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Functional Selectivity through Protean and Biased Agonism: Who Steers the Ship?

Department of Biological Reagents and Assay Development, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina

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.

Address correspondence to: Terry Kenakin, Department of Biological Reagents and Assay Development, GlaxoSmithKline Research and Development, 5 Moore Drive, Research Triangle Park, NC 27709. E-mail: terry.p.kenakin{at}gsk.com