A simple method for quantifying functional selectivity and agonist bias

Terry Kenakin, Christian Watson, Vanessa Muniz-Medina, Arthur Christopoulos, Steven Novick

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369 Citations (Scopus)


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 CCR5-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.
Original languageEnglish
Pages (from-to)193 - 203
Number of pages11
JournalACS Chemical Neuroscience
Issue number3
Publication statusPublished - 2012

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