Synthetic studies on Subtype Selective Na-channel Inhibitors based upon Saxitoxins Synthesis

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Voltage-gated sodium channels(NaVCh) are transmembrane proteins that contribute to the control of membrane excitability and the propagation of action potentials along axons. To date, nine kinds of subtyps for NaVCh were identified, and subtype selective small molecules are considered to be good candidate for NaVCh related disease. In this context, development of NaVCh-subtype selective ligand with saxitoxin(STX), a shellfish toxin, was examined based on the SAR studies of STX. In this project, general synthetic method for STX was developed, and varieties of STX derivatives were synthesized. Skeletal analog of STX that posses fused-type ring system, FD-STX, was also developed. Among the compounds synthesized, FD-dcSTX shows very unique inhibitory manner, i. e., it inhibits Nav1. 5(tetrodotoxin-resistant subtype) irreversibly.