基于[3.3.3]螺桨烷的电压门控钙离子通道α2δ亚基配体的合成和生物活性研究  

Design,Synthesis and Bioactivity of[3.3.3]Propellane-Based Voltage-Gated Calcium Channelα2δSubunit Ligands

作　　者：何金燕 田富云 吴青青 郑月明 陈玉婷 许海燕 金正盛 詹丽 程新强 顾跃玲 高召兵 赵桂龙 He Jinyan;Tian Fuyun;Wu Qingqing;Zheng Yueming;Chen Yuting;Xu Haiyan;Jin Zhengsheng;Zhan Li;Cheng Xinqiang;Gu Yueling;Gao Zhaobing;Zhao Guilong(School of Pharmacy,Zunyi Medical University,Zunyi,Guizhou 563003;Zhongshan Institute for Drug Discovery,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Zhongshan,Guangzhou 528400;Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203)

机构地区：[1]遵义医科大学药学院,贵州遵义563003 [2]中科中山药物创新研究院,广东中山528400 [3]中国科学院上海药物研究所,上海201203

出　　处：《有机化学》2023年第6期2226-2238,共13页Chinese Journal of Organic Chemistry

基　　金：中山市自然科学基金(Nos.200805173640573,210730214049987);广东省自然科学基金(No.2021A1515010197);广东省高水平新型研发机构战略专项资金(No.2019B090904008);广东省高水平创新研究院战略专项资金(No.2021B0909050003)资助项目。

摘　　要：电压门控钙离子通道(VGCC)α2δ亚基配体类药物是目前治疗慢性神经疼痛最安全有效的药物之一.为了研究含有大位阻的、构象限制的烷基骨架对该类药物生物活性的影响,设计并合成了3个含有[3.3.3]螺桨烷结构和1个含二环[3.3.0]辛烷结构的γ-氨基丁酸(GABA)衍生物.所合成的化合物使用了~1H NMR,^(13)C NMR和高分辨质谱(HRMS)进行了结构表征,并测试了它们对人源化电压门控钙离子通道α2δ亚基的亲和力(IC_(50)).研究结果发现:[3.3.3]螺桨烷在VGCCα2δ配体类药物结构中具有一定的兼容性,但是其体积已经超过了脂肪族取代结构的最佳体积;VGCCα2δ配体类药物分子中的GABA链上的氨基不能有任何取代或者衍生,否则活性降低甚至完全丧失.本研究的结论对于未来设计新颖的VGCCα2δ配体类药物具有重要的指导作用.Voltage-gated calcium channel(VGCC)α2δsubunit 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 VGCCα2δsubunit ligands,threeγ-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,~(13)C NMR and high-resolution mass spectrometry(HRMS),and subjected to in vitro human VGCCα2δsubunit binding assay.The bioactivity results indicated that:[3.3.3]propellane can be tolerated in the VGCCα2δligand,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 VGCCα2δsubunit ligands.

关 键 词：螺桨烷 电压门控钙离子通道 α2δ亚基 合成 生物活性 构效关系 

分 类 号：TQ460.1[化学工程—制药化工]