Opioid receptors are key targets in the management of pain and morphine. Its derivatives induce pain relief by acting as agonists at opioid receptors, especially the μ-opioid receptor (µ-OR, MOR). μ-opioid receptor agonists are the most effective treatments for moderate to severe acute and chronic pain. However, these drugs have significant side effects. They include respiratory suppression, constipation, allodynia, tolerance, and dependence, as well as abuse potential. Safer pain therapies are desperately needed. However, the MOR agonists show efficacy in blocking pain. Thus, it continues to be a primary target for the discovery of novel pain therapies. In this study, BMS-986122 is a selective, potent positive allosteric modulator of the mu-opioid receptor (µ-OR). It shows potentiation of orthosteric agonist-mediated β-arrestin recruitment, adenylyl cyclase inhibition, and G protein activation. It also potentiates DAMGO-mediated [³⁵S]GTPγS binding in mouse brain membranes.

BMS-986122 is a selective, potent positive allosteric modulator of the mu-opioid receptor (µ-OR).

BMS-986122 increases β-arrestin recruitment stimulated by endomorphin 1 (EC₅₀=3 μM) in U2OS-OPRM1 human osteosarcoma cells. They express μ-opioid receptors. BMS-986122 also potentiates endomorphin 1-induced inhibition of forskolin-stimulated adenylyl cyclase activity in CHO cells (EC₅₀=8.9 μM). they also express human recombinant μ-opioid receptors. BMS-986122 potentiates DAMGO-mediated [³⁵S]GTPγS binding in mouse brain membranes and appears to be, at least in part, a positive affinity modulator of the μ-opioid receptor for DAMGO binding.

In addition, BMS-986122 enhances the ability of the endogenous opioid Methionine-enkephalin (Met-Enk) to stimulate G protein activity in mouse brain homogenates without activity on its own and to enhance G protein activation to a greater extent than β-arrestin recruitment in CHO cells expressing human mu-opioid receptors. BMS-986122 increases the potency of Met-Enk to inhibit GABA release in the periaqueductal gray.

In summary, BMS-986122 is selective for µ-OR and has no detectable activity at the closely related δ-OR. It produces analgesia with reduced side effects.

Reference:

Burford NT, et al. Proc Natl Acad Sci U S A. 2013;110(26):10830-10835.;Kandasamy R, et al. Proc Natl Acad Sci U S A. 2021;118(16):e2000017118.