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. 1985 Feb;84(2):561–571. doi: 10.1111/j.1476-5381.1985.tb12941.x

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

J W Black, P Leff, N P Shankley, J Wood
PMCID: PMC1987296  PMID: 3978322

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.

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Selected References

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