Brevetoxin B: Chemical Modifications, Synaptosome Binding, Toxicity, and an Unexpected Conformational Effect

Abstract

Five naturally occurring brevetoxins and seven synthetically modified brevetoxins were examined for 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 receptor site (IC50's in the range of 1-100 nM). Compound 7, having all three carbon-carbon double bonds reduced, is almost 3 orders of magnitude less strongly bound than 4, which has only two carboncarbon bonds reduced. This large effect resulting from H-ring reduction was unexpected, due to the similarity of this region of the molecule to the corresponding region of brevetoxin-A, which has a fully 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-chair conformation as does the saturated G-ring of brevetoxin A. Upon reduction, the H-ring of brevetoxin B shifts to a crown conformation. This subtle change in conformational preference induces a significant change in the gross shape of the molecule, which we believe is responsible for the loss of binding affinity and toxicity. © 1994, American Chemical Society. All rights reserved.