PHARMACOLOGICAL CHARACTERIZATION OF METABOTROPIC GLUTAMATE RECEPTORS LINKED TO THE INHIBITION OF ADENYLATE-CYCLASE ACTIVITY IN RAT STRIATALSLICES

The pharmacological profile of mGlu receptors negatively linked to ade nylyl cyclase was characterized in adult rat striatal slices. Among th e mGlu agonists tested, (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxyl ate (LY354740), was the most potent inhibitor of forskolin-stimulated cAMP formation (EC50 = 11 +/- 2nM). Inhibition of forskolin stimulatio n by the group III agonist L-2-amino-4-phosphonobutanoate (L-AP4) was biphasic, the two parts of the concentration curve having EC50 values of 6 +/- 1 mu M and 260 +/- 4 mu M, suggesting a sequential recruitmen t of mGlu4/8 and mGlu7. The effects of several new phenylglycine deriv ative antagonists were tested on the inhibition of forskolin cAMP resp onse by (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG I) and L-AP4 . At 500 mu M, (RS)-alpha-methyl-3-carboxy-methyl-phenyl-glycine was u nable to antagonize the effect of L-CCG I or L-AP4 but (S)-alpha-methy l-3-carboxy-phenylalanine inhibited the effect of L-AP4 with a low pot ency. Finally, (RS)-alpha-methyl-4-tetrazolylphenylglycine and particu larly (RS)-alpha-methyl-4-phosphonophenylglycine, appeared to be the m ost potent and selective antagonists of L-AP4 induced inhibition of fo rskolin-stimulated cAMP production in adult rat striatal slices. (C) 1 997 Elsevier Science Ltd.