Effects of two structurally diverse positive allosteric modulators on signaling bias at the μ-opioid receptor

Mol Pharmacol. 2025 Sep 26;107(11):100079. doi: 10.1016/j.molpha.2025.100079. Online ahead of print.

ABSTRACT

The μ-opioid receptor (MOR) is responsible for the analgesic actions of opioid drugs as well as their unwanted actions, including respiratory depression and addiction liability. Following agonist occupancy, MOR can signal via G-protein and/or β-arrestin. However, MOR agonists may show an imbalance between activating these 2 pathways. Evidence from studies of G-protein-coupled receptors suggests that allosteric modulators can influence agonist signaling profiles. However, no studies have examined this phenomenon at MOR. In this study, we compare the ability of various orthosteric MOR agonists to activate G-protein or recruit β-arrestin in the absence or presence of 2 structurally distinct MOR positive allosteric modulators, BMS-986187 (a xanthenedione) or BMS-986122 (a thiazolidine). We determined the potency and efficacy of 6 orthosteric agonists (DAMGO, fentanyl, methadone, morphine, Met-enkephalin, and SR17018) with and without BMS-986187 or BMS-986122, and determined bias factors for the agonists themselves and in the presence of a modulator. The 2 allosteric modulators enhanced the potency of agonists to different degrees showing probe dependence and differentially shifted the ability of agonists to activate G-protein as compared to recruitment of β-arrestin, indicating an effect on ligand bias. In both measures, in the presence of either modulator, the higher efficacy agonists showed a shift in potency. In contrast, lower efficacy compounds showed an increase in maximal effect with a smaller shift in potency. Overall, the studies provide evidence that positive allosteric modulators influence the degree and direction by which orthosteric agonists signal downstream of MOR. SIGNIFICANCE STATEMENT: Biased agonism and positive allosteric modulation at the μ-opioid receptor have been suggested as approaches to improve the therapeutic index of opioid agonists. This work shows how allosteric modulation alters the bias signaling profile of μ-opioid agonists.

PMID:41145026 | DOI:10.1016/j.molpha.2025.100079