The two-state model of antagonist-AT1 receptor interaction: an hypothesis defended but not tested.

A correlation between insurmountable antagonism and slow dissociation has been observed for the non-peptidic AT1 receptor antagonists. This commentary examines the validity of conclusions regarding a two stage binding mechanism that has been proposed in order to account for both the slow dissociation and insurmountable antagonism. Support for that hypothetical mechanism is in the form of the goodness of fit between experimental data and modelled data in a number of papers from the same laboratory. We challenge the idea that a simple match of model and data is an adequate test of an hypothesis by showing that a simpler model matches the data equally well. We conclude that two stage binding is not necessary to explain the behaviour of AT1 receptor antagonists.