CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia.
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
Mar Drugs. 2012 Oct;10(10):2349-2368. doi: 10.3390/md10102349. Epub 2012 Oct 22.
The neuronal voltage-gated N-type calcium channel (Ca(v)2.2) is a validated target for the treatment of neuropathic pain. A small library of anthranilamide-derived ω-Conotoxin GVIA mimetics bearing the diphenylmethylpiperazine moiety were prepared and tested using three experimental measures of calcium channel blockade. These consisted of a ¹²⁵I-ω-conotoxin GVIA displacement assay, a fluorescence-based calcium response assay with SH-SY5Y neuroblastoma cells, and a whole-cell patch clamp electrophysiology assay with HEK293 cells stably expressing human Ca(v)2.2 channels. A subset of compounds were active in all three assays. This is the first time that compounds designed to be mimics of ω-conotoxin GVIA and found to be active in the ¹²⁵I-ω-conotoxin GVIA displacement assay have also been shown to block functional ion channels in a dose-dependent manner.
神经元电压门控 N 型钙通道（Ca(v)2.2）是治疗神经性疼痛的有效靶点。我们制备了一组含有二苯甲基哌嗪结构的源于邻氨甲酰苯甲酸的ω-Conotoxin GVIA 模拟物，并使用三种钙通道阻断的实验方法进行了测试。这些方法包括 ¹²⁵I-ω-conotoxin GVIA 置换测定、用 SH-SY5Y 神经母细胞瘤细胞进行的基于荧光的钙反应测定以及用稳定表达人 Ca(v)2.2 通道的 HEK293 细胞进行的全细胞膜片钳电生理学测定。一组化合物在所有三种测定中均具有活性。这是首次发现设计为 ω-Conotoxin GVIA 模拟物并在 ¹²⁵I-ω-conotoxin GVIA 置换测定中具有活性的化合物也能以剂量依赖的方式阻断功能性离子通道。
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