A. J. Clark: quantitative pharmacology and the receptor theory

Trends in Pharmacological Sciences November 1982

:

lar

quantitative pharmacolog the receptor th The &air of pharmacology (or mate#ria medica, as it was formerly called) at the University of Edinburgh has had a long and distinguished history’. The subject was originally

combined

with botany,

but in

1768 the two t’ieids were separated and an independent chair of materia medica was created. Since that tinie the chair has been

lifelong

intereAt in physiology.

as evi-

denced, for example, by his researches on the metabolism of the frog’s heart _md bj the publication of his book on the I omr-

pamfive t’hysiobgy

of the

Hem.

In hi\

pharmacological researches. he made go4 use of his broad physiological education.

occupied by a succesSIon of eminent s&ntists, including Andrew Duncan (the author of the noted Edinbuqk New Dispemator)?), Robert Christison (a pioneer in Ithe development

of

scientific

toxicology),

Thomas Fraser (whose studies with Alttxander Crum Brown on the relationship of pharmacologica! activity to chemical structure helped IO open up that field of knewledge), Arthur Cushny (author of the fint Englishlanguage

textbook

of

modern

pharmacology), and A. J. Clark (the sub ject of this paper). A. J. Clark was. born in England in to a Quaker

family.

i 385

He was trained

in

physiology at Cambridge University in the period 1903-1907. Thenz he. received the broad and excellent training in physiology and experimental medicine that was characteristic of the Cambridge school of physiology at that time. Even after entering the field of pharmacology, Clark was to retain a

Fig, 1. Alfrrdlosrph Clark 1885~1~41 (by courresyof Dr D. C‘lark).

~1~ll1~1~1ng year he returned to I%gland to .~ccefrttfte chair oi pharmacology al Unirer\rty (‘oficgc. London. u position which frad become vacant when C uskn) moved to f:dinhurgh. In 1926. upon the death of Cushnv_I‘isr4 againsucceededhim, in tfte chair of’ pfrarmacology bitthe University of I3niinhurgh.a post which hc held until his r,wn &ath in 1941 at the age of 55’ -‘. At the ttmeof f&death he aa~described by his ~ucce~.sor.John Gaddum. a distinguished pharrnacoiogtrt un hrs own right. as ‘tfte icadltrgO.pNtent Of PharmaLX~lolJy tn Grc at Brttain’J. 6RN oiCiark’s mo\t ~rgniiicantconfriburrons to pharmacofogy. was probably ftis empha\r\ on the imprrtancc of making r! a nurre quantttativc *4encc, and he dc~clopcd and appiic.f concepts and technryur. to help make it vr. This interest in ~u~n!ttica~rrn apparently developed erfy rn(‘lark5 hi,-. and a Lrm~fyanecdotereia:es tfrat as a +mali fury he impressed his elders hi maktng cafcuiat¶ot&of the cubic cap& rty of 34o3haArk an~cffrn~~n~ it with that of a pan of elephants’ Such calculations beld a faumat~m for Clark. wfto in later year* attempted to quantitatively dernonrrate tire absurdity of fir ~~~~ic thcerry of ~enfiafion of drugs through rxtreme dilution by caictdatittg tfrat a rerakcdydduted in the 36th potency would ~t~fltamdihoufone m0iecuie of the active drug in a +ere with a &cr intfcrenceequal ur r& itmn Of VenU<‘ Hi’l two general treatl5eL Thp Mode of 44 rlorr of I)rugs” t puhlisbed in I933) and (;rrtrrul f’burmaco+$ (published in fV.371 s~)srematized and evaluated an cnomu~uia~mourrt cripfrarmacolog:caldata. quanntymg vherever possible. and helped 14~promote tire adoptron of more uniform irretbrrd.5 of expressrng experimenta re*uftr. Their impact on the tiefd of pharmacoiog~ b% been compared to tire inffuencc of William Bayfiss’ textbook on the fiefd of phy~ofogy~
lhc fady i’fl?(h are eSsent~affya chanting[ion of his earlier work. and i&used at first on the ei’fects of various ions on isolated organs and then later on the action of organic drugs such as ergot and adrenaline. It was the study of one of these drugs. acetyichofine. that apparently fed Clark to adopt the receptor theory. Clark studied the quimtitative relationship between c~~ncentrati~?n and action for acetylchohneand f&rnd that it followed the formula

developed by Paul Efulich in Germany and John Newport Langley in England in the Brst decade of the twentieth century. Sup porters of the physical view argued. on the other hand. that drugs generally do not combine chemically with protoplasmic constituents but exert their influence by altering tfte surface tension. efectrofytic balance. osmotic pressure. and other pftysicocfremicafpropertiesof the cell. The distinction between physical and chemical forces uds drawn more rigidly than it is soday. and pha~acologj5ts and rnedicinaf chemists tended to favor one or the other npproach’. Clark’s publications in the period fYf2-1914. when he was working in the laboratories of Dixon and Cusftny, indicate that his own interest in tfte mechanism of drug action at a cellular level developed early in ftis career. In his early papers, Clark focused on the action of incrgmrc ions and of the dipitaiis gfycosides on the &fated heart. His experiments with the giycoside stropftanthia indicated that this drug acted on the fteart without actually entering the bean cefis. He concluded that it was likely that ‘strophanfhinacts by altering rhe physicaf condition of the surface membranes of the cells, witftout entering into chemical combination with any of the cell constituents’*. Later in his career, he reversed his position and be ante a strong advocate of tfx receptor tfteo,ty. Clart’s work wan interrupted QI this time by the war. and it wi,s not until AZhad taken up fds position at tittiversity College in I%9 that he was abfe to return to his research. The paI&‘s that he published in

