Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist beta-naphthoyl-brevetoxin.

Brevetoxins are neurotoxic compounds produced by the dinoflagellate Karenia brevis. Extensive blooms induce neurotoxic shellfish poisoning (NSP) and asthma-like symptoms in humans. beta-naphthoyl-brevetoxin, the first semisynthetic brevetoxin antagonist, has been defined as the lead compound in the investigation of the mechanisms of bronchoconstriction induced by inhaled brevetoxins and relaxation or reversal of those effects by selected derivatives. In pursuit of more potent and effective brevetoxin antagonists, a series of beta-naphthoyl-brevetoxin analogues have been synthesized. Activities were determined by competitive displacement of tritiated brevetoxin-3 from rat brain synaptosomes and by lung resistance measurements in sheep. Additionally, preliminary computational structural studies have been performed. All analogues bound to rat brain synaptosomes with affinities similar to beta-naphthoyl-brevetoxin but exhibited very different responses in sheep. The biological evaluations along with computational studies suggest that the brevetoxin binding site in rat brain synaptosome might be different from the ones in lung tissue and both steric and electrostatic factors contribute to the efficacy of brevetoxin antagonism.