Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV.

The steroidal neurotoxin (-)-batrachotoxin functions as a potent agonist of voltage-gated sodium ion channels (NaVs). Here we report concise asymmetric syntheses of the natural (-) and non-natural (+) antipodes of batrachotoxin, as well both enantiomers of a C-20 benzoate-modified derivative. Electrophysiological characterization of these molecules against NaV subtypes establishes the non-natural toxin enantiomer as a reversible antagonist of channel function, markedly different in activity from (-)-batrachotoxin. Protein mutagenesis experiments implicate a shared binding side for the enantiomers in the inner pore cavity of NaV These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaV dynamics. Copyright © 2016, American Association for the Advancement of Science.

Citation

Matthew M Logan, Tatsuya Toma, Rhiannon Thomas-Tran, J Du Bois. Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV. Science (New York, N.Y.). 2016 Nov 18;354(6314):865-869

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PMID: 27856903

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