The selective group II
metabotropic glutamate receptor (mGlu(2/3)) agonists (-)-2-oxa-4-aminobicyclo[3.1.0]
hexane-4,6-dicarboxylate (
LY379268) and (-)-2-thia-4-aminobicyclo[3.1.0]
hexane-4,6-dicarboxylate (
LY389795) have been evaluated as anti-epileptic drugs in dilute brown agouti (DBA/2) mice, lethargic (lh/lh) mice, genetically epilepsy-prone-9 (GEP) rats and amygdala-kindled rats. Sound-induced
clonic seizures in DBA/2 mice were transiently inhibited by both agonists intracerebroventricularly (i.c.v.),
LY379268 ED(50)=0.08 [0.02-0.33]nmol and
LY389795 ED(50)=0.82 [0.27-3.24]nmol or intraperitoneally (i.p.),
LY379268 ED(50)=2.9 [0.9-9.6]mg/kg and
LY389795 ED(50)=3.4 [1.0-11.7]mg/kg. Both mGlu(2/3) agonists inhibited
seizures induced by the group I mGlu receptor agonist (R,S)-3,5-dihydroxyphenylglycine (
DHPG), where
LY379268, i.c.v. ED(50)=0.3 [0.02-5.0]pmol and
LY389795, i.c.v. ED(50)=0.03 [0.05-0.19]nmol. The spike and wave discharge (SWD) duration of absence
seizures in lh/lh mice was significantly reduced by both agonists at 1 and 10nmol (i.c.v.) up to 90min following infusion. The electrically induced seizure score and afterdischarge duration of amygdala-kindled rats was partially inhibited by the agonists 30min after i.p. injection of 10mg/kg. The agonists did not inhibit sound-induced
seizures in GEP rats (0.1-1mg/kg, 30min 1h, i.p.), but were proconvulsant following sound stimulus (> or =0.1mg/kg). These findings identify a potential role for mGlu(2/3) agonists in the amelioration of generalised and partial epileptic
seizures.