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

Yi Han Huang, Shu Yu Lin, Li Chin Ou, Wei Cheng Huang, Po Kuan Chao, Yung Chiao Chang, Hsiao Fu Chang, Pin Tse Lee, Teng Kuang Yeh, Yu Hsien Kuo, Ya Wen Tien, Jing Hua Xi, Pao Luh Tao, Pin Yuan Chen, Jian Ying Chuang, Chuan Shih, Chiung Tong Chen, Chun Wei Tung, Horace H. Loh, Shau Hua UengShiu Hwa Yeh

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1885-1898.e10
JournalCell Chemical Biology
Volume31
Issue number11
DOIs
Publication statusAccepted/In press - 2024

Keywords

  • addiction
  • antagonist
  • antinociception
  • G protein-coupled receptor
  • modulator
  • mu-opioid receptor
  • naloxone
  • tolerance
  • withdrawal

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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