IUPHAR 9TH INTERNATIONAL CONGRESS OF PHARMACOLOGY LONDON 1984 PROCEEDINGS IUPHAR 9TH INTERNATIONAL CONGRESS OF PHARMACOLOGY LONDON 1984 Under the Patronage of HRH The Duke of Edinburgh RG KT Sponsored by International Union of Pharmacology; British Pharmacological Society; The Royal Society PROCEEDINGS VOLUME 1 EDITORS Professor Sir William Paton Professor James Mitchell Professor Paul Turner Assistant Editors Cheryl Padgham Eileen Ashcroft ©The Macmillan Press Limited 1984 Softcover reprint of the hardcover 1st edition 1984 978-0-333-36887-9 All rights reserved. No reproduction,copy or transmission of this publication may be made without written permission. No paragraph of this publication may be reproduced,copied or transmittedsave with written permission or inaccordance with the provisions of the Copyright Act 1956(as amended). Any person who does any unauthorised act in relation to this publication may be liable to criminal prosecution and civilclaims for damages. First published 1984 Published by Scientific & Medical Division THE MACMILLAN PRESS LTD Houndmills, Basingstoke, Hampshire RG21 2XS and London Companies and representatives throughout the world ISBN978-0-333-37134-3 ISBN978-1-349-17613-7(eBook) DOI 10.1007/978-1-349-17613-7 IUPHAR 9th INTERNATIONAL CONGRESS OF PHARMACOLOGY LONDON 1984 INVITED PROGRAMME Volume One Monday 30July InvitedLectures L1 Localisation offunctional activityinthe central nervous system bymetabolic probes L. Sokoloff L2 Pharmacological approachesto neuropeptidefunction- Substance P L.L. Iversen L3 Neglectoffunctionand obsessionwithstructureintoxicity testing G.Zbinden IA Receptorlocalisation inasymmetric cells A.WoCuthbert L5 The Withering CommemorationLecture D.Noble Symposia Papers SI Modificationand turnoverofreceptors 1,3,50 S2 Beta-Iactam antibioticswithnovelnuclei 1-3,5,6. S3 Antiplateletand antithromboticdrugs 7. S4 Mechanismsofaction ofsmoothmusclerelaxants 1,3,4,6,8,9. S5 Insulinand insulin-likegrowth factors, receptorsandmediators 2. S6 Tissueselectivetoxicity 1,2,3,50 Tuesday 31July Invited Lectures L6 Molecular pharmacologyofsodiumchannel of mammalian brain W.A. Catterall L8 Dopaminergicnerves C. Bell L9 The problems ofextrapolatinglaboratorydatato manin teratology R. Jelinek Symposia Papers S7 Regulation ofadenylate cyclase 2-60 S8 Antiviral drugs 3-4,6-9. S9 Painmechanisms 1-60 Volume Two SlO Cardiacinotropicagents 1,5,8. Sll PhospholipaseA inhibitors 1,2,6,7,9. 2 S12 Repairand promotioninchemical carcinogenesis v Wednesday1August Invited Lectures L12 The role ofadrenalineinessential hypertensioninman M.J. Brown L13 Glutathioneand tissue toxicity S.Orrenius Symposia Papers S13 Analysisofdrug mechanisms bysingleionchannel recording 1. S14 Modemapproaches todrug design 1-4. S15 Novelantihypertensivedrugs 1-4,7. S16 Peptideeffectors and modulatorsofsecretion 1--6. S17 Amine oxidase enzymes and their inhibition 1-3,5,7-8. S18 Cellular injury caused byfree radicals 2--6. Thursday2 August Invited Lectures L14 Neuropeptideprecursorsand acetylcholine receptor: molecular structuresand gene expression S.Numa L15 Cancer chemotherapy:Examples ofcurrentprogress and future perspectives R.E. Handschumacher L16 Receptorsfor thromboxanesand prostaglandins R.L. Jones L17 Activationofcalmodulinbymetal cations andoccupancyofits metal binding sites W.Y. Cheung Symposia Papers S19 Drugs actingthrough calciumchannels 4,5,7,8. S20 Newstrategiesinanti-parasiticchemotherapy 1-7. VolumeThree S21 Endogenousprostanoidsinman 2--6. S22 Leukotrienesand otherlipoxygenase products 