Oxadiazolylindazole Sodium Channel Modulators are Neuroprotective toward Hippocampal Neurones
Oxadiazolylindazole Sodium Channel Modulators are Neuroprotective toward Hippocampal Neurones
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DOI：
10.1021/jm801180p
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发表时间：
2009-05-14
影响因子：
7.3
通讯作者：
Selwood, David L.
中科院分区：
文献类型：
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作者：
Clutterbuck, Lisa A.;Posada, Cristina Garcia;Selwood, David L.
我们报告了一类新的神经保护性电压依赖性钠通道调节剂的发现，以（5-（1-苄基-1H-吲唑-3-基）-1，2，4-恶二唑-3-基）甲胺为例。11（CFM 1178）。这些化合物是大鼠前脑突触体中[C-14]胍离子通量的抑制剂，并取代了钠通道配体[H-3] BW 202 W 92的结合。11和相应的N-2-苄基异构体38（CFM 6058）在海马切片中表现出与sipatrigine相当的神经保护活性。使用11观察到的CYP 450酶抑制作用降低，使用38。在对分离的海马神经元的电生理实验中，这两种化合物引起钠电流的使用和电压依赖性阻断。针对Na（v）1.1-1.8的钠通道亚型分析表明，标准钠通道阻断剂拉莫三嗪对Na（v）1.1具有中等活性，而西帕曲嗪通常更有效，选择性更低。11和38显示出针对Na（v）1.6的有效活性，表明该同种型的药理学阻断与神经保护作用一致。38在HEK细胞中也显示Na（v）1.6的使用依赖性阻断。
We report the discovery of a new class of neuroprotective voltage-dependent sodium channel modulators exemplified by (5-(1-benzyl-1H-indazol-3-yl)-1,2,4-oxadiazol-3-yl)methanamine. 11 (CFM1178). The compounds were inhibitors of [C-14]guanidinium ion flux in rat forebrain synaptosomes and displaced binding of the sodium channel ligand [H-3]BW202W92. 11 and the corresponding N-2-benzyl isomer, 38 (CFM6058), demonstrated neuroprotective activity in hippocampal slices comparable to sipatrigine. CYP450 enzyme inhibition observed with 11 was reduced with 38. In electrophysiological experiments on dissociated hippocampal neurons, these two compounds caused use- and voltage-dependent block of sodium currents. Sodium channel isoform profiling against Na(v)1.1-1.8 demonstrated that the standard sodium channel blocker lamotrigine had modest activity against Na(v)1.1, while sipatrigine was generally more potent and less selective. 11 and 38 showed potent activity against Na(v)1.6, pointing to pharmacological block of this isoform being consistent with the neuroprotective effect. 38 also showed use dependent block of Na(v)1.6 in HEK cells.