Non-competitive antagonists of the
N-methyl-D-aspartate (
NMDA) receptor have been evaluated as
anticonvulsants against sound-induced
seizures in DBA/2 mice. The ED50 values for protection against sound-induced
clonic seizures 15 min following the intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) administration are:
MK-801, ED50 = 0.5 nmol (i.c.v.); 0.14 mumol/kg (i.p.);
phencyclidine, ED50 = 14 nmol (i.c.v.); 1.9 mumol/kg (i.p.);
dextrorphan, ED50 = 35 nmol (i.c.v.); 18.5 mumol/kg (i.p.);
tiletamine, ED50 = 40 nmol (i.c.v.); 5.6 mumol/kg (i.p.);
SKF-10047, ED50 = 50 nmol (i.c.v.); 23.5 mumol/kg (i.p.);
dextromethorphan, ED50 = 70 nmol (i.c.v.); 28.0 mumol/kg (i.p.);
ketamine, ED50 = 110 nmol (i.c.v.); 15.5 mumol/kg (i.p.). The
anticonvulsant effects of
ketamine and
tiletamine are of short duration (10-30 min), whereas the
anticonvulsant effects of
MK-801 and
dextromethorphan last for 45 min or longer. The effects of
phencyclidine,
SKF-10047 and
dextrorphan are of intermediate duration. Mild to moderate behavioural excitation is associated with the
anticonvulsant activity of all the non-competitive
NMDA antagonists. For
MK-801,
phencyclidine,
dextrorphan,
SKF-10047 and
ketamine there is a close correlation between their relative
anticonvulsant potencies and their potencies for displacing [3H]
MK-801. The
anticonvulsant effect is likely to be primarily mediated via
NMDA antagonism at the PCP/
MK-801 site.