Anticonvulsant activity of antagonists for the NMDA-associated glycine binding site

Coupled to the N-methyl-D-aspartate (NMDA) receptor-channel complex is a strychnine-insensitive binding site for glycine. Pharmacological antagonism of glycine binding at this site can produce anticonvulsant activity. Derivatives of the glycine antagonists kynurenic acid and 2-carboxy-indole were synthesized and evaluated for anticonvulsant effects. Compounds were tested in mice against seizures induced by electroshock and pentylenetetrazole, and in the rotorod assay for neurological deficit. The derivatives were also assayed for binding at the NMDA-associated glycine site. The most potent anticonvulsant was ethyl 4-methylamino-5,7-dichloro-2-quinoline carboxylate. This compound provided protection against maximal electroshock (MES) induced seizures at a dose level including 5-fluoro-2-indole carboxylic acid and the diethyl ester of 2,6-pyridine dicarboxylic acid.