Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid derivatives that are antagonists at the NMDA-associated glycine binding site

摘要: Twelve 4-urea-5,7-dichlorokynurenic acid derivatives were synthesized by reacting the 4-tosylimino derivative of 5,7-dichlorokynurenate methyl ester first with triphosgene and then a secondary amine. Compounds screened in mice for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole (Met), threshold tonic extension (TTE) tests. A rotorod test was used to determine neurotoxicity. Seven had TTE testing at 100 mg/kg. One compound, 2-methyl carboxylate-5,7-dichloro-4-([{diphenylamino}-carbonyl]amino)-quinoline, an ED50 value 134 mg/kg (95% conf. int.: low—78.5, high— 205.7; slope 1.9 SE=0.44) testing. Two MES activity. Only one anN,N-diethylamino derivative, neurotoxic test. 10-μM concentration displacing 5,7-dichlorokynurenic from synaptosomal membrane fragments. Since 9 12 compounds tested have demonstrated activity, this class chemicals offers promise production useful therapeutic agents.