Application of the operational model of agonism to establish conditions when functional antagonism may be used to estimate agonist dissociation constants

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Abstract
1 The operational model of agonism (Black & Leff, 1983) has been used to analyse comparatively functional antagonism and irreversible antagonism as methods for estimating agonist dissociation constants (KAs). 2 A general condition is established in terms of the model parameters which defines the type of experimental interventions at the receptor and the post-receptor level that allow valid KA estimation. 3 It is shown that functional antagonism and other post-receptor interventions may produce changes in agonist-concentration effect curves which are qualitatively indistinguishable but quantitatively distinct, from those produced by irreversible antagonism. 4 Experimental data obtained with the guinea-pig tracheal strip preparation are in keeping with the theoretical predictions and show how studies using functional antagonism may overestimate agonist affinity. 5 In general, functional antagonism, unlike irreversible antagonism, is in principle an unreliable method for quantifying agonism.