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 X 10(-6) M for remacemide and 1.2 X 10(-6) M for FPL 12495AA (P < 0.05 vs. remacemide). Stereoisomers of the desglycinate limited SRF with IC50 values of 3.3 X 10(-6) M and 3.5 X 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 (Vmax) 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 of Vmax 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 desglycinate 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.