An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

Abstract

An operational model of pharmacological agonism has been analysed to predict the behaviour of rectangular hyperbolic and non‐hyperbolic agonist‐concentration effect, E/[A], curves with variation in receptor concentration, [Ro]. Irreversible antagonism is predicted to cause E/[A] curve gradient changes in non‐hyperbolic cases but not in hyperbolic cases; in both cases estimation of agonist dissociation constants (KAS) is theoretically valid. 5‐Hydroxytryptamine (5‐HT) produced ‘steep’ E/[A] curves in contracting the rabbit isolated aorta preparation. Irreversible antagonism by phenoxybenzamine (Pbz) produced a flattened E/[A] curve, consistent with theoretical predictions. Fitting 5‐HT E/[A] curves in the presence and absence of Pbz to the model provided an estimate of KA for 5‐HT which was not significantly different from the estimate obtained using Furchgott's null method. The operational model of agonism appears to account qualitatively and quantitatively for the effects of [Ro] changes on hyperbolic and non‐hyperbolic E/[A] curves. Under conditions where irreversible antagonism may be used to estimate KAS, fitting the operational model directly to E/[A] data represents a valid, economical and analytically simple alternative to the conventional null method. 1985 British Pharmacological Society