The concept that receptors mediated the effects of drugs was based on a number of observations made during the late nineteenth and the early twentieth centuries. These observations connected chemical structure with biological activity, as well as demonstrating the fact that relatively small amounts of drug can elicit an effect.
One of the earliest suggestions, which associated chemical structure with function, was that of Blake in 1848. Blake proposed that the biological activity of certain metallic salts be due to their metallic component, rather than the entire complex (e.g. the lead moiety in lead acetate). This concept received support in 1884 when Arrhenius introduced his theory of electrolyte dissociation (salts dissolved in water become dissociated into oppositely charged ions.
The effects of ionisation on the pharmacological action of drugs were also recognised by Crum Brown and Fraser in Scotland during the late nineteenth century. They demonstrated that quaternization (the addition of a fourth alkyl group) of a number of alkaloids resulted in their change from a muscle contractor to a muscle relaxant. Thus they concluded that a relationship existed between the physiological action of a substance and its chemical structure.
Meyer and Overton, at the turn of the twentieth century also contributed somewhat to the receptor theory from their work on the importance of lipid solubility in drug action. However their theory correlated pharmacological effects with a physical property (i.e. lipid solubility) rather than the structural-activity relationship. Meyer and Overton's theory was attempting to explain the diverse chemical structures that exist within the hypnotic and general anaesthetic classes of drugs. Today we realise the limitations of this theory and appreciate that chemical structure is a determinant of physical properties.
Despite the importance of Meyer and Overton's observation, a number of experimental reports of drug action were surfacing that clearly indicated that drug molecules must be concentrating on small specific areas of cells in order to produce their effects. These characteristics included:
The concept of drugs acting on receptors is generally credited to John Langley 1878. Langley while studying the antagonistic effects of atropine against pilocarpine induced salivation wrote "that there is some substance or substances in the nerve ending or gland cell with which both atropine and pilocarpine are capable of forming compounds". He later referred to this factor as a "receptive substance". Despite this observation, the word "receptor" was not introduced into the medical literature until the turn of the century by Paul Ehrlich.
Ehrlich based his hypothesis upon his experiences in the treatment of infectious diseases with drugs derived from the German dye industry. He postulated that a drug could have a therapeutic effect only if it has the "right sort of affinity". Ehrlich specifically wrote "that combining group of the protoplasmic molecule to which the introduced group is anchored will hereafter be termed receptor". At this time Ehrlich visualised receptors as being part of side-chains in mammalian cells, today we realise that drug-binding sites may be part of any cellular constituent.