S,3'R)-2-(2'-CARBOXY-3'-PHENYLCYCLOPROPYL)GLYCINE, A POTENT AND SELECTIVE ANTAGONIST OF TYPE-2 METABOTROPIC GLUTAMATE RECEPTORS

The pharmacological profile of 'S,3'R)-2-(2'-carboxy-3'-phenylcyclopro pyl)glycine (PCCG-IV) at metabotropic glutamate receptor (mGluR) subty pes mGluR1a, mGluR2, mGluR4a, and mGluR5 was examined. PCCG-IV potentl y antagonized glutamate-induced inhibition of forskolin-stimulated cAM P formation in baby hamster kidney cells expressing mGluR2 in a compet itive manner (K-B = 8.2 +/- 0.4 mu M). PCCG-IV was a weak agonist at m GluR4a but inactive at the cloned phosphoinositide-coupled mGluRs (mGl uR1a and mGluR5a). PCCG-IV was significantly more potent and selective as an antagonist at mGluR2 compared with previously described mGluR2 antagonists, including alpha-methyl-4-carboxyphenylglycine. In mice co rtical neurons, PCCG-IV antagonized the neuroprotective effects of a s elective mGluR2 agonist, ,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)gly cine, at low doses (0.2-20 mu M), whereas a higher dose of PCCG-IV (80 mu M) was similarly neuroprotective to L-2-amino-4-phosphonobutanoate . The neuroprotective effect of PCCG-IV was blocked by an antagonist o f mGluR4a, alpha-methyl-4-phosphonophenylglycine. Thus, PCCG-IV is a n ovel and useful tool for delineating the physiological roles of group II mGluRs in the central nervous system.