A Short History of the Drug Receptor Concept PDF
Preview A Short History of the Drug Receptor Concept
Science,TechnologyandMedicineinModernHistory GeneralEditor:JohnV.Pickstone,CentrefortheHistoryofScience,Technology andMedicine,UniversityofManchester,England(www.man.ac.uk/CHSTM). Onepurposeofhistoricalwritingistoilluminatethepresent.Atthestartofthe thirdmillennium,science,technologyandmedicineareenormouslyimportant, yettheirdevelopmentislittlestudied. The reasons for this failure are as obvious as they are regrettable. Education in manycountries, notleastinBritain, drawsdeepdivisionsbetweenthesciences andthehumanities.Menandwomenwhohavebeentrainedinsciencehavetoo oftenbeentrainedawayfromhistory, orfromanysustainedreflectiononhow societieswork.Thoseeducatedinhistoricalorsocialstudieshaveusuallylearned solittleofsciencethattheyremainthereaftersuspicious,overawed,orboth. Suchadiagnosisisbynomeansnovel,norisitparticularlyoriginaltosuggestthat goodhistoricalstudiesofsciencemaybepeculiarlyimportantforunderstanding our present. Indeed this series could be seen as extending research undertaken overthelasthalf-century.Butmuchofthatworkhastreatedscience,technology andmedicineseparately; thisseriesaimstodrawthemtogether, partlybecause the three activities have become ever more intertwined. This breadth of focus and the stress on the relationships of knowledge and practice are particularly appropriateinaserieswhichwillconcentrateonmodernhistoryandonindus- trialsocieties. Furthermore, whilemuchoftheexistinghistoricalscholarshipis onAmericantopics,thisseriesaimstobeinternational,encouragingstudieson Europeanmaterial.Theintentionistopresentscience,technologyandmedicine as aspects of modern culture, analysing their economic, social and political aspects,butnotneglectingtheexpertcontentwhichtendstodistancethemfrom otheraspectsofhistory.Thebookswillinvestigatetheusesandconsequencesof technicalknowledge,andhowitwasshapedwithinparticulareconomic,social andpoliticalstructures. Such analyses should contribute to discussions of present dilemmas and to assessments of policy. ‘Science’ no longer appears to us as a triumphant agent of Enlightenment, breaking the shackles of tradition, enabling command over nature. Butneitherisittobeseenasmerelyoppressiveanddangerous. Judge- mentrequiresinformationandcarefulanalysis,justasintelligentpolicy-making requiresacommunityofdiscoursebetweenmenandwomentrainedintechnical specialitiesandthosewhoarenot. Thisseriesisintendedtosupplyanalysisandtostimulatedebate.Opinionswill varybetweenauthors;weclaimonlythatthebooksarebasedonsearchinghis- torical study of topics which are important, not least because they cut across conventional academic boundaries. They should appeal not just to historians, norjusttoscientists, engineersanddoctors, buttoallwhosharetheviewthat science,technologyandmedicinearefartooimportanttobeleftoutofhistory. Titlesinclude: JulieAnderson,FrancisNearyandJohnV.Pickstone SURGEONS,MANUFACTURERSANDPATIENTS ATransatlanticHistoryofTotalHipReplacement RobertaE.Bivins ACUPUNCTURE,EXPERTISEANDCROSS-CULTURALMEDICINE RogerCooter SURGERYANDSOCIETYINPEACEANDWAR OrthopaedicsandtheOrganizationofModernMedicine,1880–1948 Jean-PaulGaudillièreandIlanaLöwy(editors) THEINVISIBLEINDUSTRIALIST ManufactureandtheConstructionofScientificKnowledge AyeshaNathoo HEARTSEXPOSED TransplantsandtheMediain1960sBritain NeilPembertonandMichaelWorboys MADDOGSANDENGLISHMEN RabiesinBritain,1830–2000 Cay-RüdigerPrüll,Andreas-HolgerMaehleandRobertFrancisHalliwell ASHORTHISTORYOFTHEDRUGRECEPTORCONCEPT ThomasSchlich SURGERY,SCIENCEANDINDUSTRY ARevolutioninFractureCare,1950s–1990s