A receptive audience
However, the interwar period had also brought two important supporters of Langley's theory of receptive substances and of receptor theory more generally on the scene. Alfred Joseph Clark (1885–1941), who succeeded Cushny in the chair at UCL in 1920 and again, after Cushny's death in 1926, in the Edinburgh chair of Materia Medica; and John Henry Gaddum (1900–1965), who became professor of pharmacology at UCL in 1935. Both Clark and Gaddum had been students of Langley in Cambridge.
Based on quantitative dose-effect studies with the transmitter substance acetylcholine, Clark suggested the so-called receptor occupancy theory. According to this theory the intensity of the pharmacological effect of a substance was directly proportional to the number of cell receptors occupied by the substance [21]. Gaddum, working on the dose-effect relations of adrenalin and ergotamine elucidated the competitive antagonism between two substances at receptors and introduced the notion of receptor blockage by the antagonistic substance [22]. Clark publicly attacked Straub over his physical potential-poison theory, saying at a meeting of the Royal Society in London in 1936 that it assumed processes that were unknown in physical chemistry [23].
Despite such support and development of the receptor concept, the critics remained vocal. Important was the position of Sir Henry Dale, who was awarded the Nobel Prize for his neurotransmitter research in 1936. Dale was much more interested in the transmitter substances in the nervous system than in their potential receptors. As late as 1943, at a conference of the Faraday Society in London, he called the worth of the receptor concept for explaining specific drug action into question:It is a mere statement of fact to say that the action of adrenaline picks out certain such effector-cells and leaves others unaffected; it is a simple deduction that the affected cells have a special affinity of some kind for adrenaline; but I doubt whether the attribution to such cells of “adrenaline-receptors” does more than re-state this deduction in another form[24].
When, 5 years later, the American pharmacologist Raymond P. Ahlquist (1914–1983) proposed the existence of two types of adrenaline-receptors, alpha and beta, mediating different patterns of pharmacological action, his paper on this topic was rejected by the Journal of Pharmacology and Experimental Therapeutics. Through personal contacts with the editor of the American Journal of Physiology he eventually managed to get it published [25]. Ironically, Ahlquist's distinction between the two types of adrenaline-receptors became the basis for the development of the first therapeutically useful receptor blocking drug, the beta-blocker propranolol, which was introduced by (Sir) James Black in 1965. Only then did most pharmacologists start to believe that receptors were more than hypothetical entities, or as de Jongh had called them, ‘beautiful but remote ladies’.