REMACEMIDE HCL AND ITS METABOLITE, FPL 12495AA, LIMIT ACTION-POTENTIAL FIRING FREQUENCY AND BLOCK NMDA RESPONSES OF MOUSE SPINAL-CORD NEURONS IN CELL-CULTURE

The novel anticonvulsant, remacemide HCl -)-2-amino-N-(1-methyl-1,2-di phenylethyl)acetamide monohydrochloride; FPL12924AA], and a desglycina ted metabolite [(+/-)-1-methyl-1,2-diphenylethylamine monohydrochlorid e; FPL 12495AA] reversibly limited sustained high-frequency repetitive firing (SRF) of sodium-dependent action potentials by mouse spinal co rd 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 F PL 12495AA (P < 0.05 vs. remacemide). Stereoisomers of the desglycinat e limited SRF with IC50 values of 3.3 X 10(-6) M and 3.5 x 10(-6) M fo r the S(+) and R(-) compounds, respectively. The concentration of race mic desglycinate and of either stereoisomer that produced limitation i n all neurons tested was 10(-4) M. Maximal rate of rise (Vover dot(max )) of action potentials decreased progressively until firing ceased du ring 400-ms depolarizing pulses, Efficacy of remacemide, but not of th e desglycinate, increased with time (maximum at 16-36 h). The limitati on was voltage dependent, In addition, reduction of Vover dot(max) and action potential failure occurred during stimulation with 400-ms puls es 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 desg lycinate also significantly reduced the amplitude of neuronal response s to pressure application of NMDA in use-dependent manner at concentra tions equal to the IC50 values for limitation of action potential firi ng. Resting potential and input resistance were not changed significan tly by either drug. Limitation of high-frequency firing of action pote ntials by both remacemide HCl and FPL 12495AA may contribute to the an ticonvulsant efficacy of these compounds at concentrations overlapping the range required to block glutamatergic hyperexcitability.