EveSeguin(editor) INFECTIOUSPROCESSES Knowledge,DiscourseandthePoliticsofPrions CrosbieSmithandJonAgar(editors) MAKINGSPACEFORSCIENCE TerritorialThemesintheShapingofKnowledge StephanieJ.Snow OPERATIONSWITHOUTPAIN ThePracticeandScienceofAnaesthesiainVictorianBritain CarstenTimmermannandJulieAnderson(editors) DEVICESANDDESIGNS MedicalTechnologiesinHistoricalPerspective Science,TechnologyandMedicineinModernHistory SeriesStandingOrderISBN978–0–333–71492–8hardcover SeriesStandingOrderISBN978–0–333–80340–0paperback (outsideNorthAmericaonly) Youcanreceivefuturetitlesinthisseriesastheyarepublishedbyplacingastand- ingorder.Pleasecontactyourbookselleror,incaseofdifficulty,writetousatthe addressbelowwithyournameandaddress,thetitleoftheseriesandoneofthe ISBNsquotedabove. Customer Services Department, Macmillan Distribution Ltd, Houndmills, Basingstoke,HampshireRG216XS,England A Short History of the Drug Receptor Concept Cay-Rüdiger Prüll Albert-Ludwigs-UniversitätFreiburg,Germany Andreas-Holger Maehle DurhamUniversity,UK Robert Francis Halliwell UniversityofthePacific,USA ©Cay-RüdigerPrüll,Andreas-HolgerMaehle,RobertFrancisHalliwell2009 Softcover reprint of the hardcover 1st edition 2009 Allrightsreserved.Noreproduction,copyortransmissionofthis publicationmaybemadewithoutwrittenpermission. Noportionofthispublicationmaybereproduced,copiedortransmitted savewithwrittenpermissionorinaccordancewiththeprovisionsofthe Copyright,DesignsandPatentsAct1988,orunderthetermsofanylicence permittinglimitedcopyingissuedbytheCopyrightLicensingAgency, SaffronHouse,6–10KirbyStreet,LondonEC1N8TS. Anypersonwhodoesanyunauthorizedactinrelationtothispublication maybeliabletocriminalprosecutionandcivilclaimsfordamages. Theauthorshaveassertedtheirrightstobeidentifiedastheauthorsof thisworkinaccordancewiththeCopyright,DesignsandPatentsAct1988. Firstpublished2009by PALGRAVEMACMILLAN PalgraveMacmillanintheUKisanimprintofMacmillanPublishersLimited, registeredinEngland,companynumber785998,ofHoundmills,Basingstoke, HampshireRG216XS. PalgraveMacmillanintheUSisadivisionofStMartin’sPressLLC, 175FifthAvenue,NewYork,NY10010. PalgraveMacmillanistheglobalacademicimprintoftheabovecompanies andhascompaniesandrepresentativesthroughouttheworld. Palgrave®andMacmillan®areregisteredtrademarksintheUnitedStates, theUnitedKingdom,Europeandothercountries ISBN 978-1-349-36377-3 ISBN 978-0-230-58374-0 (eBook) DOI 10.1007/978-0-230-58374-0 Thisbookisprintedonpapersuitableforrecyclingandmadefromfully managedandsustainedforestsources.Logging,pulpingandmanufacturing processesareexpectedtoconformtotheenvironmentalregulationsofthe countryoforigin. AcataloguerecordforthisbookisavailablefromtheBritishLibrary. LibraryofCongressCataloging-in-PublicationData Prüll,Cay-Rüdiger. Ashorthistoryofthedrugreceptorconcept/Cay-RüdigerPrüll, Andreas-HolgerMaehle,RobertFrancisHalliwell. p.cm.–(Science,technology,andmedicineinmodern history) Includesbibliographicalreferencesandindex. (alk.paper) 1.Drugreceptors–History.I.Maehle,Andreas-Holger,1957–II. Halliwell,RobertFrancis,1957–III.Title.IV.Series. [DNLM:1.Receptors,Drug–history.2.BiomedicalResearch– history.3.History,19thCentury.4.History,20thCentury. 