Drug Discovery World

Drug responses reflect both a ligand’s intrinsic properties and the sensitivity of the biological assay. Receptor abundance and signal-transduction efficiency can therefore alter observed activity and complicate translation from laboratory assays to living systems. Terry Kenakin examines controlled changes in system sensitivity as a way to distinguish the underlying properties of GPCR ligands. Adjusting receptor density and cellular responsiveness permits affinity and efficacy to be assessed within a common operational framework. Lower sensitivity can reveal partial agonism and support estimates of intrinsic efficacy and affinity; further reduction may make weak agonists behave as measurable antagonists. Raising sensitivity can uncover partial or inverse agonism in compounds previously considered neutral antagonists. The presentation also examines how this approach separates allosteric modulation of affinity from effects on efficacy. These methods aim to improve quantitative interpretation of assays and their ability to predict drug activity in vivo, followed by questions and discussion.