BMS-986122

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.

The antinociceptive effect of the opioid drugs is achieved through activation of the µ-opioid receptor (MOP). The orthosteric and allosteric sites of opioid receptors may be modulated, orthosteric site by endogenous i.e.β-endorphin and exogenous opioids (morphine, oxycodone, fentanyl); whereas BMS-986121, BMS-986122, Comp5, MS1, Ignavine or even oxytocin act on the allosteric site of the MOP. Opioid therapy is associated with numerous side effects, such as: respiratory depression, sedation, constipation, and importantly, prolonged therapy can influence the development of tolerance, overdose, and addiction. Opioid tolerance is a result of MOP internalization and desensitization, preceded by MOP phosphorylation, performed by protein kinases such as: PKA, PKC, GRKs or CaMKII. In vitro and in vivo data suggest that positive allosteric modulators may enhance antinociception triggered by orthosteric ligands and reduce side effects, which would allow the dose of opioids to be reduced and thus provide a more effective therapy. In this review, we present that positive modulation of the allosteric sites of MOP may constitute a new strategy for pain therapy.