Receptor theory

Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years.John Newport Langley and Paul Ehrlich introduced the concept of a receptor that would mediate drug action at the beginning of the 20th century. A J Clark was the first to quantify drug-induced biological responses (using an equation described firstly by A V Hill in 1909 and then in 1910) and propose a model to explain drug-mediated receptor activation. So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and GPCRs.

In 1901, Langley challenged the dominant hypothesis that drugs act at nerve endings by demonstrating that nicotine acted at sympathetic ganglia even after the degeneration of the severed preganglionic nerve endings. In 1905 he introduced the concept of a receptive substance on the surface of skeletal muscle that mediated the action of a drug. It also postulated that these receptive substances were different in different species (citing the fact that nicotine-induced muscle paralysis in mammals was absent in crayfish). Around the same time, Ehrlich was trying to understand the basis of selectivity of agllents. He theorized that selectivity was the basis of a preferential distribution of lead and dyes in different body tissues. However, he later modified the theory in order to explain immune reactions and the selectivity of the immune response. 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 when Ahlquist showed the differential action of adrenaline demonstrated its effects on two distinct receptor populations, did the theory of receptor-mediated drug interactions gain acceptance.

The receptor occupancy model, which describes agonist and competitive antagonists, was built on the work of Langley, Hill, and Clark. The occupancy model was the first model put forward by Clark to explain the activity of drugs at receptors and quantified the relationship between drug concentration and observed effect. It is based on mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. In particular, the magnitude of the response is directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium. He applied mathematical approaches used in enzyme kinetics systematically to the effects of chemicals on tissues. He showed that for many drugs, the relationship between drug concentration and biological effect corresponded to a hyperbolic curve, similar to that representing the adsorption of a gas onto a metal surface and fitted the Hill–Langmuir equation. Clark, together with Gaddum, was the first to introduce the log concentration–effect curve and described the now-familiar 'parallel shift' of the log concentration–effect curve produced by a competitive antagonist. Attempts to separate the binding phenomenon and activation phenomenon were made by Ariëns in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding). Classic occupational models of receptor activation failed to provide evidence to directly support the idea that receptor occupancy follows a Langmuir curve as the model assumed leading to the development of alternative models to explain drug behaviour.

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