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 (Na_Vs). 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 Na_V 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 Na_V These findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate Na_V dynamics.