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

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

  • Cell Chem Biol. 2024 Nov 21;31(11):1885-1898.e10. doi: 10.1016/j.chembiol.2024.06.013.
Yi-Han Huang 1,  Shu-Yu Lin 2,  Li-Chin Ou 2,  Wei-Cheng Huang 2,  Po-Kuan Chao 2,  Yung-Chiao Chang 2,  Hsiao-Fu Chang 2,  Pin-Tse Lee 2,  Teng-Kuang Yeh 2,  Yu-Hsien Kuo 2,  Ya-Wen Tien 2,  Jing-Hua Xi 3,  Pao-Luh Tao 4,  Pin-Yuan Chen 5,  Jian-Ying Chuang 6,  Chuan Shih 2,  Chiung-Tong Chen 2,  Chun-Wei Tung 2,  Horace H Loh 7,  Shau-Hua Ueng 8,  Shiu-Hwa Yeh 9
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan; Research Center for Neuroscience, Taipei Medical University, Taipei 110, Taiwan.
  • 2 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan.
  • 3 Department of Pharmacology, Medical School University of Minnesota, Minneapolis, MN 55455-0217, USA.
  • 4 Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli 35053, Taiwan.
  • 5 Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Chang Gung University, Keelung 20401, Taiwan.
  • 6 Research Center for Neuroscience, Taipei Medical University, Taipei 110, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan.
  • 7 Department of Pharmacology, Medical School University of Minnesota, Minneapolis, MN 55455-0217, USA; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China. Electronic address: lohxx001@yahoo.com.
  • 8 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan; School of Pharmacy, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. Electronic address: shueng@nhri.edu.tw.
  • 9 Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Miaoli 35053, Taiwan; Ph.D. Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University and National Health Research Institutes, Taipei 110, Taiwan. Electronic address: bau9763@nhri.edu.tw.
PMID: 39025070 DOI: 10.1016/j.chembiol.2024.06.013
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.

Keywords

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

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