A Simple Method for Quantifying Functional Selectivity and Agonist Bias

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 (K(A) (-1)) for the receptor and efficacy (τ) in activating a particular signaling pathway. Utilizing a "transduction coefficient" term, log(τ/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.

Biased Signaling Favoring Gi over β-Arrestin Promoted by an Apelin Fragment Lacking the C-terminal Phenylalanine

“…Ligand bias was quantified by analyzing the concentration-response curves using the operational model of agonism, as described previously (41)(42)(43).…”

The Effective Application of Biased Signaling to New Drug Discovery

“…A modification and extension of this approach amenable to the statistical comparison of multiple agonists to yield DDLog(t/K A ) values (denoted as transducer coefficients) has been published to furnish logarithms of bias factors between signaling pathways (Kenakin et al, 2012). Transducer coefficients are based on allosteric constants among ligands, receptors, and signaling proteins and thus yield bias within the allosteric vector defined by this ternary complex (Kenakin and Christopoulos, 2013).…”

Biased Agonism of Endogenous Opioid Peptides at theμ-Opioid Receptor

“…Opioids that are currently used as therapeutics, such as morphine, predominantly exert both their analgesic effects and undesirable effects through activation of the m-opioid receptor (MOP) subtype (Matthes et al, 1996;Cox et al, 2015). It is now accepted that chemically distinct ligands binding to the same G protein-coupled receptor (GPCR) can stabilize the receptor in multiple active conformations, which results in differential activation of cell signaling pathways and, eventually, in different physiologic outcomes, a phenomenon known as biased agonism (Kenakin et al, 2012). Biased agonism can be exploited to design drugs that selectively activate signaling pathways, leading to the desired physiologic effects while minimizing on-target side effects elicited by activation of other signaling pathways via the same receptor subtype (Gesty-Palmer et al, 2009;Walters et al, 2009;Valant et al, 2014).…”