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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

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 and Steven M. Rothman
Journal of Pharmacology and Experimental Therapeutics June 1998, 285 (3) 1303-1309;
Matthew W. Hill
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P. Amruta Reddy
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Douglas F. Covey
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Steven M. Rothman
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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 GABAA 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 GABAA 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 GABAAreceptors, 3-BEP modulates sodium channels. Therefore this compound may prevent seizures by both enhancing inhibition and diminishing neuronal excitability.

Footnotes

  • Send reprint requests to: Dr. Steven Rothman, Department of Neurology, St. Louis Children’s Hospital, Room 12E/25, One Children’s Place, St. Louis, MO 63110.

  • ↵1 This work was supported by National Institutes of Health Grant NS14834.

  • Abbreviations:
    GABA
    γ-aminobutyric acid
    ATP
    adenosinetriphosphate
    3-BEP
    3-benzyl-3-ethyl-piperidinone
    • Received September 4, 1997.
    • Accepted February 9, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 285, Issue 3
1 Jun 1998
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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

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 and Steven M. Rothman
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1303-1309;

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OtherCELLULAR AND MOLECULAR PHARMACOLOGY

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 and Steven M. Rothman
Journal of Pharmacology and Experimental Therapeutics June 1, 1998, 285 (3) 1303-1309;
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