Pharmacological characterization of metabotropic glutamate receptors linked to the inhibition of adenylate cyclase activity in rat striatal slices.
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-di carboxylate (LY354740), was the most potent inhibitor of forskolin-stimulated cAMP formation (EC50 = 11 +/- 2 nM). 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 EC50 values of 6 +/- 1 microM and 260 +/- 4 microM, suggesting a sequential recruitment of mGlu4/8 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-(carboxy-cyclopropyl)-glycine (L-CCG I) and L-AP4. At 500 microM, (RS)-alpha-methyl-3-carboxy-methyl-pheny lglycine was unable to antagonize the effect of L-CCG I or L-AP4 but (S)-alpha-methyl-3-carboxy-phenylalanine inhibited the effect of L-AP4 with a low potency. Finally, (RS)-alpha-methyl-4-tetrazolylphenylglyc ine and particularly (RS)-alpha-methyl-4-phosphonophenylglyci ne, appeared to be the most potent and selective antagonists of L-AP4 induced inhibition of forskolin-stimulated cAMP production in adult rat striatal slices.
Schaffhauser
H
H
Pharma Division Preclinical CNS Research, F. Hoffmann-La Roche Ltd, Basel, Switzerland. HERVE.SCHAFFHAUSER@Roche.COM
Cartmell
J
J
Jakob-Røtne
R
R
Mutel
V
V
D000262:Adenylyl Cyclases / Q000187:drug effects*; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000201:enzymology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects*
D001643:Bridged Bicyclo Compounds; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D005576:Colforsin; D000262:Adenylyl Cyclases; C104753:eglumetad