[2] John Newport Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the beginning of the 20th century.
Langley postulated that these receptive substances were different in different species (citing the fact that nicotine-induced muscle paralysis in mammals was absent in crayfish).
[6] Thinking that selectivity was derived from interaction with the tissues themselves, Ehrlich envisaged molecules extending from cells that the body could use to distinguish and mount an immune response to foreign objects.
However, it was only after Ahlquist demonstrated the differential effects of adrenaline on two distinct receptor populations, that the theory of receptor-mediated drug interactions gained acceptance.
[7][8] The receptor occupancy model, which describes agonist and competitive antagonists, was built on the work of Langley, Hill, and Clark.
[12] The development of the classic theory of drug antagonism by Gaddum, Schild and Arunlakshana built on the work of Langley, Hill and Clark.
[12] Gaddum described a model for the competitive binding of two ligands to the same receptor in short communication to The Physiological Society in 1937.
[16] Similar to the receptor occupancy model, the theory originated from earlier work by del Castillo & Katz on observations relating to ligand-gated ion channels.
[15] Further, the α parameter can be added as a subtle but highly useful extension to the ATCM in order to include effects of an allosteric modulator on the efficacy (as distinct from the affinity) of another ligand that binds the receptor, such as the orthosteric agonist.