Biased agonism at β-adrenergic receptors

The β-adrenergic receptors (βARs) include three subtypes, β 1 , β 2 and β 3 . These receptors are widely expressed and regulate numerous physiological processes including cardiovascular and metabolic functions and airway tone. The βARs are also important targets in the treatment of many diseases including hypertension, heart failure and asthma. In some cases, the use of current βAR ligands to treat a disease is suboptimal and can lead to severe side effects. One strategy to potentially improve such treatments is the development of biased agonists that selectively regulate a subset of βAR signaling pathways and responses. Here we discuss the compounds identified to date that preferentially activate a G s - or β-arrestin-mediated signaling pathway through βARs. Mechanistic insight on how these compounds bias signaling sheds light on the potential development of even more selective compounds that should have increased utility in treating disease. • G protein and β-arrestin biased agonists have been characterized for the βARs. • Biased β-agonists may improve clinical outcomes compared to balanced β-agonists. • TM VII / ECL movements and GRK interaction are implicated in bias mechanism. • Biased drug discovery efforts and experimental design require careful consideration.