Synthesis of Skeletal Analogues of Saxitoxin Derivatives and Evaluation of Their Inhibitory Activity on Sodium Ion Channels Nav1.4 and Nav1.5

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 4a-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 (4a) and (-)-FD-dcSTX (4b), which showed moderate inhibitory activity, were further evaluated by the use of the patch-clamp method in cells that expressed Na(v)1.4 (a tetrodotoxin-sensitive sodium channel subtype) and Na(v)1.5 (a tetrodotoxin-resistant sodium channel subtype). These compounds showed moderate inhibitory activity towards Na(V)1.4, and weaker inhibitory activity towards Na(v)1.5. Uniquely, however, the inhibition of Na(v)1.5 by (-)-FD-dcSTX (4b) was irreversible.