Development of TTX-resistant voltage-gated sodium channel inhibitor

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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.