A Complementary Scale of Biased Agonism for Agonists with Differing Maximal Responses

Abstract

Compelling data in the literature from the recent years leave no doubt about the pluridimensional nature of G protein-coupled receptor function and the fact that some ligands can couple with different efficacies to the multiple pathways that a receptor can signal through, a phenomenon most commonly known as functional selectivity or biased agonism. Nowadays, transduction coefficients (log(τ/KA)), based on the Black and Leff operational model of agonism, are widely used to calculate bias. Nevertheless, combining both affinity and efficacy in a single parameter can result in compounds showing a defined calculated bias of one pathway over other though displaying varying experimental bias preferences. In this paper, we present a novel scale (log(τ)), that attempts to give extra substance to different compound profiles in order to better classify compounds and quantify their bias. The efficacy-driven log(τ) scale is not proposed as an alternative to the affinity&efficacy-driven log(τ/KA) scale but as a complement in those situations where partial agonism is present. Both theoretical and practical approaches using μ-opioid receptor agonists are presented.

A tetrapeptide class of biased analgesics from an Australian fungus targets the µ-opioid receptor

“…It remains uncertain, however, whether G protein bias per se is the sole property contributing to the improved safety of new opioid drugs such as oliceridine (9). Using receptor knockdown, we have shown here that oliceridine has very low G protein efficacy compared with morphine, similar to findings using receptor depletion with a cAMP assay system (37). Similar low efficacy results have recently been reported for another opioid, PZM21, also claimed to be safer than morphine (4, 51).…”

“…S2) (35). Calculation of relative efficacy from maximum response in each pathway provides a complementary estimate of bias in signaling assays where all agonists are partial (36, 37). This approach ( SI Appendix , Fig.…”

Investigating the Role of G-protein Bias in the Anti-Nociceptive and Side Effect Profiles of Two Novel Mu Opioid Receptor Agonists Kurkinol and Kurkinorin

“…This includes the identification of Loperamide (peripherally restricted anti-diarrheal) and Buprenorphine (opioid replacement therapy) as G-protein biased agonists with improved side effect profiles. These effects are now believed to be due to their recently discovered G-protein bias (Burgueño et al, 2017, Ray et al, 2008, Tayrouz et al, 2001 (Table 3.6).…”

A method for the quantification of biased signalling at constitutively active receptors

“…Leff et al ., ). In this regard, a complementary scale of biased agonism for partial agonists based on τ values has been recently developed (Burgueño et al ., ). Secondly, normalization to the values of a reference agonist removes the impact of the bias inherent in the different coupling efficiencies of different signalling pathways, which would otherwise form part of an analysis based on the operational model τ parameter.…”

“…In summary, current approaches for quantification of biased agonism based on operational models may include (Ehlert et al ., ) or not (Kenakin et al ., ; Burgueño et al ., ) constitutive receptor activity but all require the presence of a reference agonist for within signalling pathway normalization (because they include pathway‐dependent coupling efficiency in the operational efficacy, τ). Thus, there is value in developing a new analytical methodology in this field, which includes constitutive receptor activity but does not require the normalization to the properties of reference ligands.…”