Abstract
Binding and signaling kinetics have previously proven important in validation of biased agonism at GPCRs. Here we provide a comprehensive kinetic pharmacological comparison of clinically relevant μ-opioid receptor agonists, including the novel biased agonist oliceridine (TRV130) which is in clinical trial for pain management. We demonstrate that the bias profile observed for the selected agonists is not time-dependent and that agonists with dramatic differences in their binding kinetic properties can display the same degree of bias. Binding kinetics analyses demonstrate that buprenorphine has 18-fold higher receptor residence time than oliceridine. This is thus the largest pharmacodynamic difference between the clinically approved drug buprenorphine and the clinical candidate oliceridine, since their bias profiles are similar. Further, we provide the first pharmacological characterization of (S)-TRV130 demonstrating that it has a similar pharmacological profile as the (R)-form, oliceridine, but displays 90-fold lower potency than the (R)-form. This difference is driven by a significantly slower association rate. Finally, we show that the selected agonists are differentially affected by G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5) expression. GRK2 and GRK5 overexpression greatly increased μ-opioid receptor internalization induced by morphine, but only had modest effects on buprenorphine and oliceridine-induced internalization. Overall, our data reveal that the clinically available drug buprenorphine displays a similar pharmacological bias profile in vitro compared to the clinical candidate drug oliceridine and that this bias is independent of binding kinetics suggesting a mechanism driven by receptor-conformations.This article is part of the Special Issue entitled ‘New Vistas in Opioid Pharmacology’.
Highlights
Gprotein-coupled receptors (GPCRs) are a major drug target family through which ~30% of all medicines in the clinic mediate their action, and with ~20% of all drugs in clinical trials targeting these receptors (Hauser et al, 2017)
Today, increasing evidence shows that GPCR functionality is pluridimensional, meaning GPCRs can interact with multiple G proteins, β-arrestins, G protein-coupled receptor kinases (GRKs) and other effectors (Daaka et al, 1997; Schönegge et al, 2017; Violin et al, 2006; Zhang et al, 2015)
TRV130 was selected since it is a biased μ-opioid receptor (μ-OR) clinical candidate having improved analgesic properties and reduced side-effects compared to morphine in rodents (DeWire et al, 2013) and to some degree in humans (Singla et al, 2017; Soergel et al, 2014; Viscusi et al, 2019, 2016)
Summary
Gprotein-coupled receptors (GPCRs) are a major drug target family through which ~30% of all medicines in the clinic mediate their action, and with ~20% of all drugs in clinical trials targeting these receptors (Hauser et al, 2017). The conventional model of GPCR activation describes that binding of agonists stabilize a receptor state that leads to activation of its cognate G protein, whereas antagonist binding. GPCR signaling was traditionally interpreted in a linear fashion as a switch that could either turn a given signaling pathway “on” or “off” (Costa-Neto et al, 2016). Ubiquitous expression of GPCRs combined with the pluridimensional signaling, can lead to activation of non-desired signaling pathways in either therapeutically relevant or non-relevant tissues upon drug administration. Selective activation of signaling pathways by a GPCR has in recent years been shown to hold a great potential in drug discovery (DeWire et al, 2013; Violin et al, 2014). Ligands were found to differentially regulate these different pathways through their action on a unique receptor leading to the concept of biased agonism (Costa-Neto et al, 2016)
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