Identifying novel modulators of G protein-coupled receptors via interaction at allosteric sites.

Allosteric intervention at G protein-coupled receptors is considered an alternative approach to developing new drugs for both classical and novel biological targets. Allosteric compounds, which by definition bind at sites spatially separated from those of the endogenous ligands, may offer benefits over orthosteric ligands in terms of providing therapeutic benefits with reduced side effects due to increased selectivity and the temporal nature of their duration of action. The aim of this review is to assess, with reference to recent data and concepts, the potential benefits and pitfalls in the discovery and development of small-molecule allosteric compounds as novel therapeutics.