Discovery of a mu-opioid receptor modulator that in combination with morphinan antagonists induces analgesia.

Morphinan antagonists, which block opioid effects at mu-opioid receptors, have been studied for their analgesic potential. Previous studies have suggested that these antagonists elicit analgesia with fewer adverse effects in the presence of the mutant mu-opioid receptor (MOR; S196A). However, introducing a mutant receptor for medical applications represents significant challenges. We hypothesize that binding a chemical compound to the MOR may elicit a comparable effect to the S196A mutation. Through high-throughput screening and structure-activity relationship studies, we identified a modulator, 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid (BPRMU191), which confers agonistic properties to small-molecule morphinan antagonists, which induce G protein-dependent MOR activation. Co-application of BPRMU191 and morphinan antagonists resulted in MOR-dependent analgesia with diminished side effects, including gastrointestinal dysfunction, antinociceptive tolerance, and physical and psychological dependence. Combining BPRMU191 and morphinan antagonists could serve as a potential therapeutic strategy for severe pain with reduced adverse effects and provide an avenue for studying G protein-coupled receptor modulation. [Display omitted] • BPRMU191 exemplifies an antagonist-to-agonist modulator of mu-opioid receptor (MOR) • BPRMU191 converts opioid antagonists to G protein-biased agonists of MOR • BPRMU191 /opioid antagonist combination induces analgesia while minimizing side effects • Antagonist-to-agonist modulators of GPCRs display strong therapeutic potential Huang, Lin, and Ou et al. identified BPRMU191 , a small molecule that endows morphinan antagonists of mu-opioid receptor with agonistic properties, thereby activating the receptor and inducing analgesia. This work demonstrates an effective approach for modulating the activity of G protein-coupled receptors by small molecules that modulate the receptor conformation. [ABSTRACT FROM AUTHOR]