title: Inhibition of brevetoxin binding to the voltage-gated sodium channel by gambierol and gambieric acid-A.
abstract: Brevetoxins (BTXs) and ciguatoxins (CTXs) bind to site 5 of the voltage-gated sodium channel of excitable membranes. In the present study, we performed a competitive inhibition assay with other structurally distinct naturally occurring polyethers using isotope-labeled dihydro BTX-B ([3H]PbTx-3), which showed, for the first time, that gambierol and gambieric acid-A inhibit the binding of [3H]PbTx-3 while yessotoxins are inactive in this assay. The inhibition assay also suggested that there is a significant relationship between the size of the polycyclic region and inhibitory activity. Interestingly, the acute mouse toxicities of the compounds do not correspond directly to their inhibitory activities. These observations will serve as a guide for designing artificial polyethers with desired activity.
authors.affiliation: Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and Technology Corporation (JST), Sendai 980-8578, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Inoue
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hirama
authors.forename: Masayuki
authors.initials: M
authors.lastname: Satake
authors.forename: Kiminori
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yasumoto
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001921:Brain; D002922:Ciguatoxins / Q000737:chemistry / Q000378:metabolism; D004347:Drug Interactions; D004988:Ethers, Cyclic / Q000737:chemistry / Q000494:pharmacology*; D008387:Marine Toxins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D015394:Molecular Structure; D008978:Mollusk Venoms; D035964:Oxocins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D015222:Sodium Channels / Q000378:metabolism*; D013574:Synaptosomes; D000095702:Polyether Toxins
chemical_list: D002922:Ciguatoxins; D004988:Ethers, Cyclic; D008387:Marine Toxins; D008978:Mollusk Venoms; D035964:Oxocins; D011083:Polycyclic Compounds; D015222:Sodium Channels; C435770:gambierol; C080898:gambieric acid A; C053342:brevetoxin; D000095702:Polyether Toxins; C066632:yessotoxin