ABSTRACT
Recently, however, evidence has been accumulating that suggests that some unliganded G-protein-coupled receptors exhibit spontaneous activity and are signaling cellular responses in the absence of any agonist stimulation and that ligands previously considered as competitive antagonists can inhibit such spontaneous activity. These ligands, which have now been termed inverse agonists, therefore appear to possess negative intrinsic activities. The simplest way to rationalize these data is to propose a model consisting of the receptor in equilibrium between at least two conformational states, the classic, inactive conformation, which lacks affinity for G-proteins (R), and a conformation exhibiting affinity for G-proteins in the absence of ligand (R*). Also, central to drug development is the possible redefinition of ligand efficacy. The most parsimonious explanation of ligand efficacy in a multistate model is simply the differential affinity of the ligand for the conformational states ( 4-7). In the two-state model, ligands exhibiting higher affinity for the active conformation (R *) would stabilize that conformation and reset the equilibrium to increase the total amount of R * and thus function as agonists, ligands with higher affinity for R would result in a decrease in R * and be inverse agonists, and ligands with equal affinity for R and R * would not alter the equilibrium but would be antagonists of both agonists and inverse agonists. Thus, ligand efficacy would perhaps be viewed as conformational selection of already preexisting states. Although this selected-fit model offers an easy explanation for the mode of action of inverse agonists, various lines of evidence including molecular-dynamic simulation (8) still suggest that different ligands may promote ligand-specific conformational changes. In that respect, the evidence suggesting that different agonists may stabilize and/or promote distinct active conformations has recently been reviewed and termed agonist trafficking (9). Conformational induction and conformational selection may therefore be two inseparable consequences of receptor binding systems.
