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
  • 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.
Products