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.
Highlights
Materials and MethodsIt is known that the operational model cannot be applied to fit a single effect/agonist concentration (E/[A]) curve because there is not a single solution for the estimated parameters[12]
Plasticity is a property inherent to the flexible nature of proteins which GPCRs make proficient use of for signaling purposes[3]
The two scales for biased agonism we discuss are based on the operational model of agonism, presented in a seminal work by Black and Leff[15]
Summary
It is known that the operational model cannot be applied to fit a single effect/agonist concentration (E/[A]) curve because there is not a single solution for the estimated parameters[12]. In this regard, two different fitting procedures, namely, the receptor inactivation and the comparative methods, were followed depending on the experimental assay performed. The Emax and m parameters of Damgo curve were used as fixed Em and n values in the fitting of the selected compounds under the operational model (Equation 1, this article). Due to the statistical consistency of both inference methods, confidence intervals and hypothesis testing produced the same conclusion (biased agonism or not) for each of the compounds
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