Remacemide HC1 and its metabolite, FPL 12495AA, limit action potential firing frequency and block NMDA responses of mouse spinal cord neurons in cell culture

Wamil, Artur W.; Cheung, Helen; Harris, Eric W.; McLean, Michael J.

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Volume 23, Issue 1 , Pages 1-14, February 1996

Remacemide HC1 and its metabolite, FPL 12495AA, limit action potential firing frequency and block NMDA responses of mouse spinal cord neurons in cell culture

Artur W. Wamil
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
- Current address: Department of Anesthesiology, VUMC, 1161 21st Avenue South, T-4216 Medical Center North, Nashville, TN 37232-2125, USA. Tel.: (615) 322-4000; fax (615) 322-7446.
Helen Cheung
- Department of Biology, Astra Arcus USA, P.O. Box 20890, Rochester, NY 14602, USA
Eric W. Harris
- Department of Biology, Astra Arcus USA, P.O. Box 20890, Rochester, NY 14602, USA
Michael J. McLean
- Corresponding author. Department of Neurology, VUMC, 2100 Pierce Avenue, 351 MCS Nashville, TN 37212, USA. Tel.: (615) 936-0060; fax: (615) 936-0223.
- Department of Neurology, Veterans Administration Medical Center, Nashville, TN, USA
- Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA

Received 22 February 1993; received in revised form 21 March 1995; accepted 31 July 1995.

Abstract

The novel anticonvulsant, remacemide HCl [(±)-2-amino-N-(1-methyl-1,2-diphenylethyl)acetamide monohydrochloride; FPL12924AA], and a desglycinated metabolite [(±)-1-methyl-1,2-diphenylethylamine monohydrochloride; FPL 12495AA] reversibly limited sustained high-frequency repetitive firing (SRF) of sodium-dependent action potentials by mouse spinal cord neurons in monolayer dissociated cell culture. Limitation occurred with an IC₅₀ of 7.9 × 10⁻⁶ M for remacemide and 1.2 × 10⁻⁶ M for FPL 12495AA (P < 0.05 vs. remacemide). Stereoisomers of the desglycinate limited SRF with IC₅₀ values of 3.3 × 10⁻⁶ M and 3.5 × 10⁻⁶ M for the S(+) and R(−) compounds, respectively. The concentration of racemic desglycinate and of either stereoisomer that produced limitation in all neurons tested was 10⁻⁴ M. Maximal rate of rise () of action potentials decreased progressively until firing ceased during 400-ms depolarizing pulses. Efficacy of remacemide, but not of the desglycinate, increased with time (maximum at 16–36 h). The limitation was voltage dependent. In addition, reduction and action potential failure occurred during stimulation with 400-ms pulses and trains of brief (1 ms) depolarizations at different frequencies. These findings suggest an effect on voltage-sensitive sodium current that generates the action potential upstroke. Remacemide and the desylycinate also significantly reduced the amplitude of neuronal responses to pressure application of NMDA in use-dependent manner at concentrations equal to the IC₅₀ values for limitation of action potential firing. Resting potential and input resistance were not changed significantly by either drug.

Limitation of high-frequency firing of action potentials by both remacemide HCl and FPL 12495AA may contribute to the anticonvulsant efficacy of these compounds at concentrations overlapping the range required to block glutamatergic hyperexcitability.

Keywords: Antiepileptic drug, Remacemide HCl, FPL12495AA, Sodium-dependent action potential, Sustained repetitive firing, Cultured neuron

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