title: The effect of the desglycinyl metabolite of remacemide on cortical wedges prepared from DBA/2 mice.
abstract: Remacemide hydrochloride is currently undergoing clinical trials for use as an anticonvulsant agent in the treatment of epilepsy. It is considered that the desglycinyl metabolite (FPL 12495AA) of the parent compound accounts for the majority of the anticonvulsant activity. In this study we have investigated the effects of FPL 12495AA on electrical activity in the cortical wedges prepared from audiogenic seizure-prone DBA/2 mice. FPL 12495AA at varying concentrations (50-200 microM) significantly reduced both the spontaneous depolarizations (IC50 102 microM) and the associated afterpotentials (IC50 50 microM) which are characteristic in this preparation under magnesium-free conditions. The compound also concentration-dependently reduced N-methyl-D-aspartate (NMDA)-induced depolarizations of the tissue (IC50 43 microM) and the antagonism by FPL 12494AA was not overcome by increasing NMDA concentrations. FPL 12495AA had no effect on (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-induced depolarizations. The results suggest that FPL 12495AA has a specific antagonistic effect on the NMDA receptor complex possibly through non-competitive inhibition at the phenycyclidine site in the ion channel. Such an action could contribute to its anticonvulsant properties.
authors.affiliation: Department of Pharmacology and Therapeutics, University of Wales College of Medicine, Cardiff, UK.
authors.forename: R Q
authors.initials: RQ
authors.lastname: Hu
authors.forename: J A
authors.initials: JA
authors.lastname: Davies
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism / Q000494:pharmacology*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004594:Electrophysiology; D005260:Female; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000378:metabolism; D010627:Phenethylamines / Q000378:metabolism / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D007473:Ion Channels; D010627:Phenethylamines; D016194:Receptors, N-Methyl-D-Aspartate; C089135:FPL 12495; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C067553:remacemide; D010622:Phencyclidine