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 τ = 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_Areceptors, 3-BEP modulates sodium channels. Therefore this compound may prevent seizures by both enhancing inhibition and diminishing neuronal excitability.