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Pain in the Periphery - Nociception SHL ITEM BARCODE 19 1702512 9 REFERENCE ONLY UNIVERSITY OF LONDON THESIS Degree Year i o o ^ Name of Author C O P YR IG H T This is a thesis accepted for a Higher Degree of the University of London. It is an unpublished typescript and the copyright is held by the author. All persons consulting the thesis must read and abide by the Copyright Declaration below. COPYRIGHT DECLARATION I recognise that the copyright of the above-described thesis rests with the author and that no quotation from it or information derived from it may be published without the prior written consent of the author. LOANS Theses may not be lent to individuals, but the Senate House Library may lend a copy to approved libraries within the United Kingdom, for consultation solely on the premises of those libraries. Application should be made to: Inter-Library Loans, Senate House Library, Senate House, Malet Street, London WC1E 7HU. REPRODUCTION University of London theses may not be reproduced without explicit written permission from the Senate House Library. Enquiries should be addressed to the Theses Section of the Library. Regulations concerning reproduction vary according to the date of acceptance of the thesis and are listed below as guidelines. A. Before 1962.Permission granted only upon the prior written consent of the author. (The Senate House Library will provide addresses where possible). B. 1962- 1974. In many cases the author has agreed to permit copying upon completion of a Copyright Declaration. C. 1975 - 1988. Most theses may be copied upon completion of a Copyright Declaration. D. 1989 onwards. Most theses may be copied. This thesis comes within category D. u This copy has been deposited in the Library of _________________________ H i / This copy has been deposited in the Senate House Library, Senate House, L_J Malet Street, London WC1E 7HU. C:\Documents and Settings\lproctor\Local Settings\Temporary Internet Files\OLK8\Copyright - thesis (2).doc NOVEL, POTENT ANTAGONISTS OF CAPSAICIN by GLYN ALAN HUGHES Thesis submitted in accordance with the requirements of the University of London, for the degree of Doctor of Philosophy. Department of Chemistry, University College, London June 2005 1 UMI Number: U592880 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. Dissertation Publishing UMI U592880 Published by ProQuest LLC 2013. Copyright in the Dissertation held by the Author. Microform Edition © ProQuest LLC. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The aim of this project was to explore and refine the conformational rationale for the activity of capsazepine (CPZ) as a blocker of the ion channel TRPV1 (transient receptor potential vanilloid type 1), by the synthesis and biological evaluation of further conformationally constrained capsaicin analogues. The resolution of the stereoisomers of N-(4-chlorophenethylthiocarb amo y 1) - 6,7 - dihydroxy-1 -methyl-1,2,3,4-tetrahydroisoquino-line 29, Af-(4-chlorophenethylthio- carbamoyl)-6,7-dihydroxy-3-methyl-l,2,3,4-tetra-hydroisoquinoline 30 and N-(4- chlorophenethylthiocarbamoyl)-6,7-dihydroxy-1,3-dimethyl-1,2,3,4-tetrahydroiso- quinoline 31 by stereoselective synthetic methodology is described, and some of the more unusual and interesting mechanisms are discussed. The novel asymmetric chemistry described includes the separation of the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by crystallisation with the enantiomers of mandelic acid, the use of sodium triacetoxyborohydride in the stereoselective reduction of 6,7-dimethoxy-1,3-dimethyl-3,4-dihydroiso- quinoline 171, to give the c/s-diastereomers of 6,7-dimethoxy-1,3-dimethyl-1,2,3,4- tetrahydroisoquinoline 44, and the novel stereoselective route to the trans- diastereomers of 6,7-dimethoxy-1,3-dimethyl-1,2,3,4-tetrahydroisoquinoline 44 from the enantiomers of 2-(3,4-dimethoxyphenyl)-l-methylethylamine 38 by the Michael addition of A-benzyl-2-(3,4-dimethoxyphenyl)-1 -methylethylamine 155 to ethynyl- 4-tolylsulfone 150, followed by TFA-mediated cyclisation, single electron reductive desulfonylation and palladium-catalysed hydrogenolysis. The results of investigations into the conformational behaviour of the resolved stereoisomers of 29, 30 and 31 by techniques of NMR spectroscopy and molecular modelling, the evaluation of their biological activity at the rat and human orthologues of the ion channel TRPV1, and the attempted correlation of the two sets of data, with respect to the published conformational rationale for the activity of CPZ, are also described. The biological evaluation of these compounds has identified one analogue 31(15,31?) with a similar activity profile to CPZ, which has allowed a more accurate definition of the requirements for biological activity akin to CPZ at the human and rat orthologues of TRPV1. In addition, four analogues (295, 301?, 305 and 31(15,35)) have been identified with potent antagonism (IC5o<100nM) of capsaicin-induced 2 activation of the human orthologue of TRPV1, and potent agonism (EC5o<60nM) of the rat orthologue of TRPV1. Compounds possessing opposing activities for different mammalian orthologues of TRPV1 have not been described previously in the literature. 3 Table of Contents Abstract .........................................................................................................................2 Table of Contents ......................................................................................................... 4 Index of Tables ............................................................................................................10 Index of Figures ..........................................................................................................11 Acknowledgements .................................................................................................... 24 Abbreviations ..............................................................................................................25 Dedication ............................................................................. 27 INTRODUCTION..................................................................................................... 28 Pain, Capsaicin and TRPV1 ....................................................................................... 29 The Sensation of Pain ............................................................................................. 29 o Pain in the Periphery - Nociception ....................................................................... 31 Subtypes of Primary Afferent Neurones of the Somatic Sensory System8 ............ 31 Capsaicin, an Exogenous Noxious Chemical Stimulus .......................................... 33 Early Vanilloid Pharmacology ................................................................... 34 Capsaicin and Sensory Neurones ............................................................................ 35 Nociceptor subtypes .................................................................................................36 Key Features of the Neuronal Membrane ............................................................... 37 Ion Pumps ................................................................................................................38 Ion Channels ............................................................................................................39 Generation and Propagation of the Action Potential63’64 ........................................ 40 Capsaicin, the Capsaicin Receptor and TRPV1 ...................................................... 42 The Transient Receptor Potential (TRP) Superfamily of Ion Channels .................44 Pain from the PNS to the CNS - Synaptic Transmission107 .................................... 47 Nociceptive Action of Capsaicin - Summarised ..................................................... 50 4 Pathological Pain .....................................................................................................50 Inflammatory Pain ...................................................................................................50 Neurogenic Inflammation ........................................................................................51 Peripheral Sensitisation ............................................................................................51 TRPV1 in Inflammatory Pain ..................................................................................52 TRPV1 and Noxious Heat .......................................................................................55 Pain in the CNS - Central Sensitisation ................................................................. 56 Secondary Hyperalgesia ................ 56 Wind-up ...................................................................................................................57 Neuropathic Pain ......................................................................................................57 Endogenous pain modulation and analgesia ........................................................... 58 Pain modulation - the Gate-Control Theory of Pain1,214 .......................................
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