(S)-4-carboxy-3-hydroxyphenylglycine, an antagonist of metabotropic glutamate receptor (mGluR) 1a and an agonist of mGluR2, protects against audiogenic seizures in DBA/2 mice.

The in vivo anticonvulsant effects and in vitro metabotropic glutamate receptor selectivity of (S)-4-carboxy-3-hydroxy-phenylglycine [(S)-4C3HPG] were examined. Intracerebroventricular injection of (S)-4C3HPG dose-dependently antagonized audiogenic-induced clonic and tonic convulsions in DBA/2 mice with ED50 values of 76 and 110-nmol per mouse, respectively. (S)-4C3HPG dose-dependently inhibited the spontaneously evoked epileptic spikes in a cingulate cortex-corpus callosum slice preparation. (S)-4C3HPG displaced the binding of [3H]glutamate in membranes prepared from baby hamster kidney (BHK) cells expressing the metabotropic glutamate receptor mGluR1a with an EC50 of 5 +/- 1 microM. (S)-4C3HPG dose-dependently antagonized glutamate-stimulated phosphoinositide hydrolysis in BHK cells expressing mGluR1a with an IC50 of 15 +/- 3 microM. (S)-4C3HPG was, however, an agonist at mGluR2 with an EC50 of 21 +/- 4 microM for inhibition of forskolin-stimulated cyclic AMP formation in BHK cells expressing the mGluR2. (S)-4C3HPG had no effects at mGluR4a. These data suggest that the anticonvulsant action of (S)-4C3HPG is mediated by combined antagonism of mGluR1a and agonism of mGluR2. These results suggest the importance of mGluR1a and/or mGluR2 in the control of epileptic activity.