ANTICONVULSANT ACTIVITY OF A NOVEL NMDA GLYCINE SITE ANTAGONIST, MDL-104,653, AGAINST KINDLED-INDUCED AND SOUND-INDUCED SEIZURES

MDL 104,653 (3-phenyl-4-hydroxy-7-chloro-quinolin-2(1H)-one), acts as an antagonist at the glycine site of the NMDA receptor. MDL 104,653 pr otects against sound-induced clonic seizures in DBA/2 mice following i ntracerebroventricular (ED(50) = 19.1 nmol, 30 min), intraperitoneal ( i.p.; ED(50) = 6.1 mu mol/kg, 45 min), or oral (EDS, = 23.0 mu mol/kg, 2 h) administration. Optimal protection by MDL 104,653 was observed 1 5-60 min after i.p. administration, and the therapeutic index, as asse ssed by rotarod performance, was 4.0 at 45 min after i.p. administrati on. Fully amygdala-kindled motor seizures in rats were significantly r educed at 15, 30 and 60 min, and the duration of the after-discharge w as significantly shortened at 30 min after the i.p. administration of 74 mu mol/kg MDL 104,653. A lower dose of MDL 104,653 (37 mu mol/kg) h ad no significant effect on either motor seizures or after-discharge d uration. The rate of amygdala kindling was also significantly retarded following the daily administration of 56 mu mol/kg MDL 104,653 (1 tim es daily for 6 days; i.p. 30 min before kindling stimulus).