Fig. 1.

Diagrammatic representation of biased signaling at a G-protein coupled receptor (GPCR). In this example, an unbiased agonist is depicted that engages the GPCR and activates both G protein-dependent [i.e., adenylyl cyclase/cyclic adenosine monophosphate (cAMP)] and -independent (i.e., β-arrestin) signaling pathways. A biased agonist engages the receptor to generate a GPCR-ligand conformational ensemble that preferentially activates one or the other signaling cascade. If the preferentially activated signaling pathway were associated with a therapeutic effect vs. a harmful response from the non-preferred signaling pathway, the resulting signal bias could generate a pharmacologically improved therapeutic with less risk of on-target adverse events as compared to the unbiased ligand.