Received for publication July 31, 2007.
Revised September 26, 2007.
Accepted for publication September 27, 2007.

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

Abstract

This paper describes functional selectivity of agonists and antagonists and distinguishes classical 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 where 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 therefore is more likely to be a viable avenue for therapeutic selectivity in the clinic. Reasons are given for differentiating receptor active-state based selectivity from classical functional organ selectivity.

Key words: Molecular dynamics, Structure-activity relationships and modeling, Thermodynamic and kinetic processes and modeling

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