Biased G Protein-Coupled Receptor Signaling Changing the Paradigm of Drug Discovery

G protein-coupled receptors (GPCRs) are a family of 7 transmembranespanning proteins that collectively serve as the largest group of therapeutic targets. Within cardiology, GPCRs such as α-and β-adrenergic receptors, the angiotensin type I receptor, and the P2Y 12 receptor as well, are the targets of a variety of widely used medications. Ligands for GPCRs have been characterized canonically as agonists, which promote or stabilize conformational changes in the receptor that result in the activation of heterotrimeric G proteins and the generation of second-messenger systems, or antagonists that block such activation. Work over the past 2 decades, however, has found that ligands can induce distinct active receptor conformations that activate only specific subsets of a given receptor's functional repertoire.1 In particular, ligands have been identified that exhibit bias or functional selectivity toward specific G proteins or even other signal transducers such as β-arrestins. Further exploration of this biased signaling biology has led to important changes in the way pharmacological agents are developed and screened. Although these terms have been used interchangeably to characterize a variety of GPCR signaling and biological functions, for the purpose of this review, we will use the terms bias or functional selectivity to refer specifically to the ability of a GPCR ligand to stimulate signaling through 1 signal transducer over another (eg, β- arrestin versus G protein). Beyond the recognition and development of these biased agonists, researchers have discovered novel mechanisms by which these ligands interact with receptors and engender unique functional profiles (Figure). The majority of pharmacological GPCR ligands target orthosteric binding sites, ie, the binding site of the endogenous ligand on a given receptor. Recent work has also identified ligands that bind to allosteric, or topographically distinct, binding sites on the receptors. It is perhaps not surprising that allosteric ligands have been identified that stabilize biased receptor conformations and thus function as biased allosteric modulators. © 2018 American Heart Association, Inc.