Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na V1.4 and Na V1.5

Ryoko Shinohara, Takafumi Akimoto, Osamu Iwamoto, Takatsugu Hirokawa, Mari Yotsu-Yamashita, Kaoru Yamaoka, Kazuo Nagasawa

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

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".

Original languageEnglish
Pages (from-to)12144-12152
Number of pages9
JournalChemistry - A European Journal
Volume17
Issue number43
DOIs
Publication statusPublished - 2011 Oct 17

Keywords

  • inhibitors
  • ion channels
  • patch-clamp method
  • saxitoxins
  • sodium
  • structure-activity relationships

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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