Abstract
We prepared 13 derivatives of N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound's whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI=TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.
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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Anticonvulsants / administration & dosage
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Anticonvulsants / chemistry*
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Anticonvulsants / pharmacology*
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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HEK293 Cells
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Humans
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Male
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Mice
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Molecular Structure
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Rats
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Rats, Sprague-Dawley
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Seizures / drug therapy*
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Serine / administration & dosage
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Serine / analogs & derivatives*
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Serine / chemistry
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Serine / pharmacology
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Sodium / metabolism*
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Sodium Channel Blockers / administration & dosage
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Sodium Channel Blockers / chemistry*
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Sodium Channel Blockers / pharmacology*
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Structure-Activity Relationship
Substances
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Anticonvulsants
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Biphenyl Compounds
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Sodium Channel Blockers
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Serine
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Sodium