2. Academic Validation
  3. Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities

Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities

  • Eur J Med Chem. 2025 Feb 26:289:117449. doi: 10.1016/j.ejmech.2025.117449.
Siyuan Tang 1,  Shuyang Hu 2,  Lijing Feng 3,  Linghui Kong 4,  Jiangwen Gui 5,  Ying Zhang 6,  Zi-Han Liu 7,  Denggao Zhang 4,  An-An Liu 7,  Xiao Liu 4,  Chuyuan Hu 8,  Yingjie Lan 4,  Xiaoning Liu 3,  Zixiang Li 4,  Panwen Liu 3,  Shaoliang Duan 4,  Zeyi Du 4,  Min Liu 3,  Qiong Xie 4,  Jinggen Liu 9,  Liming Shao 10,  Wei Fu 4,  Yujun Wang 11,  Wei Li 12
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China; School of Physical Science and Technology, ShanghaiTech University, No. 393 Huaxiazhong Road, Shanghai, 201210, China.
  • 2 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 3 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China.
  • 4 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; School of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China.
  • 6 School of Physical Science and Technology, ShanghaiTech University, No. 393 Huaxiazhong Road, Shanghai, 201210, China.
  • 7 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 8 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; University of Chinese Academy of Sciences, No. 19 A Yuquan Road, 100049, Beijing, China.
  • 9 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China. Electronic address: jgliu@simm.ac.cn.
  • 10 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: limingshao@fudan.edu.cn.
  • 11 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, 264117, China; University of Chinese Academy of Sciences, No. 19 A Yuquan Road, 100049, Beijing, China. Electronic address: yjwang@simm.ac.cn.
  • 12 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai, 201203, China. Electronic address: wei-li@fudan.edu.cn.
PMID: 40068406 DOI: 10.1016/j.ejmech.2025.117449
Abstract

Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa Opioid Receptor (KOR), especially those with additional mu Opioid Receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of meta-substituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound 10a. Unlike its para-positional isomer SLL-1062, where KOR activity is completely abolished, compound 10a displayed a single-digit nanomolar affinity for KOR, while its binding profiles for MOR and delta Opioid Receptor (DOR) were comparable to those of SLL-1062. Functional assays in vitro confirmed that compound 10a exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound 10a was further elucidated. Although compound 10a did not produce apparent antinociception in vivo, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD.

Keywords

KOR agonist; MOR antagonist; N-Cyclopropylmethyl-nornepenthones; Structure-activity relationship; Substance use disorder.

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