2. Academic Validation
  3. Structure-activity relationship of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives as G-protein-biased KOR-selective agonists

Structure-activity relationship of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives as G-protein-biased KOR-selective agonists

  • Eur J Med Chem. 2026 Mar 15:306:118591. doi: 10.1016/j.ejmech.2026.118591.
Siyuan Tang 1,  Jiangwen Gui 2,  Yingjie Lan 1,  Panwen Liu 3,  Yuliang Lin 1,  Meng Sun 4,  Shaoliang Duan 1,  Chao Zhang 5,  Denggao Zhang 1,  Min Liu 3,  Xiaobo Mai 1,  Jiaqi Tan 6,  Zhiwen Wang 5,  Jinggen Liu 7,  Liming Shao 1,  Wei Fu 8,  Yujun Wang 9,  Wei Li 10
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
  • 2 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Anhui University of Chinese Medicine, Hefei, 230012, Anhui, China.
  • 3 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China.
  • 4 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Yantai University, Yantai, 264117, Shandong, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Jiangxi University of Chinese Medicine, Nanchang, 330004, Jiangxi, China.
  • 6 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Shenyang Pharmaceutical University, No. 103 Wenhua Road, Shenyang, 110016, Liaoning, China.
  • 7 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; The Third Affiliated Hospital of Zhejiang Chinese Medical University, No.548 Binwen Road, Hangzhou, 310053, Zhejiang, China. Electronic address: [email protected].
  • 8 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China; Shanghai Fudan Zhangjiang Technology Transfer Co., Ltd., Room 402, No. 3, Lane 180, Zhangheng Road, China (Shanghai) Pilot Free Trade Zone, Shanghai, 201203, China. Electronic address: [email protected].
  • 9 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China. Electronic address: [email protected].
  • 10 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: [email protected].
PMID: 41570729 DOI: 10.1016/j.ejmech.2026.118591
Abstract

4,5-Epoxymorphinan derivatives represent a privileged chemotype among opioid ligands, with well-established clinical utility, and continue to serve as a widely used scaffold for the development of novel opioid-like therapeutics. This work describes the design and synthesis of a series of N-cyclopropylmethyl-7α-(m-methylaminophenyl)-6,14-endoethano-northebaine derivatives and identifies compound 8a as a structurally optimized KOR agonist with high KOR affinity, pronounced MOR/KOR and DOR/KOR subtype selectivity, and marked G-protein bias. In vivo, compound 8a exhibited robust, dose-dependent antinociceptive activity in both the hot-plate and abdominal constriction assays, with ED50 values of 8.2 and 0.5 mg/kg, respectively. Nevertheless, the emergence of motor impairment and aversive effects at behaviorally relevant doses underscores a critical limitation of relying solely on cell-based G-protein bias as a predictor of improved central nervous system safety for KOR agonists.

Keywords

4,5-Epoxymorphinan derivatives; Antinociceptive activity; G Protein–Biased KOR agonists; KOR-Selective agonists.

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