRPV1 and various types of pain. Preclinical studies provide a strong case for the benefi cial effects of TRPV1 blockade for the treatment of infl ammatory, osteoarthritic, and bone cancer pain. The effi cacy of TRPV1 antagonists in animal models of infl ammatory pain is discussed in the chapter by Bhattacharya et al. Several preclinical studies have shown the benefi t of TRPV1 antagonists in treating the pain associated with osteoarthritis (Joshi and Honore). It has also been shown that bone cancer pain, which is often poorly controlled by existing analgesics, can be successfully attenuated in mice by treatment with TRPV1 antagonists (Jimenez- Andrade and Mantyh). TRPV1 has been actively inves- tigated as a potential target for conditions such as visceral pain and the treat- ment of lower urinary tract symptoms, including urinary frequency, urgency, and incontinence (Avelino and Cruz). Evidence for the role of TRPV1 in migraine (Holland and Goadsby) and in neuropathic pain (Palazzo et al.) is limited and inconclusive. To conclude the theme of TRPV1 antagonists and pain, two medi- cinal chemistry chapters summarize structural and structure – activity rela- tionship information on the two major classes of TRPV1 antagonists: aryl - ureas (Gomtsyan) and pyridinylpiperazine carboxamides (Hawryluk and Carruthers). While the blockade of receptor activation by TRPV1 antagonists attenuates pain transmission, TRPV1 agonists have also been shown to be effective in pain management, especially for peripheral neuropathies (Bley). Antinociception induced by TRPV1 agonists is the result of receptor desen- sitization/defunctionalization after prolonged administration of the agonist. In fact, capsaicin cream has been used for many years to treat peripheral neu- ropathies, and new topical and injectable formulations of capsaicin with better safety margins are undergoing late - stage clinical trials. This volume also presents experts ’ opinions on the links between TRPV1 and disease states other than pain. Some of these links are well established. For example, high expression of TRPV1 on sensory nerves in airways led PREFACE AND ACKNOWLEDGMENTS xi scientists to explore the potential for TRPV1 antagonists in treating chronic cough, asthma, and other respiratory diseases (Materazzi et al.).
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