Trends in Pharmacological Sciences November 1982 A. J. Clark: quantitative pharmacology and the receptor theory ‘The chair of pharmacology (or materia medica, as it was formerly called) at the University of Edinburgh has had along ind distinguished hisory'. The subject was originally combined with botany, but in 1768 the two fds were separated and an independent chair of materia medica was created. Since that tine the chair has been ‘occupied by a succession of eminent sci ‘ss, including Andrew Duncan (the author of the noted Edinburgh New Dispensat- ory), Rober Chrstson (a pioneer in the develosment of scicnlfic. toxicology), ‘Thomes Fraser (whase studies with Alex- ander Crum Brown on the relationship of pharmacological activity © chemical stuc- tre helped to open up that field of knew. ledge), Arthur Cushny (author of the English-language textbook of modem pharmacology), and A. J. Clark (the sab- ject this paper) ‘A.J. Clork was bor in Eogland in 1385, to a Quaker family. He was trained in physiology at Cambridge University in the petiod 1903-1907. There be received the broaa and excellent taining in physiology and experimental medicine that was charac- teristic ofthe Cambridge school of physiol- ‘ogy at that time. Even after entering the field of pharmacology, Clark wastoretin lifelong interest in physiology. as evie enced, for example, hy his researches on the metabolism of the frog's heart and by the publication of his book on the Com parative Physiology of the Heart in bis pharmacological researches, he made goo Use of his broad physiological education, Fig, Alfred Joseph Clark 1895-1045 (iy soanesy of DED. Ce focusing mueh of his attention dating cae on the mg of ation wf deugs pon the cell subject which he de the science of peneral pharmacelo Atter 2 sears of niedical staies at St Bartholomes's Hospital in Lordon, Clark returned Uo Cambridge for a seat % be house surgeon at Adkdenbroshe’s Hospi His inerest in pharmaco soem to have teen stimulated during ny Cambridge ears by. Walter Divon, whe ad been teaching there since the tn ofthe seotur, Dixon was one of the proneers of modem ‘experimental pharmacology in Britain, At his suggestion, Chirk studied the pressor action of tyramine in man, leine 69 fs first pharmacological publication mn 1980 ssfler another year at St Burelowiews Hospital ss house pty sian, Clath served fn turn as am assistn tm pharmacology Cusing. who 35 then, London. In TU, the year that he revived his Doctorate ut Medicine from Cambeidge University ‘Clark's career was interrupted by the cute break of the warin Europe: Afler 4 years of ative muitary service. fhe was made professor o: pharmacclogy at the University of Cape Town, South twa. when the war ended in 1918, Thefolowing yeat he returned co England 10 ~cept the chair of pharmacology at U Seraty College. Loran «postion wich faa ecome vacant when Cushny moved to Edinburgh tn 1926, upon the death of ‘Cushay Clark sain seceded him, inthe ir of pharmacology al the University of Elinbursh, a post which he held ntl his coun death in JOSH atthe ape of 55°. At the tine of his death he way deseribed by his succes. Join Gadde, a distinguished pharmaxollognt an his owe ight, as “the eating exponent of pharmacology im Great Britain" ‘One of Clark's most significant contribs swan b> phammacology, was probably his ‘enphasivon the importance of making a owe quantirive science, and be developed and applied concepts and tech- ‘ghee to help make its, This sotezes _yuusiticaton apparently developed cay ta Clark she, and tary aneedote relates that asa smal by he impressed is elders by making calculations ofthe cubic capre- sof Noak’y Atk and comparing with hat ‘oa pate of elephants" Such calculations held fascmatun for Clark. who in fer ears atempied to quantitatively deme Strate the absurdity of the homeopathic theory of potentiation of drugs through extreme dilution by calculating that a cmeds diluted to the 30h potency would Contam about ope mslecue of the active dug ma sphere ith ate erence equal tevth wba of Veuus® fi two genera teatses. The Mode of Acs of Drags” (publiste i 1933) snd General Pharmacology’ (published 1987) spstematized and evaluated an porous amount of pharmacological da, “qsantitying vherever possible, and helped te promt the adopuon of mare uniform siztbods. of expressing experimental revs. Thee impact on the Field of phar. ‘hacolngs hasbeen compared 1 the inf ence of Willams Bayles’ textbook on the fald of physiology ‘Crk was greatly terested inthe ques: thon of whet quantitative pharmaco gical ‘xpenment> could reveal about the fundi- tmental pole of how Crags at. Ht w38 thyowgh hs work that te dru receptor theory become finly established in phos macolegy ‘When Clark began his pharmacological ‘escanhes n about 1910 the question as hein debated as o whether or not chemical 2 physal itractions played more of « ‘olen deternining drug ation. The chemi- al view held that drugs generally acted