COMPETITIVE ANTAGONISM BY PHENYLGLYCINE DERIVATIVES AT TYPE-1 METABOTROPIC GLUTAMATE RECEPTORS

The metabotropic glutamate receptors (mGluRs) form a family of G-prote in-coupled receptors which consists of at least seven members termed m GluR1-mGluR7. These members are classified into subfamilies according to their sequence similarities, signal transduction mechanisms and ago nist selectivities. mGluR1 and mGluR5 are coupled to the phosphoinosit ide hydrolysis/Ca2+ signal transduction and efficently respond to quis qualate. In this study, we have stably expressed mGluR1 in Chinese ham ster ovary cells on which the activation of the phosphoinositide signa l transduction pathway was evaluated by means of two methods and their degree of correspondence was analyzed. These two methods involve the Li+-dependent accumulation of [H-3]inositol-labeled inositol phosphate s or the [H-3]cytidine-labeled phospholiponucleotide cytidine diphosph o (CDP)- diacylglycerol (DAG). The correlation between the two measure s was found to be generally uniform for the different agonists evaluat ed. However, the levels of CDP-DAG were found to be consistently highe r. Furthermore, quisqualate showed a differential activity on the two methods behaving as a partial agonist and as a full agonist on the ino sitolphosphate and the CDP-DAG responses, respectively. On the same ce lls the activity of a series of carboxyphenylglycines recently describ ed as possible new tools for investigating the role of mGluRs has been evaluated. Three phenylglycine derivatives were tested and found to b e competitive antagonists at this mGluR subtype. They inhibited both t he phosphoinositide signal transduction pathway and the release of int racellular Ca2+ induced by quisqualate the most potent agonist at mGlu R1. The pharmacological nature of these compounds and their relative p otencies in antagonizing mGluR1 activation are described. (C) 1994 Aca demic Press, Inc.