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

doi:10.6023/cjoc202210007

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

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

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^,^*()

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:
^† 共同第一作者
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 He^a^,^b, Fuyun Tian^b^,^c, Qingqing Wu^b, Yueming Zheng^c, Yuting Chen^b, Haiyan Xu^c, Zhengsheng Jin^b, Li Zhan^c, Xinqiang Cheng^b, Yueling Gu^c, Zhaobing Gao^a^,^b^,^c,*(), Guilong Zhao^a^,^b^,^c,*()

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: zhao_guilong@126.com; zbgao@simm.ac.cn
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)

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Abstract

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

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Jinyan He, Fuyun Tian, Qingqing Wu, Yueming Zheng, Yuting Chen, Haiyan Xu, Zhengsheng Jin, Li Zhan, Xinqiang Cheng, Yueling Gu, Zhaobing Gao, Guilong Zhao. Design, Synthesis and Bioactivity of [3.3.3]Propellane-Based Voltage-Gated Calcium Channel α2δ Subunit Ligands[J]. Chinese Journal of Organic Chemistry, 2023, 43(6): 2226-2238.

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Fig. & Tab. 5

Figure 1. Structures of γ-aminobutyric acid (GABA) and voltage-gated calcium channel α2δ subunit ligands approved and in active clinical trials (Part A) and designed in the present study (Part B)

Scheme 1. Synthetic route to designed target compounds 1~3

Scheme 2. Initially attempted unsuccessful synthetic routes to target compound 1

Scheme 3. Synthetic route to designed target compound 4

Compd	IC₅₀/(μmol•L^–1)	Inhibition rate	K_i/(μmol•L^–1)	n_H
1•HCl	1.63		1.31	0.86
2•HCl	>7.29	31% at 7.29 μmol/L	—	—
3	>7.29	–5% at 7.29 μmol/L	—	—
4•HCl	1.09		0.87	0.97
4A•HCl	6.51		5.21	0.83
Mirogabalin	0.0066		0.00528	1.35

Table 1. Result of inhibition of [3H]gabapentin binding to human recombinant calcium channel Cav2.2/β3/α2δ-1 receptor expressed in CHO cells by synthesized target compounds 1~4 and 4A

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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 Channel α2δ Subunit Ligands

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