title: Synthesis of skeletal analogues of saxitoxin derivatives and evaluation of their inhibitory activity on sodium ion channels Na(V)1.4 and Na(V)1.5.
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 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".
authors.affiliation: Tokyo University of Agriculture and Technology, Department of Biotechnology and Life Science, Koganei, Tokyo 184-8588, Japan.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Shinohara
authors.forename: Takafumi
authors.initials: T
authors.lastname: Akimoto
authors.forename: Osamu
authors.initials: O
authors.lastname: Iwamoto
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Mari
authors.initials: M
authors.lastname: Yotsu-Yamashita
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamaoka
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
mesh_terms: D001665:Binding Sites; D007700:Kinetics; D012530:Saxitoxin / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D012964:Sodium / Q000737:chemistry* / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013779:Tetrodotoxin / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D026941:Sodium Channel Blockers; D015222:Sodium Channels; D012530:Saxitoxin; D013779:Tetrodotoxin; D012964:Sodium