Chinese Journal of Organic Chemistry >
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)
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.
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 . DOI: 10.6023/cjoc202210007
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