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

doi:10.1002/chem.201101058

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

AGR - Bioscience and Biotechnology for Future Bioindustries

Research output: Contribution to journal › Article › peer-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 language	English
Pages (from-to)	12144-12152
Number of pages	9
Journal	Chemistry - A European Journal
Volume	17
Issue number	43
DOIs	https://doi.org/10.1002/chem.201101058
Publication status	Published - 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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10.1002/chem.201101058

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Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na _V1.4 and Na _V1.5. / Shinohara, Ryoko; Akimoto, Takafumi; Iwamoto, Osamu; Hirokawa, Takatsugu; Yotsu-Yamashita, Mari; Yamaoka, Kaoru; Nagasawa, Kazuo.

In: Chemistry - A European Journal, Vol. 17, No. 43, 17.10.2011, p. 12144-12152.

Research output: Contribution to journal › Article › peer-review

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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{"}.",

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AU - Hirokawa, Takatsugu

AU - Yotsu-Yamashita, Mari

AU - Yamaoka, Kaoru

AU - Nagasawa, Kazuo

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