Pharmacological characterization of metabotropic glutamate receptors linked to the inhibition of adenylate cyclase activity in rat striatal slices

Abstract

The pharmacological profile of mGlu receptors negatively linked to adenylyl cyclase was characterized in adult rat striatal slices. Among the mGlu agonists tested, (+)-2-aminobicyclo[3.1.0]hexane-2, 6-dicarboxylate (LY354740), was the most potent inhibitor of forskolin-stimulated cAMP formation (EC 50 = 11 ± 2nM). Inhibition of forskolin stimulation by the group III agonist L-2-amino-4-phosphono butanoate (L-AP4) was biphasic, the two parts of the concentration curve having EC 50 values of 6 ± 1 μM and 260 ± 4 μM, suggesting a sequential recruitment of mGlu 4 8 and mGlu7. The effects of several new phenylglycine derivative antagonists were tested on the inhibition of forskolin cAMP response by (2S, 1′S,2′S)-2-(carboxycyclopropyl)glycine (L-CCG I) and l-AP4. At 500 μM, (RS)-α-methyl-3-carboxy-methyl-phenylglycine was unable to antagonize the effect of l-CCG I or l-AP4 but (S)-α-methyl-3-carboxy-phenylalanine inhibited the effect of l-AP4 with a low potency. Finally, (RS)-α-methyl-4-tetrazolylphenylglycine and particularly (RS)-α-methyl-4-phosphonophenylglycine, appeared to be the most potent and selective antagonists of l-AP4 induced inhibition of forskolin-stimulated cAMP production in adult rat striatal slices.