(S)-4-CARBOXY-3-HYDROXYPHENYLGLYCINE, AN ANTAGONIST OF METABOTROPIC GLUTAMATE-RECEPTOR (MGLUR)1A AND AN AGONIST OF MGLUR2, PROTECTS AGAINSTAUDIOGENIC-SEIZURES IN DBA 2 MICE/

The in vivo anticonvulsant effects and in vitro metabotropic glutamate receptor selectivity of (S)-4-carboxy-3-hydroxyphenylglycine [(S)-4C3 HPG] were examined. Intracerebroventricular injection of (S)-4C3HPG do se-dependently antagonized audiogenic-induced clonic and tonic convuls ions in DBA/2 mice with ED(50) values of 76 and 110-nmol per mouse, re spectively. (S)-4C3HPG dose-dependently inhibited the spontaneously ev oked epileptic spikes in a cingulate cortex-corpus callosum slice prep aration. (S)-4C3HPG displaced the binding of [H-3]glutamate in membran es prepared from baby hamster kidney (BHK) cells expressing the metabo tropic glutamate receptor mGluR1a with an EC(50) of 5 +/- 1 mu M. (S)- 4C3HPG dose-dependently antagonized glutamate-stimulated phosphoinosit ide hydrolysis in BHK cells expressing mGluR1a with an IC50 of 15 +/- 3 mu M. (S)-4C3HPG was, however, an agonist at mGluR2 with an EC(50) o f 21 +/- 4 mu M for inhibition of forskolin-stimulated cyclic AMP form ation in BHK cells expressing the mGluR2. (S)-4C3HPG had no effects at mGluR4a. These data suggest that the anticonvulsant action of (S)-4C3 HPG is mediated by combined antagonism of mGluR1a and agonism of mGluR 2. These results suggest the importance of mGluRla and/or mGluR2 in th e control of epileptic activity.