Table Of ContentScience,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
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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
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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
