Anticonvulsant activity of a novel NMDA/glycine site antagonist, MDL 104,653, against kindled 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 protects against sound-induced clonic seizures in DBA/2 mice following intracerebroventricular (ED50 = 19.1 nmol, 30 min), intraperitoneal (i.p.; ED50 = 6.1 mumol/kg, 45 min), or oral (ED50 = 23.0 mumol/kg, 2 h) administration. Optimal protection by MDL 104,653 was observed 15-60 min after i.p. administration, and the therapeutic index, as assessed by rotarod performance, was 4.0 at 45 min after i.p. administration. Fully amygdala-kindled motor seizures in rats were significantly reduced at 15, 30 and 60 min, and the duration of the after-discharge was significantly shortened at 30 min after the i.p. administration of 74 mumol/kg MDL 104,653. A lower dose of MDL 104,653 (37 mumol/kg) had no significant effect on either motor seizures or after-discharge duration. The rate of amygdala kindling was also significantly retarded following the daily administration of 56 mumol/kg MDL 104,653 (1 times daily for 6 days; i.p. 30 min before kindling stimulus).
Chapman
A G
AG
Department of Neurology, Institute of Psychiatry, London, UK.
Dürmüller
N
N
Harrison
B L
BL
Baron
B M
BM
Parvez
N
N
Meldrum
B S
BS
D000284:Administration, Oral; D000679:Amygdala / Q000187:drug effects / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007274:Injections, Intraperitoneal; D007276:Injections, Intraventricular; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012640:Seizures / Q000517:prevention & control*; D013016:Sound / Q000009:adverse effects
D015363:Quinolones; D016194:Receptors, N-Methyl-D-Aspartate; C093895:3-phenyl-4-hydroxy-7-chloroquinolin-2(1H)-one