The Potency Problem in GPCR Biased Agonism

Abstract Biased agonism promised a new generation of GPCR therapeutics capable of selectively engaging beneficial signaling pathways while avoiding those associated with adverse effects. Yet contemporary bias metrics largely quantify signaling efficiency through potency-centric measures, emphasizing pathway preference over the pathway exclusion that may better align with the original promise of biased agonism. I argue that efficacy-centered descriptors, including a simple complementary E-factor (ΔΔlog(EMax)), may help identify ligands with therapeutically relevant functional selectivity and should be reported alongside conventional bias factors to provide a more complete assessment of biased signaling.