Abstract
A novel family of small molecule inhibitors of voltage-gated sodium channels (NaVs) based on the structure of batrachotoxin (BTX), a well-known channel agonist, is described. Protein mutagenesis and electrophysiology experiments reveal the binding site as the inner pore region of the channel, analogous to BTX, alkaloid toxins, and local anesthetics. Homology modeling of the eukaryotic channel based on recent crystallographic analyses of bacterial NaVs suggests a mechanism of action for ion conduction block.
Keywords:
SAR; Site II; batrachotoxin; electrophysiology; protein mutagenesis; sodium channel.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Batrachotoxins / analysis*
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Batrachotoxins / chemical synthesis
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Batrachotoxins / pharmacology*
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CHO Cells
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Cricetulus
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical
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Models, Molecular
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Molecular Structure
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Mutation
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Patch-Clamp Techniques
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Rats
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Sodium Channel Blockers / chemical synthesis
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Sodium Channel Blockers / pharmacology*
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Sodium Channels / genetics
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Sodium Channels / metabolism
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Structure-Activity Relationship
Substances
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Batrachotoxins
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Muscle Proteins
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Scn4a protein, rat
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Sodium Channel Blockers
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Sodium Channels