A Novel Bifunctional μOR Agonist and σ 1 R Antagonist with Potent Analgesic Responses and Reduced Adverse Effects

作者：Zhuang Miao, Yuhan Zhong, Yu Gan, Kequan Fu, Wen‐Cheng Liu, Zhihua Cao, Tiantian Zhao, Ziyuan Li, Ao Hai, Yanlai Peng, Zeping Zuo, Tian Zhang, Shilong Hu, Chunxia Chen, Ting Kang, Tianguang Huang, Dong Guo, Bowen Ke · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.3c01637 · 被引用次数：6 · 研究领域：Pharmacological Receptor Mechanisms and Effects、Neuropeptides and Animal Physiology、Receptor Mechanisms and Signaling

Bifunctional ligands possessing both μOR agonism and σ 1 R 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/σ 1 R antagonist was reported. Through structure–activity relationship analyses, we identified the optimal compound, 4x, which displayed picomolar μOR agonism activity (EC 50: 0.6 ± 0.2 nM) and good σ 1 R inhibitory activity ( K i: 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.