A 3-STATE RECEPTOR MODEL OF AGONIST ACTION

The concept that receptors can exist in multiple conformational states is becoming a physical reality. A fundamental question is how many ac tive states need to be proposed in order to account for pharmacologica l observations, in particular, the finding that the same receptor type can exhibit a different agonist pharmacology when coupled to differen t effector pathways. In this article, Paul Leff, Glare Scaramellini, G lare Law and Ken McKechnie propose and develop a three-state receptor model in which two active conformations are assumed to exist. They sho w that this relatively simple theoretical model provides a basis for p redicting variable agonist and inverse agonist behaviour in different systems containing the same receptor, and that it is able to account f or emerging data obtained on promiscuously coupled receptors. It is ar gued that, while these new theoretical considerations challenge the fu ndamental assumptions and concepts of traditional receptor theory, the general principles of pharmacological receptor classification are lar gely preserved.