(2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, a potent and selective antagonist of type 2 metabotropic glutamate receptors.
The pharmacological profile of (2S,1'S,2'S,3'R)-2-(2'-Carboxy-3'-phenylcyclopropyl)glycine (PCCG-IV) at metabotropic glutamate receptor (mGluR) subtypes mGluR1a, mGluR2, mGluR4a, and mGluR5 was examined. PCCG-IV potently antagonized glutamate-induced inhibition of forskolin-stimulated cAMP formation in baby hamster kidney cells expressing mGluR2 in a competitive manner (KB = 8.2 +/- 0.4 microM). PCCG-IV was a weak agonist at mGluR4a but inactive at the cloned phosphoinositide-coupled mGluRs (mGluR1a 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 cortical neurons, PCCG-IV antagonized the neuroprotective effects of a selective mGluR2 agonist, (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, at low doses (0.2-20 microM), whereas a higher dose of PCCG-IV (80 microM) was similarly neuroprotective to L-2-amino-4-phosphonobutanoate. The neuroprotective effect of PCCG-IV was blocked by an antagonist of mGluR4a, alpha-methyl-4-phosphonophenylglycine. Thus, PCCG-IV is a novel and useful tool for delineating the physiological roles of group II mGluRs in the central nervous system.
Thomsen
C
C
Department of Molecular Pharmacology, Novo Nordisk A/S, Malov, Denmark. cht@novo.dk
Bruno
V
V
Nicoletti
F
F
Marinozzi
M
M
Pellicciari
R
R
D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives / Q000494:pharmacology; D003521:Cyclopropanes / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005333:Fetus; D018698:Glutamic Acid / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D007668:Kidney; D007700:Kinetics; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C099854:2-(2'-carboxy-3'-phenylcyclopropyl)glycine; D003521:Cyclopropanes; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D010716:Phosphatidylinositols; D018094:Receptors, Metabotropic Glutamate; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D018698:Glutamic Acid; D016202:N-Methylaspartate; D000242:Cyclic AMP; D005998:Glycine