Chinese Journal of Organic Chemistry ›› 2023, Vol. 43 ›› Issue (6): 2226-2238.DOI: 10.6023/cjoc202210007 Previous Articles     Next Articles


何金燕a,b, 田富云b,c, 吴青青b, 郑月明c, 陈玉婷b, 许海燕c, 金正盛b, 詹丽c, 程新强b, 顾跃玲c, 高召兵a,b,c,*(), 赵桂龙a,b,c,*()   

  1. a 遵义医科大学药学院 贵州遵义 563003
    b 中科中山药物创新研究院 广东中山 528400
    c 中国科学院上海药物研究所 上海 201203
  • 收稿日期:2022-10-09 修回日期:2022-11-17 发布日期:2022-12-14
  • 作者简介:
  • 基金资助:
    中山市自然科学基金(200805173640573); 中山市自然科学基金(210730214049987); 广东省自然科学基金(2021A1515010197); 广东省高水平新型研发机构战略专项资金(2019B090904008); 广东省高水平创新研究院战略专项资金(2021B0909050003)

Design, Synthesis and Bioactivity of [3.3.3]Propellane-Based Voltage-Gated Calcium Channel α2δ Subunit Ligands

Jinyan Hea,b, Fuyun Tianb,c, Qingqing Wub, Yueming Zhengc, Yuting Chenb, Haiyan Xuc, Zhengsheng Jinb, Li Zhanc, Xinqiang Chengb, Yueling Guc, Zhaobing Gaoa,b,c,*(), Guilong Zhaoa,b,c,*()   

  1. a School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou 563003
    b Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan, Guangzhou 528400
    c Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
  • Received:2022-10-09 Revised:2022-11-17 Published:2022-12-14
  • Contact: E-mail:;
  • About author:
    These authors contributed equally to this work
  • Supported by:
    Zhongshan Municipal Natural Science Foundation(200805173640573); Zhongshan Municipal Natural Science Foundation(210730214049987); Guangdong Provincial Basic and Applied Basic Research Foundation(2021A1515010197); Guangdong Provincial High-Level New R&D Institute Strategic Special Fund(2019B090904008); Guangdong Provincial High-level Innovative Research Institute Strategic Special Fund(2021B0909050003)

Voltage-gated calcium channel (VGCC) α2δ subunit ligands represent one of the most efficacious and safest classes of drugs for the treatment of chronic neuropathic pain. In order to investigate the effect of the sterically bulky alkyl moieties with constrained conformation on the bioactivity of VGCC α2δ subunit ligands, three γ-aminobutyric acids (GABAs) substitued with [3.3.3]propellane and one GABA with bicyclo[3.3.0]octane were designed and synthesized. All the syntheszied compounds were characterzied by 1H NMR, 13C NMR and high-resolution mass spectrometry (HRMS), and subjected to in vitro human VGCC α2δ subunit binding assay. The bioactivity results indicated that: [3.3.3]propellane can be tolerated in the VGCC α2δ ligand, but its size is bulkier than the optimal size. The amino group in GABA chain can not be modified or replaced; otherwise, the bioactivity will decrease dramatically or even be lost. The structure-activity relationship revealed in the present study may be helpful for the future design of novel VGCC α2δ subunit ligands.

Key words: propellane, voltage-gated calcium channel, α2δ subunit, synthesis, bioactivity, structure-activity relationship