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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).

Abstract
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.
AuthorsR X Moldrich, M Jeffrey, A Talebi, P M Beart, A G Chapman, B S Meldrum
JournalNeuropharmacology (Neuropharmacology) Vol. 41 Issue 1 Pg. 8-18 (Jul 2001) ISSN: 0028-3908 [Print] England
PMID11445181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Amino Acids
  • Anticonvulsants
  • Bridged Bicyclo Compounds, Heterocyclic
  • Excitatory Amino Acid Agonists
  • LY 379268
  • LY 389795
  • Receptors, Metabotropic Glutamate
Topics
  • Acoustic Stimulation
  • Amino Acids (pharmacology)
  • Amygdala (physiology)
  • Animals
  • Anticonvulsants (pharmacology)
  • Bridged Bicyclo Compounds, Heterocyclic (pharmacology)
  • Electric Stimulation
  • Epilepsy, Tonic-Clonic (chemically induced)
  • Excitatory Amino Acid Agonists (pharmacology)
  • Female
  • Injections, Intravenous
  • Kindling, Neurologic (drug effects)
  • Male
  • Mice
  • Mice, Inbred DBA
  • Postural Balance (drug effects)
  • Rats
  • Receptors, Metabotropic Glutamate (agonists)

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