Vol. 285, Issue 3, 1303-1309, June 1998

Inhibition of Voltage-Dependent Sodium Channels by the Anticonvulsant -Aminobutyric Acid Type A Receptor Modulator, 3-Benzyl-3-Ethyl-2-Piperidinone¹

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

Departments of Neurology and Neurosurgery (M.W.H., S.M.R.) and Molecular Biology and Pharmacology (P.A.R.), Washington University School of Medicine and the Department of Neurology (S.M.R.), St. Louis Children's Hospital, St. Louis, Missouri

3-Benzyl-3-ethyl-2-piperidinone (3-BEP) belongs to a family of compounds that includes - substituted -butyrolactones, -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 -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  = 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.