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Roger G. Pertwee.Pdf Handbook of Experimental Pharmacology Volume 168 Editor-in-Chief K. Starke, Freiburg i. Br. Editorial Board G.V.R. Born, London M. Eichelbaum, Stuttgart D. Ganten, Berlin F. Hofmann, München B. Kobilka, Stanford, CA W. Rosenthal, B erlin G. Rubanyi, Richmond, CA Cannabinoids Contributors M.E.Abood,S.Bátkai,T.Bisogno,G.A.Cabral,M.J.Christie, A.A. Coutts, S.N. Davies, R. de Miguel, L. De Petrocellis, V. Di Marzo, M. Egertová, M.R. Elphick, J. Fernández-Ruiz, S.J. Gatley, S.T. Glaser, M. Gómez, S. Gonzáles, M. Guzmán, C.J. Hillard, W.-S.V. Ho, A.G. Hohmann, A.C. Howlett, M.A. Huestis, A.A. Izzo, M. Karsak, G. Kunos, C. Li, A.H. Lichtman, K.P. Lindsey, M. Maccarrone, K. Mackie, A. Makriyannis, B.R. Martin, S.P. Nikas, P. Pacher, R.G. Pertwee, J.A. Ramos, P.H. Reggio, G. Riedel, P. Robson, E. Schlicker, A. Staab, B. Szabo, G.A. Thakur, O. Valverde, C.W. Vaughan, J.M. Walker, T. Wenger, A. Zimmer Editor Roger G. Pertwee 123 Professor Dr. Roger Pertwee School of Medical Sciences Institute of Medical Science University of Aberdeen Foresterhill Aberdeen AB25 2ZD Scotland, UK email: [email protected] With 84 Figures and 26 Tables ISSN 0171-2004 ISBN 3-540-22565-X Springer Berlin Heidelberg New York Library of Congress Control Number: 2004109756 This work is subject to copyright. All rights reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad- casting, reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer. Violations are liable for prosecution under the German Copyright Law. Springer is a part of Springer Science + Business Media springeronline.com © Springer-Verlag Berlin Heidelberg 2005 Printed in Germany The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Editor: Dr. R. Lange Desk Editor: S. Dathe Cover design: design&production GmbH, Heidelberg, Germany Typesetting and production: LE-TEXJelonek,Schmidt&VöcklerGbR,Leipzig,Germany Printed on acid-free paper 27/3150-YL - 5 43210 In memory of H.J.C. and Bill Paton – and for Teresa. Preface Less than 20 years ago the field of cannabis and the cannabinoids was still con- sidered a minor, somewhat quaint, area of research. A few groups were active in the field, but it was already being viewed as stagnating. The chemistry of cannabis was well known, ∆9-tetrahydrocannabinol (∆9-THC), identified in 1964, being the only major psychoactive constituent and cannabidiol, which is not psychoactive, possibly contributing to some of the effects. These cannabinoids and several syn- thetic analogs had been thoroughly investigated for their pharmacological effects. Their mode of action was considered to be non-specific. The reasons for this as- sumption were both technical and conceptual. On the technical side, it had been shown that THC was active in both enantiomeric forms (though with a different level of potency) and this observation was incompatible with action on biological substrates—a receptor, an enzyme, an ion channel—which react with a single stereoisomer only. The conceptual problem related to THC activity. This had been pointed out by several highly regarded research groups that had shown that many of the effects seen with cannabinoids were related to those of biologically active lipophiles, and that many of the effects of THC, particularly chronic ones, were comparable to those seen with anaesthetics and solvents. The technical problems were eliminated when it was found, by several groups, that cannabinoid action is actually stereospecific and most of the previous work, which had pointed to a differ- ent conclusion, was based on insufficiently purified samples. The conceptual hurdle was overcome when Allyn Howlett’s group in 1988 brought out the first evidence that a specific cannabinoid receptor exists in the brain. This receptor was cloned shortly thereafter and a second receptor, which is not present in the brain, was identified in the periphery. As, presumably, receptors do not exist in mammalian brains for the sake of a plant constituent, several groups went ahead looking for endogenous cannabinoids. The first such endocannabinoid, named anandamide, was reported in 1992, and a second major one, 2-arachidonoylglycerol (2-AG), was discovered in 1995. Several additional, apparently minor ones are now known. A research flood followed. Antagonists to both receptors have been synthesized, specific enzymes, which regulate endocannabinoid levels, have been found, and the biosynthetic and degradation patterns have been established. The endocannabi- noid system has turned out to be of major biochemical importance. It is involved in many of our physiological processes—in the nervous, digestive, reproductive, pul- monary and immune systems. Endocannabinoids