Inverse, protean, and ligand-selective agonism: matters of receptor conformation

Concepts regarding the mechanisms by which drugs activate receptors to prod uce physiological response have progressed beyond considering the receptor as a simple on-off switch. Current evidence suggests that the idea that ago nists produce only varying degrees of receptor activation is obsolete and m ust be reconciled with data to show that agonist efficacy has texture as we ll as magnitude. Thus, agonists can block system constitutive response (inv erse agonists), behave as positive and inverse agonists on the same recepto r (protean agonists), and differ in the stimulus pattern they produce in ph ysiological systems (ligand-selective agonists), The molecular mechanism fo r this seemingly diverse array of activities is the same, namely, the selec tive microaffinity of ligands for different conformational states of the re ceptor. This paper reviews evidence for the existence of the various types of agonism and the potential therapeutic utility of different agonist types .-Kenakin, T, Inverse, protean, and ligand-selective agonism: matters of re ceptor conformation.