Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na _V1.4 and Na _V1.5

Skeletal analogues of saxitoxin (STX) that possess a fused-type tricyclic ring system, designated FD-STX, were synthesized as candidate sodium ion channel modulators. Three kinds of FD-STX derivatives 4 a-c with different substitution at C13 were synthesized, and their inhibitory activity on sodium ion channels was examined by means of cell-based assay. (-)-FD-STX (4 a) and (-)-FD-dcSTX (4 b), which showed moderate inhibitory activity, were further evaluated by the use of the patch-clamp method in cells that expressed Na _V1.4 (a tetrodotoxin-sensitive sodium channel subtype) and Na _V1.5 (a tetrodotoxin-resistant sodium channel subtype). These compounds showed moderate inhibitory activity towards Na _V1.4, and weaker inhibitory activity towards Na _V1.5. Uniquely, however, the inhibition of Na _V1.5 by (-)-FD-dcSTX (4 b) was "irreversible".