RT Journal Article SR Electronic T1 Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship? JF Molecular Pharmacology JO Mol Pharmacol FD American Society for Pharmacology and Experimental Therapeutics SP 1393 OP 1401 DO 10.1124/mol.107.040352 VO 72 IS 6 A1 Terry Kenakin YR 2007 UL http://molpharm.aspetjournals.org/content/72/6/1393.abstract AB This article describes functional selectivity of agonists and antagonists and distinguishes conventional cell-based functional selectivity, where the strength of signal produces selective signaling in various organs, from true receptor active-state based selectivity, also alternatively referred to in the literature as “stimulus trafficking,” “biased agonism,” and “collateral efficacy.” This latter mechanism of selectivity depends on the ligand-related conformation of the receptor and is not compatible with the parsimonious view that agonists produce a single receptor active state. In addition, protean agonism is described, whereby a ligand produces positive agonism in quiescent systems and inverse agonism in constitutively active systems. This is a special case of active state-based selectivity in which the ligand produces an active state that is of lower efficacy than the natural constitutively active state. It is postulated that receptor active-state based selectivity, unlike cell-based functional selectivity, is controllable through the chemical structure of the ligand and is therefore more likely to be a viable avenue for therapeutic selectivity in the clinic. Reasons are given for differentiating receptor active-state based selectivity from conventional functional organ selectivity. The American Society for Pharmacology and Experimental Therapeutics