Inhibition of voltage-dependent sodium channels by the anticonvulsant γ-aminobutyric acid type a receptor modulator, 3-benzyl-3-ethyl-2- piperidinone

Matthew W. Hill, P. Amruta Reddy, Douglas F. Covey, Steven M. Rothman

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

3-Benzyl-3-ethyl-2-piperidinone (3-BEP) belongs to a family of compounds that includes α- substituted γ-butyrolactones, γ-thiobutyrolactones, 2- pyrrolidinones and hexahydro-2H-azepin-2-ones. Many of these drugs exhibit potent in vivo anticonvulsant activity in mice. Previous electrophysiological studies demonstrated that they potentiate γ-aminobutyric acid-(GABA) mediated chloride currents. This GABA(A) receptor modulation was thought to be the main mechanism of anticonvulsant activity. We report that 3-BEP also modulates sodium channels. It decreased sodium currents in cultured rat hippocampal neurons in a voltage- and concentration-dependent manner. The drug's apparent affinity increased as neurons were depolarized. At a holding potential of -60 mV, the apparent IC50 was 487 μM. This concentration is comparable to its EC50 for GABA(A) modulation (575 μM). Current blockade occurred over all activation voltages tested. The steady state inactivation curve was shifted by 600 μM 3-BEP from V50 = -65.3 mV to -72.0 mV, and recovery from inactivation was slowed from T = 4.9 to 12.8 msec. Sodium current inhibition was not observed for three related compounds, suggesting a degree of chemical specificity for this activity. We conclude that in addition to its known effects on GABA(A) receptors, 3-BEP modulates sodium channels. Therefore this compound may prevent seizures by both enhancing inhibition and diminishing neuronal excitability.

Original languageEnglish
Pages (from-to)1303-1309
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume285
Issue number3
StatePublished - Jun 1 1998
Externally publishedYes

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