Anticonvulsant activity of glycine-site NMDA antagonists. 2. trans 2-carboxy-4-substituted tetrahydroquinolines

Anticonvulsant activity has been optimized in a series of glycine-site NMDA antagonists based on 2-carboxy tetrahydroquinoline, leading to the benzylamine 7 (L-690,590), its methyl ester prodrug 13 (L-691,470) and the phenylalanine 8 (L-696,833) which have ED 50 values of 39, 31.5 and 29 mg/kg (i.p.) respectively in the DBA/2 mouse audiogenic seizure model. Correlations between in vivo and in vitro activities suggest that systemic anticonvulsant action of glycine antagonists depends on both brain penetration as well as ‘access’ to receptors within the brain.