NOVEL POTENT SELECTIVE PHENYLGLYCINE ANTAGONISTS OF METABOTROPIC GLUTAMATE RECEPTORS

The metabotropic glutamate (mGlu) receptor antagonist properties of no vel phenylglycine analogues were investigated in adult rat cortical sl ices (mGlu receptors negatively coupled to adenylyl cyclase), neonatal rat cortical slices and in cultured rat cerebellar granule cells (mGl u receptors coupled to phosphoinositide hydrolysis). (RS)-alpha-methyl -4-phosphonophenylglycine (MPPG), (RS)-alpha-methyl-4-sulphonophenylgl ycine (MSPG), (RS)-alpha-methyl-4-tetrazolylphenylglycine (MTPG), lpha -methyl-3-carboxymethyl-4-hydroxyphenylglycine (M3CM4HPG) and ha-methy l-4-hydroxy-3-phosphonomethylphenylglycine (M4H3PMPG) were demonstrate d to have potent and selective effects against 10 mu M L-2-amino-4-pho sphonobutyrate (L-AP4)- and 0.3 mu M (2S,1'S,2'S)-2-(2-carboxycyclopro pyl)glycine (L-CCG-1)-mediated inhibition of forskolin-stimulated cAMP accumulation in the adult rat cortex. In contrast, these compounds de monstrated either weak or no antagonism at mGlu receptors coupled to p hosphoinositide hydrolysis in either neonatal rat cortex or in culture d cerebellar granule cells. These compounds thus appear to be useful d iscriminatory pharmacological tools for mGlu receptors and form the ba sis for the further development of novel antagonists.