title: (Biphenyl-4-yl)methylammonium chlorides: potent anticonvulsants that modulate Na+ currents.
abstract: We have reported that compounds containing a biaryl linked unit (Ar-X-Ar') modulated Na(+) currents by promoting slow inactivation and fast inactivation processes and by inducing frequency (use)-dependent inhibition of Na(+) currents. These electrophysiological properties have been associated with the mode of action of several antiepileptic drugs. In this study, we demonstrate that the readily accessible (biphenyl-4-yl)methylammonium chlorides (compound class B) exhibited a broad range of anticonvulsant activities in animal models, and in the maximal electroshock seizure test the activity of (3'-trifluoromethoxybiphenyl-4-yl)methylammonium chloride (8) exceeded that of phenobarbital and phenytoin upon oral administration to rats. Electrophysiological studies of 8 using mouse catecholamine A-differentiated cells and rat embryonic cortical neurons confirmed that 8 promoted slow and fast inactivation in both cell types but did not affect the frequency (use)-dependent block of Na(+) currents.
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: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.forename: Erik T
authors.initials: ET
authors.lastname: Dustrude
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khanna
authors.forename: Harold
authors.initials: H
authors.lastname: Kohn
mesh_terms: D064751:Ammonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008744:Methylamines; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000187:drug effects* / Q000502:physiology
chemical_list: D064751:Ammonium Compounds; D000927:Anticonvulsants; D001713:Biphenyl Compounds; D008744:Methylamines; D015222:Sodium Channels; C027451:methylamine