by forming a chemical union with prot Plsic content ofthe el. This concep, ‘which evends hack ino the nineteenth cer ‘uty 2a general principle, had been sy ‘ematialy expressed inthe receptor theory Fig. 2. Clark photographed swrepinousy by a radon, whe ltr at Ebay cours SDE Clay developed by Paul Ehlich in Germany and John Newport Langley in England in the First decade of the twentieth century. Sup- Porters of the physical view argued, on the fther hand. that drugs generally donot combine chemically with protoplasmic constituents but exert their influence by altering the surface tension, electrolyt balance. osmotic pressure. and. other physicochemical propenies ofthe cel. The distinction between physical and chemical forces was drawn more rigily than it is voday. and phanmacologists and medicinal chemists tended to favor one or the other ‘appresch (Clark's publications inthe period 1912-1914, when he was working in the Iaboratories of Dixon and Custny. indicate that his own interest in the mechanism of drug action at a cellular level developed cearly inhis career. Inbis early papers. lark focused on the action of inorganic ions and ‘of the digitalis glycosides on the isolated heart. His experiments withthe glycoside sttophanthin indicated that this drug acted fon the heart without actually entering the heart cells. He concluded that it was likely ‘that "strophanthin acts by altering the physi- cal condition of the surface membranes of the cells, without entering into chemical combination with any of the cell con stituents". Later in bis career, he reversed his position and be: ame a strong advocate ‘of the receptor theo. (Clark's work was interrupted ot this time by the war, and itw:snot until had taken 1p his position at University College in 1919 that he was able to retum to his research. The pape that be published ia TIPS ~ November (982 the carly 1920s are essentially a continua tion of his eatlier work, and focused at ftst cn the effets of various ions on isolated organs and then later on the action of ‘ganic drugs such a ergot and adrenaline 1 vas the study of one of these drugs, acetylcholine, that apparenily ted Clark to ‘adopt the reeptor theory. Clack studied the quantitative selation- ship between concentration and action for acetylcboline and found that followed the formula Kx agp where x — concentration of the drug and y action produced. expressed in terms of percent of maxitaum action, ‘The simplest explanation for this equa- tion would be t assume that a reversible ‘monomolecular reaction occurs hetween ‘the drug and some receptor inthe cell. A similar type of curve, Clark pointed out had been observed for the dissociation of ‘oxyhemoglobin in dilute solution (i.e. for the reaction between oxygen and hemoglo- bin. Os + Hb #5 HbO:). Clark also observed that there was no ‘itect relationship between the amount of ‘the drug entering the cel andthe amount of action produced. Recall that when he ‘observed a similar phenomenon inthe case ‘of stophamhin a decade earlier, he used it asevidence agains! the ides that chemical reaction takes place between the drug and some constituent of the cell. Nov. howe ever. he suggested that such a reaction ‘might indced take place ifthe receptor were ‘onthe surface ofthe cell and not inside it In that case, the drug would not have to enter the cell in order t0 combine with the recep ‘With the aid of some clever calculations ‘volving assumptions about such things as the space occupied by an acetylcholine ‘molecule, Clark was able to convince himself thatthe drug did mot at by simply covering the surface of the cell, but that it specifically reacted with only selected por. tions of the cell surface, ie. the recep- tors, But this evidence, however suggestive, vwas of a rather tenuous nature, Clark real. raed that the level of exactness in phat- rmacological data was sufficiently low that ‘one had to be careful in drawing conclu. sions simply on the basis of iting data to ‘mathematical formulae. He warned his col Jeagues about this point a number of times inhis writings. “The fact thatthe assumption of a mono. ‘molecular reaction between the drug and a receptor on te cell would explain the curve ‘obtained forthe action of acetylcholine was ‘notin itself proof that such a reaction takes place. When Clark developed his version ofTIPS ~ November 1982 the receptor theory more fully in his book (on the Mode of Action of Drugs (1933). fhe amassed other evidence to support his views. It was extremely important to aim that an explanation of drag action be based cn a plausible physico-chemical model. ‘There was no point, be stated, in fing curves to a formula that did not expresss some possible physico-chemical process, (Clark built his model ofthe mechanism ‘of drug action on information from various Fields. He felt, forexample, that the process of catalysis provided an ‘analog for the ‘receptor concept. Recent studies of catalysis had shown