Pharmacological analysis of 4-carboxyphenylglycine derivatives: Comparison of effects on mGluR1α and mGluR5a subtypes

The antagonist effects of the 4-carboxyphenylglycines: (S)-4-carboxy-3hydroxyphenylglycine (4C3HPG), (S)-4-carboxyphenylglycine (4CPG) and (+)-α-methyl-4-carboxyphenylglycine (M4CPG) were compared on functional responses of human metabotropic glutamate receptor (mGluR) subtypes mGluR1α and mGluR5a. These receptors both belong to group 1 type mGluRs which couple to the phosphoinositide (PI) hydrolysis/[Ca2+]i mobilization signal transduction pathway and are closely related in both structure and agonist pharmacology. In this study, the IC50 values obtained for quisqualate induced PI hydrolysis responses show that although all the phenylglycines are antagonists for both mGluR1α and mGluR5a, the compounds exhibit differential potencies at these receptor subtypes. The 4C3HPG derivative was the most potent antagonist for both mGluR1α (IC50 range: 19–50μM) and mGluR5a (IC50 range: 53–280μM). 4CPG produced an IC50 range of 44–72μM for mGluR1α and 150–156 μM for mGluR5a cells. The potency of the M4CPG could not be distinguished from that of 4CPG with IC50 ranges of 29–100 μM and 115–210 μM for mGluR1α and mGluR5a respectively. Further characterization of the dose-response effects of the compounds on quisqualate induced [Ca2+]i mobilization showed that although the magnitude of phenylglycine inhibition was reduced for both mGluR subtypes compared to those observed for stimulation of PI hydrolysis (except for 4C3HPG on mGluR1α), similar differences in the relative potencies of the phenylglycines between mGluR1α (IC50s: 40 ± 10 μM for 4C3HPG: 300–1000 μM for 4CPG and M4CPG) and mGluR5a (IC50s: > 1000 μM) were evident. These results indicate that closely related receptors of the same mGluR group exhibit a different pharmacology with respect to phenylglycine antagonists.