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 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.
Cavanni
P
P
Department of Pharmacology, Glaxo Research Laboratories, Verona, Italy.
Pinnola
V
V
Mugnaini
M
M
Trist
D
D
Van Amsterdam
F T
FT
Ferraguti
F
F
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001565:Benzoates / Q000494:pharmacology*; D016466:CHO Cells / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013237:Stereoisomerism
D000262:Adenylyl Cyclases; D001565:Benzoates; D005576:Colforsin; D000242:Cyclic AMP; D005998:Glycine; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C078245:4-carboxy-3-hydroxyphenylglycine; C079694:alpha-methyl-4-carboxyphenylglycine; C079693:4-carboxyphenylglycine