title: Identification of the benzyloxyphenyl pharmacophore: a structural unit that promotes sodium channel slow inactivation.
abstract: Four compounds that contained the N-benzyl 2-amino-3-methoxypropionamide unit were evaluated for their ability to modulate Na(+) currents in catecholamine A differentiated CAD neuronal cells. The compounds differed by the absence or presence of either a terminal N-acetyl group or a (3-fluoro)benzyloxy moiety positioned at the 4'-benzylamide site. Analysis of whole-cell patch-clamp electrophysiology data showed that the incorporation of the (3-fluoro)benzyloxy unit, to give the (3-fluoro)benzyloxyphenyl pharmacophore, dramatically enhanced the magnitude of Na(+) channel slow inactivation. In addition, N-acetylation markedly increased the stereoselectivity for Na(+) channel slow inactivation. Furthermore, we observed that Na(+) channel frequency (use)-dependent block was maintained upon inclusion of this pharmacophore. Confirmation of the importance of the (3-fluoro)benzyloxyphenyl pharmacophore was shown by examining compounds where the N-benzyl 2-amino-3-methoxypropionamide unit was replaced by a N-benzyl 2-amino-3-methylpropionamide moiety, as well as examining a series of compounds that did not contain an amino acid group but retained the pharmacophore unit. Collectively, the data indicated that the (3-fluoro)benzyloxyphenyl unit is a novel pharmacophore for the modulation of Na(+) currents.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: King
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Yang
authors.forename: Yuying
authors.initials: Y
authors.lastname: Wang
authors.forename: Erik T
authors.initials: ET
authors.lastname: Dustrude
authors.forename: Cindy
authors.initials: C
authors.lastname: Barbosa
authors.forename: Michael R
authors.initials: MR
authors.lastname: Due
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Piekarz
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Wilson
authors.forename: Fletcher A
authors.initials: FA
authors.lastname: White
authors.forename: Christophe
authors.initials: C
authors.lastname: Salomé
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: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000378:metabolism*
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D015222:Sodium Channels; D000078334:Lacosamide