PT  - JOURNAL ARTICLE
AU  - Kenakin, Terry
TI  - Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship?
AID  - 10.1124/mol.107.040352
DP  - 2007 Dec 01
TA  - Molecular Pharmacology
PG  - 1393--1401
VI  - 72
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/72/6/1393.short
4100  - http://molpharm.aspetjournals.org/content/72/6/1393.full
SO  - Mol Pharmacol2007 Dec 01; 72
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