Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses

• Published in: Neuropharmacology Vol. 34; no. 8; pp. 895 - 903
• Main Authors: Brabet, I., Mary, S., Bockaert, J., Pin, J.-P.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.08.1995
• Subjects: Animals; antagonists; Cells, Cultured; CHO Cells; Cricetinae; Cricetulus; Glycine - analogs & derivatives; Glycine - pharmacology; LLC-PK1 Cells; Metabotropic glutamate receptor; Mice; Neurons - metabolism; phenylglycine derivatives; phospholipase C coupling; Rats; Receptors, Metabotropic Glutamate - agonists; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Receptors, Metabotropic Glutamate - drug effects; Swine; Transfection; antagonists; phenylglycine derivatives; phospholipase C coupling; Metabotropic glutamate receptor
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/0028-3908(95)00079-L

The effects of the phenylglycine derivatives, α-methyl-4-carboxyphenylglycine (MCPG), 4-carboxyphenylglycine (4CPG), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), 3-hydroxyphenylglycine (3HPG) and 3,5-dihydrohyphenylglycine (DHPG) were tested on LLC-PK1 cells transiently expressing the rat mGluR1a or mGluR5a receptors. As previously reported by others, ( S)-3HPG and ( RS)-DHPG were found to be partial agonists at mGluR1a, whereas (+)-MCPG, ( S)-4CPG and ( S)-4C3HPG competitively antagonized the effect of Glu. Surprisingly, the 4-carboxy derivatives of phenylglycine antagonized the effect of 1 S,3 R-ACPD on mGluR1a with lower K B values. On mGluR5a, ( S)-3HPG and ( RS)-DHPG are also partial agonists. However, in contrast to their effects on mGluR1a, ( S)-4CPG did not inhibit the effect of Glu or 1 S,3 R-ACPD, and ( S)-4C3HPG acted as an agonist at high concentration. Whereas no significant antagonism of the Glu effect on mGluR5a was observed with 1 mM (+)-MCPG, this compound was found to potently and competitively antagonize the effect of 1 S,3 R-ACPD. Finally, the effect of 4CPG was also examined on cultured cortical and cerebellar neurons that express mGluR5 and mGluR1 mRNA, respectively. 4CPG inhibited 1 S,3 R-ACPD-stimulated IP production in cerebellar neurons only. These results (1) demonstrate that phenylglycine derivatives can be used to discriminate between effects mediated by mGluR1 and mGluR5 and (2) suggest that the apparent potency of phenylglycine antagonists depends on the agonist used to activate these receptors.