wftere x - _{~ncentrati(~n oi’the drug and y = action produced, expressed in terms of percentof maximum action. The simplest e:rpianation tor this eyuation would be to assume that a reversible ~~~rnol~ular reaction occurs between the drug and some receptor in the cell. A similar type of curve, Clark pointed out, had been observed for the dissocrationof oxyhemoglobin in dilute solution (i.e. for tfte reaction between oxygen and ftemogfa bin. 02 + Hb t HbOl). Clark also observed that there was no direct relationship between the amount of tfte drug entering tfte cell and tfte amount of action produced. Recall that when he observeda similar phenomenonin the case of strophanthina decade earlier. he used it as evidence against the idea that a chemical reaction takes place between the drug and some constituent of the cell. 1vow. however. he suggested that such a reaction might indeed take place if me receptorwere on tftesurface of the cell and not inside it. In that case. the drug would not have to enter the cell in order to combine with the recep tor. With the aid of some clever calculations involving assumptionsabout such things as tfte space occupied by an acetyichofine molecule, Clark was abfe to convince himself that tfte drug did not act by simply covering the surface of the cell, but that it specifically reacted with only selectedportions of the cell surface, i.e. the recep tors*.10 But this evidence, however suggestive, was of a rather tenuous nature. Clark reairzed that the level of exactness in pharmarrofogicaidata was sufficiently iow that one had to be careful in drawing concfusions simply on the basis of fitting data to mathematical formulae. He warned his cofleagues about this point a number of times in his writings. Tfte fact that the assumptionof a monomolecular reaction between the drug and a receptoron the ceil would explain tftecurve obtained for tfre action of ace~fc~fine was not in itself proof that such a reaction takes place. When Clark developed his versionof

the rcsepmr theory more fully in his book

on the Mo&

uf At-rim of Lhgs (1933).

hc amassed orher evidcncc IO support his

views. It was extremely iinportant to nim that an explanation of dtug action be based on a plausible physic*chemical model. There was no poinl, 5e stated, in fitting cu:ves to a fomiula that did not expresss some possible physictrchemical process. Clark built his model of the mechanism of drug action on information from various

fields. He felt, forexample, that the prcKess of catalysis provided an analog for the receptor concept. Recent studies of caralysis had shown that the surface oi a contact catalvst was not uniform. but conlained cer&n ‘active patches’ which covered only a small part of the surface area and were responsiblefor the activity of the catalyst. These catalysts often selectively absorbed specific subsiances. and Clark argued that ‘active particles’ on the cell surface might similar11 be responsible for th.s adsorptionof specific drugs. He also related his receptor concept to recent biochemical evidence which suggested that cellular oxidation occurred al specific centers on the cell surface and that

the

aclivily

of

certain

large

cnL>me

molecules, such as ureaae. depended upon the presence of a few active U~L’S or recep tors. In addirion. he saw the receptor concepr as lining well within the puztureof the ccl; [bring developed by Rudolf Peters) ah an orpxnized network of protein molecules. formmg a three-dimensional mosarc extending throughout the cell. Finally. he pointed alit the similarity of the concentracurve obtained for drugs like ao:tylcholine to Langmuir’s adsorption curve”. Clark took the 5pectJative and qualitatikc receptor concept of Ehrlich and Langley and refined and developed it to the point where tt became a widely accepted and generally useful concept in pharmacology. a concept that stimulated a great deal of research and which still, in general outline tion-action

if not in detail. forms the basis of much of theoretical pharmacology today.

Acknowledgements An earlier

version

of this paper ua\

delivered at the XVth International Congress of the History of Science, Edinburgh,

Scotland, August 197’7. The research was

to the Ra and RI s!bt~m prc%p)hed h> Lnndos and U’ooli II became appa’enr during the s).rnpj~lum rhst r’dch group
1I

June

1982. The meeting was organized by R M Beme. FL. Rublo and T. W. Rail from the host inrtitution and E. Gerfach and J. Schradelr from Munich. The week’s plan was for a ,,eries of lectures delivered

by invited speakers,

pre

scnted during the n.omings and evenings. with afternoons free for informal

discus

sion. visits to local areas of inrerest and the warm hospitality of the hoers.

Receptors The opening

session on adenosine re~zep.

ton; began with an overview cyclase

structure

by

of adenylatr M.

Rodbell

(Bethesda). It was proposed that in \ lew of the limned number of ,cyclase components which have been demonstra&,

the various

classes and sub-types osfreceptors described pharmacologically

could be due not only to

the presence of different

receptor

com-

ponents but also to the nature of the rcgulatory and catalytic complonems to whit h they are coupled. A loox couplin,g between receptor

components

could

account

for

many of rhe reported interacrions ktuerlx compounds on cyclasr activation. C. Londos (Bethesda) then spesiticallb

arrs has adoprrd one cr other \.#rn ;rnJ 15 reluctant IO change. Indeed. the qju+tz<)n {,I ~e\ol\ing the problem of receptor ntmxn-

addressed the question of adenosine recrp tars linked m cyclase. Although he mod-

clature arose sexrat

estly indicated that the AI/&

changmp thesrurw I!UO. l.nndo+ also \upge!ted IhaL the dnt.l$\ln-

of Van Calkeis

classiricsrion

group might be preferable

but {here xemcd

times durmg the \rcek

to hc no enrhu~IJ.*m ((Jr