Reduction of dizocilpine and scopolamine-induced deficits in avoidance responding by SCH 54388, a metabolite of felbamate.
Felbamate (2-phenyl-1,3-propanediol dicarbamate) is a novel antiepileptic agent with a unique structure and mechanism of action, possibly involving binding sites at the N-methyl-D-aspartate receptor (NMDA) complex. A monocarbomate metabolite of felbamate (SCH 54388) was compared to felbamate using a mouse passive-avoidance paradigm (PAR). SCH 54388 was markedly free of toxic side effects up to doses of 300 mg/kg, sc. SCH 54388 reduced the deficit-producing effects of either scopolamine, a cholinergic antagonist, or dizocilpine (MK-801), an NMDA receptor channel blocker, in a dose-dependent manner. The effective dose range of SCH 54388 was between 0.01 and 10 mg/kg, sc. SCH 54388 was also orally active at doses between 0.1 and 10 mg/kg. Felbamate also reduced scopolamine and dizocilpine antagonism, but was less potent than SCH 54388, reducing scopolamine-induced deficits at 1 to 3 mg/kg, sc. in a dose-dependent manner and reducing deficits induced by dizocilpine at doses of 0.1 and 3 mg/kg, SC. The reduction of dizocilpine-induced deficits by felbamate was not dose dependent. These results suggest that SCH 54388 has a mechanism of action involving either directly or indirectly, glutaminergic and cholinergic central neuronal systems.
Smith
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RD
Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Grzelak
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ME
Coffin
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VL
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001362:Avoidance Learning / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D000078328:Felbamate; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D048448:Phenylcarbamates; D011409:Propylene Glycols / Q000494:pharmacology*; D012601:Scopolamine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D048448:Phenylcarbamates; D011409:Propylene Glycols; C110062:SCH 54388; D016291:Dizocilpine Maleate; D012601:Scopolamine; D000078328:Felbamate