Journal
ACS CHEMICAL NEUROSCIENCE
Volume 3, Issue 3, Pages 193-203Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cn200111m
Keywords
Biased agonism; drug discovery; functional selectivity; receptor theory; receptor methods; stimulus bias
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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 (K-A(-1)) for the receptor and efficacy (tau) in activating a particular signaling pathway. Utilizing a transduction coefficient term, log(tau/K-A), this scale can statistically evaluate selective agonist effects in a manner that can theoretically inform structure activity studies and/or drug candidate selection matrices. The bias of four chemokines for CCRS-mediated inositol phosphate production versus internalization is quantified to illustrate the practical application of this method. The independence of this method with respect to receptor density and the calculation of statistical estimates of confidence of differences are specifically discussed.
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