2. Academic Validation
  3. A Novel Bifunctional μOR Agonist and σ1R Antagonist with Potent Analgesic Responses and Reduced Adverse Effects

A Novel Bifunctional μOR Agonist and σ1R Antagonist with Potent Analgesic Responses and Reduced Adverse Effects

  • J Med Chem. 2023 Dec 14;66(23):16257-16275. doi: 10.1021/acs.jmedchem.3c01637.
Zhuang Miao 1,  Yuhan Zhong 2,  Yu Gan 1,  Kequan Fu 3,  Wencheng Liu 1,  Zhihua Cao 1,  Tiantian Zhao 1,  Ziyuan Li 1,  Ao Hai 1,  Yanlai Peng 2,  Zeping Zuo 1,  Tian Zhang 1,  Shilong Hu 1,  Chunxia Chen 2,  Ting Kang 1,  Tianguang Huang 1,  Dong Guo 3,  Bowen Ke 1
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 2 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
  • 3 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, 209 Tongshan Road, Xuzhou 221004, China.
PMID: 38015878 DOI: 10.1021/acs.jmedchem.3c01637
Abstract

Bifunctional ligands possessing both μOR agonism and σ1R antagonism have shown promise in producing strong analgesic effects with reduced opioid-related side effects. However, the μOR agonism activity of most dual ligands diminishes compared with classical opioids, raising concern about their effectiveness in managing nociceptive pain. In this study, a new class of dual μOR agonist/σ1R antagonist was reported. Through structure-activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar μOR agonism activity (EC50: 0.6 ± 0.2 nM) and good σ1R inhibitory activity (Ki: 363.7 ± 5.6 nM) with excellent selectivity. Compound 4x exhibited robust analgesic effects in various pain models, with significantly reduced side effects. Importantly, compound 4x also possessed good safety profiles and no abnormalities were observed in biological parameters even under a high dosage. Our findings suggest that 4x may be a promising lead compound for developing safer opioids and warrants further in-depth studies.

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