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

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]. 2 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.3 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.4 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.5 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.