文摘
We prepared 13 derivatives of N-(biphenyl-4鈥?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鈥檚 whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD<sub>50sub>/ED<sub>50sub>) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na<sup>+sup> channel slow inactivation and displayed frequency (use) inhibition of Na<sup>+sup> currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed.