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Papers of the Week


Papers: 13 Jul 2024 - 19 Jul 2024


2024 Jul 09


Cell Chem Biol


39025070

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

Authors

Huang YH, Lin SY, Ou LC, Huang WC, Chao PK, Chang YC, Chang HF, Lee PT, Yeh TK, Kuo YH, Tien YW, Xi JH, Tao PL, Chen PY, Chuang JY, Shih C, Chen CT, Tung CW, Loh HH, Ueng SH, Yeh SH

Abstract

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.