title: Asymmetric synthesis of batrachotoxin: Enantiomeric toxins show functional divergence against NaV.
abstract: 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 NaVsubtypes 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 NaVThese findings motivate and enable subsequent studies aimed at revealing how small molecules that target the channel inner pore modulate NaVdynamics.
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Logan
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Toma
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA.
authors.forename: Rhiannon
authors.initials: R
authors.lastname: Thomas-Tran
authors.affiliation: Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA. jdubois@stanford.edu.
authors.forename: J
authors.initials: J
authors.lastname: Du Bois
mesh_terms: D000818:Animals; D001496:Batrachotoxins / Q000138:chemical synthesis* / Q000494:pharmacology*; D001665:Binding Sites; D009124:Muscle Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D017354:Point Mutation; D017433:Protein Structure, Secondary; D051381:Rats; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics; D061567:Voltage-Gated Sodium Channel Blockers / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001496:Batrachotoxins; D009124:Muscle Proteins; C466180:Scn4a protein, rat; D015222:Sodium Channels; D061567:Voltage-Gated Sodium Channel Blockers; C031775:batrachotoxinin A 20-alpha-benzoate