INHIBITION OF VOLTAGE-DEPENDENT SODIUM-CHANNELS BY THE ANTICONVULSANTGAMMA-AMINOBUTYRIC-ACID TYPE-A RECEPTOR MODULATOR, 3-BENZYL-3-ETHYL-2-PIPERIDINONE

3-Benzyl-3-ethyl-2-piperidinone (3-BEP) belongs to a family of compoun ds that includes alpha- substituted gamma-butyrolactones, gamma-thiobu tyrolactones, 2-pyrrolidinones and hexahydro-2H-azepin-2-ones. Many of these drugs exhibit potent in vivo anticonvulsant activity in mice. P revious electrophysiological studies demonstrated that they potentiate gamma-aminobutyric acid-(GABA) mediated chloride currents. This GABA( A) receptor modulation was thought to be the main mechanism of anticon vulsant 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 affi nity increased as neurons were depolarized. At a holding potential of -60 mV, the apparent IC50 was 487 mu M. This concentration is comparab le to its EC50 for GABA(A) modulation (575 mu M). Current blockade occ urred over all activation voltages tested. The steady state inactivati on curve was shifted by 600 mu M 3-BEP from V-50 = -65.3 mV to -72.0 m V, and recovery from inactivation was slowed from tau = 4.9 to 12.8 ms ec. Sodium current inhibition was not observed for three related compo unds, suggesting a degree of chemical specificity for this activity. W e 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 excitab ility.