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

Sophie Michelliza, William M. Abraham, Henry M. Jacocks, Thomas Schuster, Daniel G. Baden

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Brevetoxins are neurotoxic compounds produced by the dinoflagellate Karenia brevis. Extensive blooms induce neurotoxic shellfish poisoning (NSP) and asthma-like symptoms in humans. β-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 β-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 β-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.

Original languageEnglish
Pages (from-to)2233-2239
Number of pages7
JournalChemBioChem
Volume8
Issue number18
DOIs
StatePublished - Dec 17 2007
Externally publishedYes

Fingerprint

Synaptosomes
Rats
Brain
Sheep
Shellfish Poisoning
Shellfish
Lead compounds
brevetoxin
Dinoflagellida
Lung
Bronchoconstriction
Static Electricity
Electrostatics
Asthma
Binding Sites
Tissue
Derivatives

Keywords

  • Binding assays
  • Natural products
  • Neurotoxins
  • Polyethers
  • Syntheses

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Medicine(all)

Cite this

Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist β- naphthoyl-brevetoxin. / Michelliza, Sophie; Abraham, William M.; Jacocks, Henry M.; Schuster, Thomas; Baden, Daniel G.

In: ChemBioChem, Vol. 8, No. 18, 17.12.2007, p. 2233-2239.

Research output: Contribution to journalArticle

Michelliza, Sophie ; Abraham, William M. ; Jacocks, Henry M. ; Schuster, Thomas ; Baden, Daniel G. / Synthesis, modeling, and biological evaluation of analogues of the semisynthetic brevetoxin antagonist β- naphthoyl-brevetoxin. In: ChemBioChem. 2007 ; Vol. 8, No. 18. pp. 2233-2239.
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