Early thinking
The specificity of certain drugs to particular diseases had been highlighted at least since the seventeenth century. Perhaps the best-known example is the efficacy of Peruvian bark, the predecessor of quinine, in the treatment of intermittent fevers or malaria (Figure 1) [5]. Yet, such specificity remained a mysterious phenomenon. As one sceptical author put it in 1797:… as to specifics, if their idea be explicable by supposing an admiral sent down channel, across the Bay of Biscay, and up to the Mediterranean, with express orders to attack the Maltese, but with the strictest charge not to molest any other state whatever; I cannot conceive any medicine such a specific as to conform most punctually with such orders, to act vigorously against one particular gland or humour of the body, without in the least affecting or disturbing any other … [6].
In the Romantic period, it became more commonplace to encounter discussions of specificity. Writers like the German Friedrich Sobernheim (1803–1846), for example, began to use the physico-chemical concept of elective affinities to rationalize the predilection of certain substances, including the newly isolated alkaloids, to affect particular parts of the body. For Sobernheim, strychnine had a specific affinity to the spinal cord, digitalis and tobacco to the nerves of the heart, alcohol to the brain, mercury to the salivary glands, ergot to the nerves of the uterus, and sulphur to the skin [7]. Moreover, the English physician James Blake (1814–1893) demonstrated in the 1840s that solutions of inorganic compounds with the same macroscopic crystalline structure produced similar physiological effects when infused intravenously into animals. This led to further research on the relationship between the chemical structure and pharmacological effect of substances such as salts and the substitution products of various alkaloids [8].
By the start of the twentieth century, a scientific controversy had developed over whether pharmacological action depended directly on the chemical structure of a substance or rather upon its physical properties [9]. As we shall see, this general problem formed an important background to the subsequent debate about the existence and relevance of receptors.