Lee, HyosungPark, Ki DukTorregrosa, RobertYang, Xiao-FangDustrude, Erik T.Wang, YuyingWilson, Sarah M.Barbosa, CindyXiao, YuchengCummins, Theodore R.Khanna, RajeshKohn, Harold2016-03-142016-03-142014-07-24Lee, H., Park, K. D., Torregrosa, R., Yang, X.-F., Dustrude, E. T., Wang, Y., … Kohn, H. (2014). Substituted N-(Biphenyl-4′-yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels. Journal of Medicinal Chemistry, 57(14), 6165–6182. http://doi.org/10.1021/jm500707r0022-2623https://hdl.handle.net/1805/8852, 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.en-USIUPUI Open Access PolicyAnticonvulsantschemistrypharmacologyBiphenyl CompoundsSeizuresdrug therapySerineanalogs & derivativesSodiummetabolismSodium Channel BlockersArticle