1--6. S23 Steroid receptors 2,3,5,7. S24 Modes ofaction ofantidepressivedrugs 1,3-7. Friday3 August Invited Lectures L21 Generationofdrug resistance bygene amplification R.T. Schimke Symposia Papers S25 GABA receptors 2-4,6-8. S26 Multiple forms ofdrug metabolising enzymes 1--6. S27 Salvageofthe ischaemic myocardium 1,5-7. S28 Peptidesasdrugs 2-5. S29 Interleukinsand othercytokines 1-3,5,7. S30 Gastrointestinalmucosal protection 2-7. vi CONTENTS OF VOLUME ONE Page Editorial: ProfessorPaul Turner Preface: Openingaddress by ProfessorSir Andrew Huxley,OM,PRS 1 Monday Invited Lectures Localisationof functional activityinthe central nervous system by metabolicprobes L. Sokoloff 9 Pharmacological approaches to neuropeptide function - SubstanceP L.L. Iversen 31 Neglect offunction and obsession with structure intoxicity testing G. Zbinden 43 Receptor localisation in asymmetric cells A.W. Cuthbert 51 The Withering Commemoration Lecture Withering's discovery and his modern scientificlegacy D.Noble 61 Symposium I Modification and turnoverofreceptors Introduction:Receptorsand receptor-mediated responses H. Yoshida 75 Axonal transportof receptors M.A. Zarbin and M.J. Kuhar 81 Mechanism of desensitizationof ~-adrenergic receptors J.P. Perkins and T. Kendall Harden 85 Symposium2 Beta-lactamantibiotics with novelnuclei ~-Lactam antibiotics with novel nuclei Francis O'Grady 93 Mechanisms of ~-lactamase action S.G. Waley, R.Bricknell, S.J. Cartwright and E.L. Emanuel 99 Thienamycin, imipenem and new membersof the carbapenen classof ~-lactam antibiotics F. Baker,L.D.Camia, E.G. Christensen, W.J. Leanza,D.H. Shih and K.J. Wildonger 105 Monobactams and othermonocylic ~-lactams D.P. Bonner,W.H. Koster and R.B.Sykes 111 Exploration of active sites of nn-peptidases J.M. Ghuysen 115 Symposium3 Antiplatelet and antithromboticdrugs The relative importanceof inositoll,4,5,-trisphosphate 1,2,-diacylglycerol and phosphatidicacid in mediating human plateletactivation bythrombin E.G. Lapetinaand S.P. Watson 127 vii Symposium4 Mechanisms ofaction ofsmooth musclerelaxants Cyclicnucleotidesin smooth muscle relaxation W.R. Kukovetz and S. Holzmann 135 Relaxation of vascularsmooth muscle byinhibitorsofcalmodulin and cyclicnucleotide dependent protein kinase HiroyoshiHidaka,Toshio Asano and Masaki Inagaki 143 Comparison ofendothelium-dependentrelaxation byacetylcholineand endothelium-independent relaxation bylightin the rabbit aorta Robert F. Furchgott, William Martin, DesingaraoJothianandan and Gina M. Villani 149 Non-adrenergic, non-cholinergicinhibitorymechanisms Anne Bowman 159 Mechanisms of coronaryvasodilationinduced byanti-anginal agents H. Kurigama, H. Suzuki, K. Kitamura,T.Itoh, E.Suematsu, H. Veno and Y. Kanmura 165 Activity of singlepotassium channelsrecordedfrom singleisolated visceral and vascularsmooth muscle cells T.B. Bolton, C.J. Benham, R.J. Lang and T. Takewaki 173 Symposium5 Insulinand insulin likegrowth factors, receptorsand mediators Insulin receptorstructure M.D. Baron 181 Symposium6 Tissue selectivetoxicity Introduction:Tissue selective toxicity J.R. Mitchell 191 Selective activation ofchemicals by the kidney:itsrelevance to toxicity and mutagenicity E.A. Lock and T. Green 197 Selective activation of carcinogensand othertoxicants bynasal mucosae AR. Dahl 203 Biochemicalselectivity in neurotoxicity J.E. Cremer 209 Tuesday Invited Lectures Molecular pharmacology of the sodium channel ofmammalian brain WilliamA Catterall, DonaldJ. Messner, Robert P. Hartshorne, David J. Feller, Jane A Talvenheimo, B. Keller and