Inhibition of brevetoxin binding to the voltage-gated sodium channel by gambierol and gambieric acid-A

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 ([H-3]PbTx-3), which showed, for the first time, that gambierol and gambieric acid-A inhibit the binding of [H-3]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. (C) 2003 Elsevier Science Ltd. All rights reserved.