Receptor modeling theory

Extensions of receptor modeling theory to light extinction and to reactive chemical compounds require introduction of rate process concepts. 

From the time of A. J. Clark until the late 1970s, receptor models have been refined to describe drug affinity and efficacy. These ideas are collectively referred to as classical receptor theory. 

Antidepressant drugs, by contrast, require long-term administration for their therapeutic effects to become evident. Thus, it is clear that the acute actions of these drugs, which are most often to enhance synaptic levels of monoamines, are not sufficient in themselves to mediate their therapeutic effects. Neither is the effect of increased monoamines on postsynaptic second messenger systems, which occurs relatively quickly as well, adequate to account for the therapeutic actions of antidepressants. The most obvious explanation, then, is that molecular adaptations in response to chronic exposure to these drugs are what underlie their therapeutic effects. Consistent with this idea, several hypotheses as to the nature of the relevant molecular adaptations have been proposed. Two models focus on adaptations of the 5-HTia receptor. One theory proposes that desensitization of presynaptic somatodendritic 5-HTia autoreceptors is responsible for the therapeutic action... 

The primary need of receptor modeling today is a general theory within which to operate. Each specific receptor model application should be derivable from this framework. If not, either the application of the theory is incorrect, or the theory must be changed. Throanorton and Axetell have compiled the applications. Henry J and Watson 2) have outlined the theory including some of those applications. The theory must be expanded to include them all. 

Figure 5.1 Comparison of receptor models beginning with (A) Ehrlich s first pictorial representation of his side-chain theory in 1898, (B) scheme of drug-receptor interaction in 1971, (C) acetylcholine ion-channel in 1982, and (D) G-protein-coupled receptor system in 1989.

Simple mathematical calculations by the first pharmacologists in the 1930s indicated that structurally specific drugs exert their action in very small doses and do not act on all molecules of the body but only on certain ones, those that constitute the drug receptors. For example, Clark [407] calculated that ouabain applied to the cells of the heart ventricle, isolated from the toad, would cover only 2.5% of the cellular surface. These observations prompted Clark [407,408] to apply the mathematical approaches used in enzyme kinetics to the effects of chemicals on tissues, and this formed the basis of the occupancy theory for drug-receptor interaction. Thus, pharmacological receptor models preceded accurate knowledge of receptors by many years. 

Emax Model, ftmax model was originally derived from the classic drug-receptor occupancy theory. It is an empirical function for describing a non-linear concentration-effect relationship with the general form ... 

Srivastava, S., Richardson, W.W., Bradley, M.P. and Crippen, G.M. (1993). Three-Dimensional Receptor Modeling Using Distance Geometry and Voronoi Polyhedra. In 3D QSAR in Drug Design. Theory, Methods and Applications. (Kubinyi, H., ed.), ESCOM, Leiden (The Netherlands), pp. 409-430. 

Receptor inactivation theory, initially proposed by Gosselin in 1977 has been widely disseminated by Kenakin (35)and to some degree is based on the two-state model originally proposed by Katz and Thesleff (41) for ion channels, specifically the Torpedo nicotinic receptor. where the multimeric receptor exists in active and inactive states, with ligand binding altering the equilibrium between these two states. Receptor inactivation theory reflects a synthesis of both occupancy and rate theories providing an alternative consideration for the study of the RL interaction. 

It is amazing to note that complex processes such as drug binding to protein, activation of cells, and observation of syncytial cellular response should apparently so closely follow a model based on these simple concepts. This was not lost on A. J. Clark in his treatise on drug receptor theory The Mode of Action of Drugs on Cells [4] ... 

The various components of classical theory relating receptor occupancy to tissue response are shown schematically in Figure 3.5. It will be seen that this formally is identical to the equation for response derived in the operational model (see material following), where x = [Rt]e/p. 

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