Biased ligands at G-protein-coupled receptors: promise and progress

• Biased ligands stabilize subsets of receptor conformations to engage unique pharmacology.
• Biased ligands may reduce on-target adverse effects or engender novel pharmacology.
• TRV027, in clinical trials for the treatment of acute heart failure, illustrates differentiation of a β-arrestin-biased ligand at the angiotensin II type 1 receptor.
• TRV130, in clinical development for the management of pain, illustrates differentiation of a G-protein-biased ligand at the μ opioid receptor.

Drug discovery targeting G protein-coupled receptors (GPCRs) is no longer limited to seeking agonists or antagonists to stimulate or block cellular responses associated with a particular receptor. GPCRs are now known to support a diversity of pharmacological profiles, a concept broadly referred to as functional selectivity. In particular, the concept of ligand bias, whereby a ligand stabilizes subsets of receptor conformations to engender novel pharmacological profiles, has recently gained increasing prominence. This review discusses how biased ligands may deliver safer, better tolerated, and more efficacious drugs, and highlights several biased ligands that are in clinical development. Biased ligands targeting the angiotensin II type 1 receptor and the μ opioid receptor illustrate the translation of the biased ligand concept from basic biology to clinical drug development.