5.Pharmacology–history.QV11.1P971s2008] RM301.41.P782008 615’.7–dc22 2008030447 Transferred to digital printing in 2009. Contents Preface vi Introduction 1 1. PaulEhrlichandhisReceptorConcept 16 2. TheDevelopmentoftheConceptofDrugReceptorsin thePhysiologicalResearchofJohnNewportLangley 41 3. ReceptorsandScientificPharmacologyI:Criticsof theReceptorIdeaandAlternativeTheoriesof DrugAction,c.1905–35 64 4. ReceptorsandScientificPharmacologyII:Criticsof theReceptorIdeaandAlternativeResearchStrands: theTransmitterTheory,c.1905–35 93 5. QuantitativeArgumentsfortheExistenceof DrugReceptorsandtheDevelopmentof theReceptorOccupancyTheory,c.1910–60 107 6. TheDualAdrenalinReceptorTheoryof RaymondP.Ahlquist(1914–83)anditsApplicationin DrugDevelopmentbetween1950and1970 125 7. TheEmergenceofMolecularPharmacology 146 Conclusions 158 Notes 166 ArchivalSources 195 Bibliography 198 Index 232 v Preface In historical studies such as the present one, the research becomes a ‘social event’ – not simply a critique of archival sources at an office or labdesk.Rather,thecharacterofthequestionsposedandthesubsequent interpretation and discussion of results with colleagues make scientific research a social endeavour. Our work on the history of the receptor conceptwasnoexception. In addition to many enthusiastic discussions in our own research group,wehadmanywonderfulscholarlyconversationsandexchanges withresearchersatcongresses,workshopsandseminars.Allofthesepeo- ple, friends and colleagues, contributed in some respect to our work through their helpful suggestions and comments on our project. As is often the case, many of these influences are not easily retraceable, but they do leave their mark somewhere in this work and we first wish to acknowledgetheseunnamedcolleagues. Intheparagraphsbelowwealsoidentifyandacknowledgethosewho helped us in various ways to conduct this project. At the outset we received a Wellcome Trust Project Grant (History of Medicine Project Grant061819)toenableourstudyandwearemuchindebtedtotheTrust forsponsoringthisresearch.Additionalfinancialsupportcamethrougha WellcomeTrustEnhancementAward,andthroughgrantsfromtheRock- efellerArchiveCenterandtheGlaxoSmithKlineFoundationtocarryout researchonPaulEhrlichandRaymondP.Ahlquist. We would also like to express our gratitude to the librarians and archivistsofDurham,NewcastleandCambridgeUniversityLibraries,the Archive of the Stiftung Preussischer Kulturbesitz in Berlin Dahlem, the ArchiveoftheHumboldt-UniversityinBerlinandabovealltheContem- porary Medical Archive Centre at the Wellcome Library in London for theirhelpandsupport.Furthermore,wearegratefultoMarileeS.Cree- lan,HeadoftheCollectionServicesoftheRobertB.GreenblattLibrary oftheMedicalSchoolofGeorgiaatAugusta,Georgia,andtoDavidSta- pleton, Director of the Rockefeller Archive Center at Tarrytown, New York, who was especially helpful in our research on Paul Ehrlich, as were Professor Fritz Soergel, Head of the Institute for Biomedical and Pharmaceutical Research in Nuremberg-Heroldsberg and Hans Schade- waldt,ProfessorEmeritusoftheInstitutefortheHistoryofMedicineat DüsseldorfUniversity. vi Preface vii Fritz Lembeck, Professor Emeritus of Pharmacology at the University of Graz, and Klaus Starke, Professor Emeritus of Pharmacology at the UniversityofFreiburg,bothgaveimportantinformationonOttoLoewi andWaltherStraub.DavidHazelClark,Cambridge,providedkeyinfor- mation on his father, Alfred Joseph Clark. The chapter on the work of Raymond P. Ahlquist relies very much on interviews with Richard E. White PhD, former student of Ahlquist, now Associate Professor of theDepartmentofPharmacologyandToxicologyattheMedicalCollege of Georgia, Augusta; Lois T. Ellison, MD, Medical Historian in Resi- dence, Provost Emeritus, Professor Emeritus of Medicine and Surgery, formerly Director of the Cardiopulmonary Lab of the Medical College of Georgia, Augusta; the late Armand M. Karow, PhD, Assistant Profes- sorsince1968andAssociateProfessoratthePharmacologyDepartment since 1971; and Jerry J. Buccafusco, since 