GPCR Biased Signaling: Conceptual Advancements and Therapeutic Innovation

G protein-coupled receptors (GPCRs) are key mediators of cellular signaling, governing fundamental physiological and pathophysiological processes. This central role establishes them as prominent drug targets for a wide range of diseases. The concept of GPCR biased signaling was initially defined by the receptor’s ability to differentially engage G proteins versus β-arrestins. Research has since broadened this paradigm to reveal diverse mechanisms, including preferential coupling to specific Gα subtypes, spatially segregated signaling, regulation by post-translational modifications (e.g., phosphorylation), and distinct outputs from receptor oligomers. Together, these findings illuminate the complex signaling repertoire of GPCRs. Leveraging biased signaling to activate beneficial pathways, therefore offers a compelling path toward therapeutics with enhanced efficacy and reduced adverse effects. This review explores the evolution of GPCR biased signaling concepts and evaluates the current pipeline of investigational and approved drugs emerging from this paradigm.