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NO Dalby and C Thomsen
Novo Nordisk A/S, Health Care Discovery, Malov, Denmark.
The anticonvulsant properties of ligands at metabotropic glutamate receptors (mGluRs) were examined in different seizure models by use of intracerebroventricular infusion. The mGluR1a antagonist/mGluR2 agonist, (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3HPG] dose- dependently antagonized pentylenetetrazol- and methyl-6,7-dimethoxy-4- ethyl-beta-carboline-2-carboxylate (DMCM)-induced clonic convulsions in mice with ED50 values of 400 and 180 nmol/mice, respectively. A modest increase in electrical seizure threshold was observed in mice injected with (S)-4C3HPG. No effect on seizures induced by systemic administration of N-methyl-D-aspartate was observed by prior intracerebroventricular infusion of (S)-4C3HPG. The more selective (but less potent) mGluR1a antagonist, (S)-4-carboxyphenylglycine, was a weak anticonvulsant in similar seizure models with the exception of convulsions induced by electrical stimulation. (+)-alpha-Methyl-4- carboxyphenylglycine showed no anticonvulsant activity in any of the models examined. Agonists of mGluRs which are particularly potent at mGluR2, (2S,3S,4S)-alpha-(carboxycyclopropyl)glycine and (1S,3R)-1- aminocyclopentane dicarboxylic acid significantly protected against sound-induced convulsions in DBA/2 mice and DMCM-induced seizures in mice but were inactive against seizures induced by administration of pentylenetetrazol or by electrical stimulation. These data suggest that mGluR ligands modulate seizure activity in mice and this effect may be mediated via antagonism of mGluR1a-type as well as via activation of mGluR2-type mGluRs.
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