TY - JOUR
T1 - Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na V1.4 and Na V1.5
AU - Shinohara, Ryoko
AU - Akimoto, Takafumi
AU - Iwamoto, Osamu
AU - Hirokawa, Takatsugu
AU - Yotsu-Yamashita, Mari
AU - Yamaoka, Kaoru
AU - Nagasawa, Kazuo
PY - 2011/10/17
Y1 - 2011/10/17
N2 - 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".
AB - 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".
KW - inhibitors
KW - ion channels
KW - patch-clamp method
KW - saxitoxins
KW - sodium
KW - structure-activity relationships
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U2 - 10.1002/chem.201101058
DO - 10.1002/chem.201101058
M3 - Article
C2 - 21922571
AN - SCOPUS:80054042382
VL - 17
SP - 12144
EP - 12152
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 43
ER -