Development of TTX-resistant voltage-gated sodium channel inhibitor

岩藻毒素(STX)是一种有效的NaVCH抑制剂。NaVChs在动作电位的启动和传播中起着关键作用，目前已确定了10种亚型。由于这些亚型的作用尚未得到很好的研究，因此开发专门针对NaVChs亚型的NaVCH配体非常重要。为了解决这一问题，我们对STX进行了合成孔径雷达研究，以开发TTX-r亚型选择性NaVCH调节剂。因此，我们首次合成了C13-N-取代的STX衍生物，在C13位含胍、尿素和乙酰胺。这些衍生物之所以令人感兴趣，是因为STX在C13上有一个氨甲酰基，而胍、尿素和乙酰胺基团在大小上相似，但在静电性质上不同。用膜片钳方法评价了这些新的STX对NaVCH的抑制活性，发现它们对NaV1.5的TTX-r亚型具有中等的抑制活性。这些结果表明，C13的静电特性对NaVCH的抑制活性具有重要意义。

Saxitoxin (STX) is a potent inhibitor of NaVCh. NaVChs play critical roles in the initiation and propagation of action potentials, and ten subtypes have been characterized. Since the roles of the subtypes are not well explored, development of NaVCh ligands specifically targeting subtypes of NaVChs is important. To address this issue, we performed SAR studies of STX to develop TTX-r subtype-selective NaVCh modulators.Thus, we synthesized C13-N-substituted STX derivatives, bearing guanidine, urea, and acetamide at C13 for the first time. These derivatives are of interest because STX has a carbamoyl group at C13, and guanidine, urea, and acetamide groups are similar in size, but different in electrostatic character. The NaVCh-inhibitory activity of those new STXs was evaluated by patch-clamp method, and they showed moderate inhibitory activity against TTX-r subtype of NaV1.5. These results indicate the electrostatic character of the C13 is significant for NaVCh-inhibitory activity.