A biased mu‐opioid receptor positive allosteric modulator that does not alter receptor regulation

Abstract

Currently used opioid analgesics compete with endogenous opioid peptide ligands by binding to the orthosteric site of the mu opioid receptor (MOPr). Activation of this G protein‐coupled receptor (GPCR) affords analgesia but also causes respiratory depression, sedation, constipation, and euphoria leading to a high addictive liability. Our lab is currently pursuing the idea that positive allosteric modulators of MOPr (mu‐PAMs) may be a way to treat pain with a better therapeutic profile. Such compounds, including the lead ligand BMS‐986122, enhance the affinity, potency, and efficacy of opioid agonists to bind MOPr and activate G protein. On the other hand, BMS‐986122 does not stimulate G protein activation, as measured by [35S]GTPγS binding in the absence of an orthosteric ligand. Here, we sought to determine if BMS‐986122 activates non‐G protein mediated pathways downstream of MOPr and to investigate the long‐term consequences of BMS‐986122 exposure on the regulation of MOPr in vitro using C6 rat glioma cells expressing rat MOPr. The results demonstrate that BMS‐986122 initiates phosphorylation of ERK1/2 in a pertussis‐toxin insensitive manner supporting a G protein‐independent mechanism. BMS‐986122 alone did not cause any long‐term adaptations in MOPr signaling. Moreover, in contrast to its ability to enhance agonist‐mediated activation of G protein, BMS‐986122 failed to enhance agonist‐induced desensitization of MOPr as measured by receptor downregulation, receptor phosphorylation, and loss of receptor‐mediated signaling following long‐term agonist exposure. Development of biased allosteric ligands at GPCRs represents a novel avenue for analgesic drug development. Future work will determine the physiological consequences of this biased PAM in mouse models of pain.Support or Funding InformationFunded by DA039997