enhance appetite, reduce pain, act as neuroprotectants and regulators of cytokine production and are somehow involved in the extinction of memories—to mention just a few of their effects. VIII Preface At cannabinoid meetings in the past, very few representatives of the pharmaceu- tical companies were present. Now the picture has changed. At least two synthetic cannabinoids are in advanced phase III clinical trials. SR-141716, a CB1 antagonist, developed by Sanofi, represents a new type of appetite modulator, and HU-211, developed by Pharmos, is a neuroprotectant in head trauma. If the clinical trials are successful, both drugs may represent pharmaceutical breakthroughs in important therapeutic areas. Numerous companies are following in their footsteps. Other clinical conditions apparently are also being looked into. Sleep disorders, inflam- matory conditions, neurodegenerative diseases, liver cirrhosis and even cancer represent possible targets. What can we expect in the future? Compared to the classical neurotransmit- ters dopamine, serotonin, norepinephrine, and acetylcholine, we still know very little about anandamide and 2-AG. There are strong indications that additional anandamide/cannabinoid receptors exist, but their identification and cloning is still elusive. As both anandamide and 2-AG are arachidonic acid derivatives, their leukotriene-type and prostaglandin-type metabolites may be of biological importance—but, are they? It has been shown that the cannabinoids are rather unique retrograde messengers at the synapse. But the actual messengers have not been identified. Are they anandamide and 2-AG? There are initial indications that the endocannabinoid system is involved in numerous, additional, unrelated bio- logical conditions such as stress, bone formation, aggression, addictive behaviours. We know very little of any possible endocannabinoid involvement. And the list is long. People smoke cannabis in order to change their mood. The tricyclic cannabi- noids (and possibly the endocannabinoids) certainly alter mood, social behaviour and emotions. But we know next to nothing of the chemistry of emotions. Until quite recently the field of emotions was left to the poets and some psychologists and psychiatrists. From the point of view of a chemist or a pharmacologist, un- fortunately, we have very few tools to approach problems of emotions. Could the endocannabinoids represent such tools? The present book is an outstanding summary of many aspects of cannabinoid research. It represents a stepping-stone to many unsolved problems in biochem- istry, pharmacology, physiology and the clinic. Perhaps it will help generate novel ideas, such as how to approach the scientific study of emotions. Spring, 2005 Professor Raphael Mechoulam Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem 91120, Israel (e-mail: [email protected]) List of Contributors (Addresses stated at the beginning of the respective chapters) Abood, M.E. 81 Kunos, G. 599 Bátkai, S. 599 Li, C. 209 Bisogno, T. 147 Lichtman, A.H. 691 Lindsey, K.P. 425 Cabral, G.A. 385 Christie, M.J. 367 Maccarrone, M. 555 Coutts, A.A. 573 Mackie, K. 299 Makriyannis, A. 209 Davies, S.N. 445 Martin, B.R. 691 de Miguel, R. 643 De Petrocellis, L. 147 Nikas, S.P. 209 Di Marzo, V. 147 Pacher, P. 599 Egertová, M. 283 Pertwee, R.G. 1 Elphick, M.R. 283 Ramos, J.A. 643 Fernández-Ruiz, J. 479 Reggio, P.H. 247 Riedel, G. 445 Gómez, M. 643 Robson, P. 719 Gatley, S.J. 425 Glaser, S.T. 425 Schlicker, E. 327 González, S. 479 Staab, A. 385 Guzmán, M. 627 Szabo, B. 327 Hillard, C.J. 187 Thakur, G.A. 209 Ho, W.-S.V. 187 Hohmann, A.G. 509 Valverde, O. 117 Howlett, A.C. 53 Vaughan, C.W. 367 Huestis, M.A. 657 Walker, J.M. 509 Izzo, A.A. 573 Wenger, T. 555 Karsak, M. 117 Zimmer, A. 117 List of Contents PharmacologicalActionsofCannabinoids.................. 1 R.G. Pertwee Cannabinoid Receptor Signaling . 53 A.C. Howlett Molecular Biology of Cannabinoid Receptors . 81 M.E. Abood Analysis of the Endocannabinoid System by Using CB1 CannabinoidReceptorKnockoutMice............. 117 O. Valverde, M. Karsak, A. Zimmer The Biosynthesis, Fate and Pharmacological Properties of Endocannabinoids . ........................ 147 V. Di Marzo, L. De Petrocellis, T. Bisogno Modulators of Endocannabinoid Enzymic Hydrolysis andMembraneTransport........................... 187 W.-S.V. Ho, C.J. Hillard Structural Requirements for Cannabinoid Receptor Probes . 209 G.A. Thakur, S.P. Nikas, C. Li, A. Makriyannis Cannabinoid Receptors and Their Ligands: Ligand–Ligand and Ligand–Receptor Modeling Approaches . 247 P.H. Reg g io The Phylogenetic Distribution and Evolutionary Origins of Endocannabinoid Signalling .
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