Identification of the Benzyloxyphenyl Pharmacophore: A Structural Unit That Promotes Sodium Channel Slow Inactivation
详细信息 查看全文
- 作者：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 Salom茅 ; Theodore R. Cummins ; Rajesh Khanna ; Harold Kohn
- 刊名：ACS Chemical Neuroscience
- 出版年：2012
- 出版时间：December 19, 2012
- 年：2012
- 卷：3
- 期：12
- 页码：1037-1049
- 全文大小：706K
- 年卷期：v.3,no.12(December 19, 2012)
- ISSN：1948-7193
文摘
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鈥?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.