Identification of the benzyloxyphenyl pharmacophore: A structural unit that promotes sodium channel slow inactivation

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

Research output: Contribution to journalArticle

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1037-1049
Number of pages13
JournalACS Chemical Neuroscience
Volume3
Issue number12
DOIs
StatePublished - Dec 19 2012

Keywords

  • anticonvulsant activity
  • Benzyloxyphenyl pharmacophore
  • epilepsy
  • hyperexcitable neurons
  • slow inactivation
  • voltage-gated sodium channels

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

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    King, A. M., Yang, X. F., Wang, Y., Dustrude, E. T., Barbosa, C., Due, M. R., Piekarz, A. D., Wilson, S. M., White, F. A., Salomé, C., Cummins, T. R., Khanna, R., & Kohn, H. (2012). Identification of the benzyloxyphenyl pharmacophore: A structural unit that promotes sodium channel slow inactivation. ACS Chemical Neuroscience, 3(12), 1037-1049. https://doi.org/10.1021/cn300129d