A simple method for quantifying functional selectivity and agonist bias.

TLDR: A scale based on the Black and Leff operational model that contains the key elements required to describe 7TM agonism, namely, affinity for the receptor and efficacy in activating a particular signaling pathway, can statistically evaluate selective agonist effects in a manner that can theoretically inform structure-activity studies and/or drug candidate selection matrices.

Abstract: Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are “biased” toward producing subsets of receptor behaviors. A hallmark of such “functional selectivity” is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (KA–1) for the receptor and efficacy (τ) in activating a particular signaling pathway. Utilizing a “transduction coefficient” term, log(τ/KA), this scale can statistically evaluate selective agonist effects in a manne...