title: Substituted N-(biphenyl-4'-yl)methyl (R)-2-acetamido-3-methoxypropionamides: potent anticonvulsants that affect frequency (use) dependence and slow inactivation of sodium channels.
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.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, and ‡Department of Chemistry, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
authors.forename: Hyosung
authors.initials: H
authors.lastname: Lee
authors.forename: Ki Duk
authors.initials: KD
authors.lastname: Park
authors.forename: Robert
authors.initials: R
authors.lastname: Torregrosa
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.forename: Erik T
authors.initials: ET
authors.lastname: Dustrude
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Cindy
authors.initials: C
authors.lastname: Barbosa
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Xiao
authors.forename: Theodore R
authors.initials: TR
authors.lastname: Cummins
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000188:drug therapy*; D012694:Serine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D001713:Biphenyl Compounds; D026941:Sodium Channel Blockers; D012694:Serine; D012964:Sodium