Anti-epileptic activity of group II metabotropic glutamate receptor 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)

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 (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 ED50=0.08 [0.02-0.33] nmol and LY389795 ED50=0.82 [0.27-3.24] nmol or intraperitoneally (i.p.), LY379268 ED50=2.9 [0.9-9.6] mg/kg and LY389795 ED50=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. ED50=0.3 [0.02-5.0] pmol and LY389795, i.c.v. ED50=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 10 nmol (i.c.v.) up to 90 min following infusion. The electrically induced seizure score and afterdischarge duration of amygdala-kindled rats was partially inhibited by the agonists 30 min after i.p. injection of 10 mg/kg. The agonists did not inhibit sound-induced seizures in GEP rats (0.1-1 mg/kg, 30 min 1 h, i.p.), but were proconvulsant following sound stimulus (greater than or equal to0.1 mg/kg). These findings identify a potential role for mGlu(2/3) agonists in the amelioration of generalised and partial epileptic seizures. (C) 2001 Elsevier Science Ltd. All rights reserved