Mauricio Montal 219 Dopaminergicnerves C.Bell 231 The problems ofextrapolatinglaboratorydata to man in teratology R. Jelinek 245 Symposium7 Regulation ofadenylatecyclase Inhibitorymodulation ofadenylate cyclase K.H.Jakobs, K. Aktories,M. Minuth and G. Schultz 263 Chemical modification of nucleotide regulatory proteinscatalyzed by bacterial toxins M.Vi,T. Katada,T.Murayama and H. Kurose 271 YIll Structural and regulatory properties ofnucleotide bindingregulatoryN proteins of adenylatecyclaseand theireffectson hormone receptors L. Bimbaumer, J. Codina, R. Mattera, F.J. Rojas,J.D. Hildebrandt, W. Rosenthal and T. Sunyer 279 Guanine nucleotide-binding regulatoryproteins:afamilyofmembrane- bound transducers R.A. Kahn and A.G. Gilman 287 Purification,characterization and reconstitution ofthe adenylate cyclase- coupled ~-adrenergic receptor R.J. Lefkowitz, R.A. Cerione,J.L. Benovic,B.Strulovici, G.L. Stiles, J. Codina, L. Bimbaumer and M.G. Caron 293 Symposium8 Antiviraldrugs Enzymes asantiviral targets Y. Cheng, K. Bastow,K. Frank, L. Nutter, J.F. Chiou and S. Grill 301 Modes of action ofinterferon and analogues of2-5A, amediatorof interferon action E.De Clerq, J. Content, P. Defilippi, J. Balzarini, J. Warrinnier, H. Sawai, J. Imai, K. Lesiak, J.C.Jamoulle and P.T. Torrance 307 Pharmacological considerationsof antiviral agents W.H. Prusoff,T.S. Lin,S.A. Siegel, M.L. Zucker,W.F. BrubakerJor, and J.J. Lee 319 Clinicalexperience with antiviral drugs M. Eisenberg and T.e. Merigan 323 Controlofepidemicinfluenza virus: aspects ofvaccinesand antiviral compounds J.S. Oxford 331 Prospects for the future in antiviral chemotherapy P.Wildy 341 Symposium9 Painmechanisms Pain mechanisms H.W. Kosterlitz 349 Ontogeneticand phylogeneticinfluences on the expression ofpain K.D. Craig 351 Endorphins and the control ofpain; anatomical studies ofenkephalin and dynorphin A. Basbaum 359 Opioid peptides: endogenous analgesics? J.W. Lewis, H. Khachaturian, M.E. Lewisand H. Akil 367 Techniques of the managementofpain Bengt H. Sjolund 383 Pharmacological studies of acupuncture analgesia J.S. Han 387 Index 395 ix Editorial The publication of the Proceedings of a major international Congress such as the IUPHAR9thInternationalCongressofPharmacologyisanundertakingwhichrelies on the hardwork and co-operation ofalarge numberofpeople. The Editors wish to thank all those authors who have submitted papers for in clusion,andwho,byadheringtodeadlines,havehelped toensure the rapidpublica tion of the Proceedings. We believe that in providing full editorial correction and typesetting facilities at the Congress, the Publishers offered contributors a more convenientandefficientservice,whilstalsoensuringthatthepublicationtimeforthe Proceedings was kept to a minimum. We would like to thank the Organising and Scientific Committees for producing a well balanced and comprehensive programme, in wellordered and convivialsurroundings. We hope that the reader will find that this is reflected in the Proceedings Volumes, which offer an authoritative and up-to-date review ofPharmacologyin the 1980's. The Editors and Publishers wishto thank the Congress Secretariat and the Bar bican Centre for their assistance. Finally, I wish to thank those whose efforts contributed most to the efficient publication of these Proceedings: Vera Jones, for secretarial assistance; Cheryl Padgham and David and EileenAshcroft, for editorial and indexingwork;and my colleagues asEditors, ProfessorJames Mitchell and Professor SirWilliamPaton. Professor Paul Turner Executive Editor xi