Considerations in the evaluation of inverse agonism and protean agonism at G protein-coupled receptors.

Over the past decade it has become accepted that G protein-coupled receptors (GPCRs) can activate G proteins and thus initiate signaling in the absence of agonist; this spontaneous receptor activity can be inhibited to varying degrees by antagonists, a phenomenon termed inverse ugonism. The modulation of spontaneous GPCR activity by the binding of specific ligands implies that receptors can interconvert between active (R*) and inactive forms (R), with agonists promoting the former and inverse agonists the latter. Thus, inverse agonists produce biochemical effects opposite to those of agonists. This stands in contrast to earlier theories that antagonists lack intrinsic activity and merely preclude the binding of agonists to receptors. Inverse agonism has been observed in a wide variety of systems, with both endogenously and heterologously expressed GPCRs.’ Notwithstanding these repeated observations in vitro, however, the contribution of inverse agonism to the overall therapeutic effects of antagonists is difficult to determine due to the continual presence of endogenous agonists under normal physiological conditions. Proof of the therapeutic relevance of inverse agonism awaits evidence that spontaneous receptor signaling is significant in vivo and/or that changes in receptor density,2 distribution,3,4 or posttranslational modification5 attributable to inverse agonist effects at the cellular and subcellular levels, also occur in intact organisms. An emerging concept related to inverse agonism is that of protean ugonism,6 wherein some ligands display both agonist and inverse agonist properties at a single GPCR. Although this phenomenon has only been observed at a handful of GPCRs and is poorly understood at present, it may ultimately provide a key to understanding how all ligands modulate GPCR behavior.