Operational models of pharmacological agonism

Abstract

The traditional receptor-stimulus model of agonism began with a de­scription of drug action based on the law of mass action and has developed by a series of modifications, each accounting for new experimental evidence. By contrast, in this paper an approach to modelling agonism is taken that begins with the observation that experimental agonist-concentration effect, E /[A], curves are commonly hyperbolic and develops using the deduction that the relation between occupancy and effect must be hyperbolic if the law of mass action applies at the agonist-receptor level. The result is a general model that explicity describes agonism by three parameters: an agonist-receptor dissociation constant, K A ; the total receptor concentration, [R 0 ]; and a parameter, K E , defining the transduction of agonist-receptor complex, AR, into pharmacological effect. The ratio, [R 0 ]/ K E , described here as the ‘transducer ratio’, τ , is a logical definition for the efficacy of an agonist in a system. The model may be extended to account for non-hyperbolic E /[A] curves with no loss of meaning. Analysis shows that an explicit formulation of the traditional receptor-stimulus model is one particular form of the general model but that it is not the simplest. An alternative model is proposed, representing the cognitive and transducer functions of a receptor, that describes agonist action with one fewer parameter than the traditional model. In addition, this model provides a chemical definition of intrinsic efficacy making this parameter experimentally accessible in principle. The alter­native models are compared and contrasted with regard to their practical and conceptual utilities in experimental pharmacology.