Principles: Receptor theory in pharmacology

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Abstract

Pharmacological receptor theory is discussed with special reference to advances made during the past 25 years. Thus, the operational model has supplanted analysis of drug–receptor interaction in functional systems whereas the extended ternary complex model is used routinely to simulate quantitatively G-protein-coupled receptor (GPCR) behavior. Six new behaviors for GPCRs, centered on spontaneous production of receptor active states, ligand-selective receptor active states, oligomerization with other proteins (receptor and non-receptor) and allosteric mechanisms, have been characterized and each holds the potential for new drug discovery for therapeutic benefit.

Section snippets

Occupation theory

An important difference between the effects of drugs on enzymes versus tissues is the quantification and prediction of agonist response. Empirical proportionality constants such as intrinsic activity [5] were used to make the equations better describe the experimental data obtained from tissues. Progress was made when a powerful framework was constructed around the theoretical quantities stimulus, stimulus–response functions and efficacy and published in an article by R.P. Stephenson [6]. In

The operational model

One theoretical shortcoming of occupation theory is the ad hoc nature of the efficacy term. In 1989, Black and Leff [20] introduced a revolutionary idea that obviated the need for an empirical constant to account for efficacy; this formed the basis for the operational model. The ingenious premise on which this model is built is the fact that the efficacy term emerges from an experimentally observed behavior of pharmacological systems, namely the saturable relationship between receptor

The biochemical study of GPCRs and the ternary complex model

With the advent of biochemical binding techniques came the capability of characterizing some of the players on the pharmacological receptor stage. Benefiting most from this increased technology was the study of G-protein coupled receptors (GPCRs). The current model(s) of GPCR function uses the concept of allosterism, which was first described for ion channels 22, 23 and enzymes [24] and subsequently applied to receptors 7, 25, 26. These ideas culminated in the ternary complex model for GPCRs,

Opening Pandora's (molecular) toolbox and extending models

Before the widespread use of recombinant receptor systems, pharmacologists were confined in terms of the systems they had at their disposal. Most receptor work was performed on relatively few isolated tissues (e.g. guinea-pig ileum, rat atria and rat trachea). As put succinctly by Sir William Paton:

`The guinea pig longitudinal muscle is a great gift to the pharmacologist. It has low spontaneous activity; nicely graded responses (not too many tight junctions); is highly sensitive to a very wide

Beyond linkage models

Linkage models such as the ETC and CTC models are extremely useful for deriving methods to quantify drug effect. However, they are constrained in that they must specifically pre-define the species present in thermodynamic space. If there are more species than are defined, then the models fall short. A completely different approach is taken by a probabilistic model of GPCR behavior 41, 42. This model assumes that a receptor, not bound by ligand, possesses a particular state distribution in

A renaissance in receptor theory?

The past 25 years have amounted to a virtual revolution in pharmacology with respect to receptor theory. In some cases, experiments necessitated modification of a theory, as in the discovery of constitutive activity by Costa and Herz [30] and the resulting ETC model [32]. In other cases, theory preceded experiment as, for example, in the prediction of protean agonism (positive agonism in non-constitutive systems and inverse agonism in constitutive systems as a result of α>1 and γ<1 in the ETC

The next 25 years?

Considering the advancements made over the past 25 years, it is difficult to envisage GPCR-based therapeutics in the year 2029. However, in view of the emergence of GPCRs as complex information-processing units that are capable of differential cryptography, it might be supposed that new chemical scalpels will glean therapeutically useful behaviors. The advancements made during the past 25 years reinforce the belief that receptor theory is an indispensable tool in the drug discovery process.

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