Abstract
Excerpt: Five naturally occurring brevetoxins and seven synthetically modified brevetoxins were examinedfor their affinity for site 5 of the voltage-gated sodium channel and their toxicity to mosquito fish,Gambusia affinis. All but three of the toxins studied still retained some affinity for their receptorsite (ICso’s in the range of 1-100 nM). Compound 7, having all three carbon-carbon double bondsreduced, is almost 3 orders of magnitude less strongly bound than 4, which has only two carbon-carbon bonds reduced. This large effect resulting from H-ring reduction was unexpected, due to thesimilarity of this region of the molecule to the corresponding region of brevetoxin-A, which has afully saturated eight-membered G-ring and is the most strongly bound toxin of those studied.Conformational analysis revealed that the unsaturated H-ring of brevetoxin B favors the boat-chairconformation as does the saturated G-ring of brevetoxin A. Upon reduction, the H-ring of brevetoxinB shifts to a crown conformation. This subtle change in conformational preference induces a significantchange in the gross shape of the molecule, which we believe is responsible for the loss of bindingaffinity and toxicity.