that the surface of @ ‘contact catalyst was not uniform, but con- {tained certain ‘active patches’ which covered only a small part ofthe surface area and were responsible forthe activity of the catalyst. These catalysts often selectively absorbed specific substances, and Clark argued that active panicles’ on the cell sur- {ace might similarly be responsible for adsorption of specif: drugs. He also related his receptor concept to recent biochemical evidence which sug ested that cellular oxidation occurred at specific centers the cell surface and that the activity of certain large enzyme ‘molecules, such us urease, depended upon esr recep. n, he saw the cveptor von ‘cept a iting well within the picture of the cel: ceing developed by Rudolf Peters) as ax orpanized network of protein molecules. forming 2 three.dimensional mosaic ‘extending throughout the cell, Finally. he pointed out the similarity ofthe concentra jon-action curve obtained for drugs like acctyleholine to Langmui’s adsorption Clark twok the speculative and qualita. tive receptor concept of Ehrlich and Lang- ley and refined and developed tothe point where it became widely accepted and generally useful concept in pharmacology. 2 concept that stimulated a great deal of research and which sill, in general culine if not in detail, forms the basis of much ot ‘theoretical pharmacology today Acknowledgements, ‘An eater version of this paper was elivered at the XVth International Con {gress of the History of Science, Edinburgh Scotland, August 1977. The research was 43 ‘Supported by grants trom the National Soi. ‘ence Foundation (GS-41462) and the Unie veruty of Wisconsin Graduate Schoo! JON PARASC ANDO 8 Seta of Pharma. 12S Sette «bare Stee Madon. 1 St700, OS Reading list Galan. 1 119620 Yo0w Re. hare reise 2 Nemes, FR UMEL he Sor fl 8 um. HO US4 harman ap Gatun 3 M9819 Naar Ho SC ADSI) he Mode of fawn of Dragon Cols st Ars ean AS 197) Geral dod Spee. Ben 7 Purscanla 1197) Phar tH. 10, S03 SGuALAT COMM Phares fap Ter WW Chek (IS2TIY Pina 12K IAT John Prasat» Priest} the Hoss Parma unl Hate uf Saree [ant fp Wigenown Madson, He sanrnt mkine#) {Psd wf lob Fhe an te slp ‘wnora parnar Adenosine symposium The second Intemational Symposium on Adenosine was held at the University of Virginia. Charewtesvill, from 7 10 11 June 1982. The mecting was organized by R. M Beme, R. Rubio and T. W. Rall from the host institution and E. Gerlach and J Schrader from Munich ‘The week's plan was fora series of le: tures delivered by svited speakers, pre- sented curing the n.omings and evenings, with afternoons free for informal discus. sion, visits 10 local areas of interest and the warm hospitality of the hosts. Receptors "The opening session on adenosine recep. tors began with an overview of adenylate seyelase structure by M.— Rodbell (Bethesda). It was propesed that in view of the limited number of eyclase components which have been demonstrated, the various classes and substypes of recepvors described ppharmacologically could be due no only to the presence of different receptor com. ‘ponents but also to the nature ofthe reyulat- ‘ory and catalytic components to which they are coupled. A loose coupling between receptor components could account for any of the reported interactions between compounds on cyclase activation, CC. Londos (Bethesda) then specitially addressed the question of adenosine evep- tors linked to eyclase. Although he mod eslly indicated thatthe As/As clansitiation of Van Calker's group might be preferable Purine receptors (requiring aa unchanged ‘The R site (equi ‘locked by methybzanhies the Ri and Rass respectively. References Thyce types of clasifcatio are cuca in use for porine recepors |G) PIR. Proposed by Loads and Wolf, his i a biochemical | Purine riety) is inracellar and inhibits adenylate cyclase. | ‘Ribose moiety) has now been subdivided into Ra | (pctivating cycle) and Ri Gahibiing cyclase) components. Eihylerboramide adenosine sopropyladenosine tw the Ra-and Ri system prpised by Le an Woo sae app s 1 Spmiponium thst each Broup of We Keshav adepedione crete and feluctan tochunge. Indeed. the que-twn ot sesolving the problem of receptor nomen lature arose several times during the fut there seemed t0 be no changing the status go. They are: (POP. Prope by Bors hist ncn clithatin; o examle, ‘renounce mapanes Te eer stacy ats ATP nd 2) | ATP adesoane Only te Pie nce by methane: ce Bop ‘he P sie at Ra ses and vice versa for Ri. The Res ae Gii)AW An. Independently proposed by VanCalkeret a" thse receplorsae equivaleat1o ‘Moe detail maybe found in receatreviews*®, 1 Burnstock, G.(1978)ia Cell membrane receptors for Drugsand Hormones (Siw. [RW and Bois Leds), pp. 107-118, Raven Press, N.Y. 2 Lows, C: and Weill J. (1977) Proc: Nat! Acad. Sct. U.S.A. 74, 482-5480 3 Van Calter, D., Muller, M. and Hamprecht, B. (1979)J. Neurochem. 33 we | 4 Stone, T. W. (1981) Newoscience 6, 523-555 15 Stone. T. W. (1982) Biosci. Rep. 2.77-90