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nists produce only varying degrees of receptor activation is obsolete and m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.