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 language | English (US) |
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Pages (from-to) | 1037-1049 |
Number of pages | 13 |
Journal | ACS Chemical Neuroscience |
Volume | 3 |
Issue number | 12 |
DOIs | |
State | Published - Dec 19 2012 |
Externally published | Yes |
Keywords
- Benzyloxyphenyl pharmacophore
- anticonvulsant activity
- epilepsy
- hyperexcitable neurons
- slow inactivation
- voltage-gated sodium channels
ASJC Scopus subject areas
- Biochemistry
- Physiology
- Cognitive Neuroscience
- Cell Biology