PHENYLGLYCINE DERIVATIVES DISCRIMINATE BETWEEN MGLUR1-MEDIATED AND MGLUR5-MEDIATED RESPONSES

The effects of the phenylglycine derivatives, alpha-methyl-4-carboxyph enylglycine (MCPG), 4-carboxyphenylglycine (4CPG), 4-carboxy-3-hydroxy phenylglycine (4C3HPG), 3-hydroxyphenylglycine (3HPG) and 3,4-dihydroh yphenylglycine (DHPG) were tested on LLC-PK1 cells transiently express ing the rat mGluRla or mGluR5a receptors. As previously reported by ot hers, (S)-3HPG and (RS)-DHPG were found to be partial agonists at mGlu R la, whereas (+)-MCPG, (S)-4CPG and (S)-4C3HPG competitively antagoni zed the effect of Glu. Surprisingly, the 4-carboxy derivatives of phen ylglycine antagonized the effect of 1S,3R-ACPD on mGluR1a with lower K -B values. On mGluRSa, (S)-3HPG and (RS)-DHPG are also partial agonist s. However, in contrast to their effects on mGluR1a, (S)-4CPG did not inhibit the effect of Glu or 1S,3R-ACPD, and (S)-4C3HPG acted as an ag onist at high concentration. Whereas no significant antagonism of the Glu effect on mGluRSa was observed with 1 mM(+)-MCPG, this compound wa s found to potently and competitively antagonize the effect of 1S,3R-A CPD. Finally, the effect of 4CPG was also examined on cultured cortica l and cerebellar neurons that express mGluR5 and mGluR1 mRNA, respecti vely. 4CPG inhibited 1S,3R-ACPD stimulated IP production in cerebellar neurons only. These results (1) demonstrate that phenylglycine deriva tives can be used to discriminate between effects mediated by mGluR1 a nd mGluR5 and (2) suggest that the apparent potency of phenylglycine a ntagonists depends on the agonist used to activate these receptors.