PHARMACOLOGICAL ANALYSIS OF CARBOXYPHENYLGLYCINES AT METABOTROPIC GLUTAMATE RECEPTORS

Three carboxyphenylglycine derivatives were examined for their activity on glutamate metabotropic receptors negatively linked to adenylate cyclase. Chinese hamster ovary cells stably expressing mGlu(2) and mGlu(4) were utilised for this study. A receptor binding analysis was also performed for the main classes of glutamate ionotropic receptors and for the glycine binding site on the NMDA-receptor complex. In mGlu(2) expressing cells (S)4-carboxy-3-hydroxyphenylglycine and (S)4-carboxyphenylglycine antagonized forskolin-stimulated cAMP levels, with EC(50) of 21 and 970 mu M, respectively, acting as agonists at this receptor subtype, whereas (RS)alpha-methyl-4-carboxyphenylglycine antagonized glutamate response in these cells. None of these compounds showed any agonistic or antagonistic activity on mGlu(4) expressing cells. No affinity for the ionotropic receptors (NMDA, AMPA and kainate) and for the glycine site of the NMDA-receptor complex was found using the receptor binding approach, except for (RS)4-carboxy-3-hydroxyphenylglycine which showed a pK(i) of 5.68 in ((+/-)2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding for NMDA receptor, although this can be ascribed to the (R) form of the racemic mixture.