1979 assistant at the Depart- ment, currently Director of the Alzheimer’s Research Centre, Professor of Pharmacology and Toxicology, Professor of Psychiatry and Health Behavior, Medical College of Georgia, Augusta. We are grateful for the materialsaswellastheinformationtheyallprovided.Concerningthese interviews, we are especially indebted to Lowell Greenbaum, the suc- cessor of Ahlquist in the Chair of Pharmacology and Toxicology at the Medical School of Georgia, and his wife Gloria, who established the contactswiththeintervieweesandalsosupplieduswithmaterialsand personalreminiscencesonAhlquist.Thankstoallofthemandalsotothe Nobel Laureate Professor Sir James Black for additional information on Ahlquist’swork. Also, we express our thanks to the research group of Judy Slinn at Oxford Brookes University for valuable comments on the trends in pharmacologyoverthetwentiethcentury.TillyTansey,WellcomeTrust Centre for the History of Medicine at University College London, sup- ported our research in London and contributed, with her expertise, to ourworkontheNobelLaureateSirHenryHallettDale. The last decisive steps in preparing this book were supported by VivianeQuirke,OxfordBrookesUniversity,andJohnParascandola,for- mer President of the American Association for the History of Medicine and an internationally recognized expert on the history of pharma- cology, who read the manuscript and delivered important advice and help. Thanks are also due to Danny Knapp and Katherine Smith for checking the language and also Elisabeth Ahner for her work on style and layout. Last but not least, we would like to express our gratitude to John Pickstone, editor of the series, for his support and advice, and Michael Strang, Ruth Ireland and Barbara Slater from Palgrave viii Preface Macmillan,fortheirkindcooperationinpublishingtheoutcomeofall theseefforts. C.-R.PRÜLL(FREIBURG), A.-H.MAEHLE(DURHAM), R.F.HALLIWELL(CALIFORNIA) OCTOBER2008 Introduction Generally speaking, until really quite recently – well into the 20th century in fact – treatment by most available medicines was at best only marginally beneficial and at worst positively harmful. (WilliamC.Bowman,1999) This book deals with the concept of receptors – a fundamental idea in science and medicine. Receptors are defined as proteins at the cell sur- faceandwithincellsthatmediatetheeffectofchemicalmessengersand hormones and the actions of many drugs in the body.1 Although this conceptisapproximately100yearsold, itwasnotuntilthe1960sthat itbecamefullyacceptedandexploitedinthescientificcommunity. Thereceptorconceptisoneofthoseideasinbiomedicalscienceswhich has had a great impact. Humans have utilized plant and other natural extractsasmedicinestoalleviatepainandillnessformillennia.Yet,Sir Henry Dale, as a young medical student at the turn of the twentieth century, coulddescribehisgreatdisappointmentwhenherealizedjust how few (perhaps fewer than 20) useful drugs were available to him, and how little was known about how even the effective ones worked.2 Manyofthesedrugs,suchasamylnitrite,atropine,digitalis,ephedrine, cocaine,morphine,physostigmine,quinineandsalicylates,wereinfact ofancientorigin. Sinceitsintroduction, theconceptofreceptorshasservedasascien- tific basis for understanding how such drugs act in the body and has providedasignificantimpetustothedevelopmentofnewdrugstotar- get these receptors. This fits the argument, as proposed by Drews, that drugresearchhascontributedmoretotheprogressofmedicineduring thepastcenturythananyotherscientificfactor.3Now,atthebeginning 1
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