title: Anticonvulsant activity of 4-urea-5,7-dichlorokynurenic acid derivatives that are antagonists at the NMDA-associated glycine binding site.
abstract: 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 with a secondary amine. Compounds were screened in mice for anticonvulsant activity using maximal electroshock (MES), subcutaneous pentylenetetrazole (Met), and threshold tonic extension (TTE) tests. A rotorod test was used to determine neurotoxicity. Seven of the derivatives had anticonvulsant activity in TTE testing at 100 mg/kg. One compound, 2-methyl carboxylate-5,7-dichloro-4-([¿diphenylamino¿-carbonyl]amino)-quino line, had an ED50 value of 134 mg/kg (95% conf. int.: low-78.5, high-205.7; slope 1.9, SE = 0.44) in TTE testing. Two derivatives had MES activity. Only one compound, an N,N-diethylamino derivative, was neurotoxic in the rotorod test. Compounds were screened at a 10-microM concentration for activity in displacing 5,7-dichlorokynurenic acid from synaptosomal membrane fragments. Since 9 of the 12 compounds synthesized and tested have demonstrated anticonvulsant activity, this class of chemicals offers promise for the production of useful therapeutic agents.
authors.affiliation: Department of Chemistry, University of North Alabama, Florence 35632, USA. anichols@unanov.una.edu
authors.forename: A C
authors.initials: AC
authors.lastname: Nichols
authors.forename: K L
authors.initials: KL
authors.lastname: Yielding
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D004597:Electroshock; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism*; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D051379:Mice; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012640:Seizures / Q000188:drug therapy* / Q000503:physiopathology; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine