Referenced in: none

Automatically associated channels: Slo1

Title: Identification of the benzyloxyphenyl pharmacophore: a structural unit that promotes sodium channel slow inactivation.

Authors: Amber M King, Xiao-Fang Yang, Yuying Wang, Erik T Dustrude, Cindy Barbosa, Michael R Due, Andrew D Piekarz, Sarah M Wilson, Fletcher A White, Christophe Salomé, Theodore R Cummins, Rajesh Khanna, Harold Kohn

Journal, date & volume: ACS Chem Neurosci, 2012 Dec 19 , 3, 1037-49

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23259039

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.