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 mGlu2 and mGlu4 were utilised for this study. A receptor binding analysis was also performed for the main...

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Bibliographic Details
Published in:	European journal of pharmacology Vol. 269; no. 1; p. 9
Main Authors:	Cavanni, P, Pinnola, V, Mugnaini, M, Trist, D, Van Amsterdam, F T, Ferraguti, F
Format:	Journal Article
Language:	English
Published:	Netherlands 15-09-1994
Subjects:	Adenylyl Cyclases - metabolism Animals Benzoates - pharmacology CHO Cells - drug effects Colforsin - pharmacology Computer Simulation Cricetinae Cricetulus Cyclic AMP - metabolism Dose-Response Relationship, Drug Glycine - analogs & derivatives Glycine - metabolism Glycine - pharmacology Male Radioligand Assay Rats Rats, Sprague-Dawley Receptors, AMPA - metabolism Receptors, Kainic Acid - metabolism Receptors, Metabotropic Glutamate - drug effects Receptors, Metabotropic Glutamate - metabolism Receptors, N-Methyl-D-Aspartate - metabolism Stereoisomerism
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Summary:	Three carboxyphenylglycine derivatives were examined for their activity on glutamate metabotropic receptors negatively linked to adenylate cyclase. Chinese hamster ovary cells stably expressing mGlu2 and mGlu4 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 mGlu2 expressing cells (S)4-carboxy-3-hydroxyphenylglycine and (S)4-carboxy-phenylglycine antagonized forskolin-stimulated cAMP levels, with EC50 of 21 and 970 microM, 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 mGlu4 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 pKi 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.
ISSN:	0014-2999
DOI:	10.1016/0922-4106(94)90020-5