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
收稿日期: 2022-10-09
修回日期: 2022-11-17
网络出版日期: 2022-12-14
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
Received date: 2022-10-09
Revised date: 2022-11-17
Online published: 2022-12-14
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)
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, 13C 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(IC50). 研究结果发现: [3.3.3]螺桨烷在VGCC α2δ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; VGCC α2δ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VGCC α2δ配体类药物具有重要的指导作用.
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 . 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[J]. 有机化学, 2023 , 43(6) : 2226 -2238 . DOI: 10.6023/cjoc202210007
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.
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