2. Academic Validation
  3. Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[ para-(arylcarboxamido)phenyl]-6,14- endo ethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists

Structure-Activity Relationship of N-Cyclopropylmethyl-7α-[ para-(arylcarboxamido)phenyl]-6,14- endo ethano-tetrahydronorthebaines as Potent and Selective Kappa Opioid Receptor Agonists

  • J Med Chem. 2025 Aug 14;68(15):15889-15909. doi: 10.1021/acs.jmedchem.5c00882.
Linghui Kong 1,  Songyu Yao 2 3,  Denggao Zhang 1,  Jiangwen Gui 4 5,  Baiyu Chen 1,  Min Liu 5,  Siyuan Tang 1,  Chuyuan Hu 3 5,  Shaoliang Duan 1,  Biying Wang 5,  Zixiang Li 1,  Yiquan Shen 6,  Yingjie Lan 1,  Xiaoning Liu 5,  Zeyi Du 1,  Zihan Liu 2 3,  Qiong Xie 1,  Anan Liu 2 3,  Jingrui Chai 3,  Jinggen Liu 2 3 6,  Liming Shao 1,  Wei Fu 1,  Yujun Wang 3 5,  Wei Li 1
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Shanghai 201203, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 3 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, No. 555 Zuchongzhi Road, Shanghai 201203, China.
  • 4 School of Pharmacy, Anhui University of Chinese Medicine, Hefei 230012, China.
  • 5 Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China.
  • 6 School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou 310053, China.
PMID: 40721665 DOI: 10.1021/acs.jmedchem.5c00882
Abstract

Research on KOR agonists with reduced central nervous system side effects represents a significant area in analgesic studies. Herein, a structure-activity relationship analysis was performed for a series of N-cyclopropylmethyl-7α-[para-(arylcarboxamido)phenyl]-6,14-endoethano-tetrahydronorthebaines. Several highly selective and potent KOR agonists have been identified. Notably, compound 5i exhibited a subpicomolar binding affinity for KOR and exceptional subtype selectivity over MOR and DOR, consistent with its in vitro functional activities. It was identified as a G protein-biased KOR agonist, and its molecular interactions with KOR were elucidated. Additionally, this compound exhibited potent, dose-dependent, long-lasting, and KOR-mediated antinociceptive activity in both hot plate and abdominal constriction assays. It did not display any noticeable aversion or sedation in rodent models. These pharmacological characteristics suggest that compound 5i is a promising candidate for further studies.

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