Regular ArticleCompetitive Antagonism by Phenylglycine Derivatives at Type 1 Metabotropic Glutamate Receptors
Abstract
The metabotropic glutamate receptors (mGluRs) form a family of G-protein-coupled receptors which consists of at least seven members termed mGluR1-mGluR7. These members are classified into subfamilies according to their sequence similarities, signal transduction mechanisms and agonist selectivities. mGluR1 and mGluR5 are coupled to the phosphoinositide hydrolysis/Ca2+ signal transduction and efficently respond to quisqualate. In this study, we have stably expressed mGluR1 in Chinese hamster ovary cells on which the activation of the phosphoinositide signal 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 [3H]inositol-labeled inositol phosphates or the [3H]cytidine-labeled phospholiponucleotide cytidine diphospho (CDP)- diacylglycerol (DAG). The correlation between the two measures was found to be generally uniform for the different agonists evaluated. However, the levels of CDP-DAG were found to be consistently higher. Furthermore, quisqualate showed a differential activity on the two methods behaving as a partial agonist and as a full agonist on the inositol phosphate and the CDP-DAG responses, respectively. On the same cells the activity of a series of carboxyphenylglycines recently described as possible new tools for investigating the role of mGluRs has been evaluated. Three phenylglycine derivatives were tested and found to be competitive antagonists at this mGluR subtype. They inhibited both the phosphoinositide signal transduction pathway and the release of intracellular Ca2+ induced by quisqualate the most potent agonist at mGluR1. The pharmacological nature of these compounds and their relative potencies in antagonizing mGluR1 activation are described.
References (0)
Cited by (17)
Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists
2003, Bioorganic and Medicinal ChemistryMetabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.
Production of ring-substituted D-phenylglycines by microbial or enzymatic hydrolysis/deracemisation of the corresponding DL-hydantoins
1997, Tetrahedron AsymmetryA series of 17 ring-mono and -disubstituted D-phenylglycine derivatives was prepared in high enantiomeric purity by enzymatic hydrolysis and deracemisation of the corresponding DL-hydantoins, using D-hydantoinase activities of microorganisms or purified enzymes, followed by diazotation of the resulting N-carbamyl D-amino acids. No significant L-hydantoinase activity was found to produce the corresponding L-enantiomers.
Pharmacological tools for the investigation of metabotropic glutamate receptors (mGluRs): Phenylglycine derivatives and other selective antagonists-an update
1995, NeuropharmacologyGlutamate is known to produce many of its pre-and post-synaptic effects through interaction with at least three groups of G-protein-coupled metabotropic receptors. While molecular biological approaches have revealed a great deal about the nature of these receptors and their neuroanatomical localization, elucidation of their role in both physiological and pathological processes has been hampered by the lack of appropriate pharmacological agents. However, the situation is rapidly changing with the discovery of antagonist phenylglycine derivatives, and other compounds. Not only is it now possible to discriminate between the individual metabotropic glutamate receptor groups but, in several cases, between individual group members. The future development of potent and subtype-specific antagonists will greatly facilitate the advancement of our understanding of these receptors as well as providing the potential for novel therapeutic approaches in a variety of neuropathological states.
Pharmacological analysis of 4-carboxyphenylglycine derivatives: Comparison of effects on mGluR1α and mGluR5a subtypes
1995, NeuropharmacologyThe 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.
Phenylglycine derivatives discriminate between mGluR1- and mGluR5-mediated responses
1995, NeuropharmacologyThe effects of the phenylglycine derivatives, α-methyl-4-carboxyphenylglycine (MCPG), 4-carboxyphenylglycine (4CPG), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), 3-hydroxyphenylglycine (3HPG) and 3,5-dihydrohyphenylglycine (DHPG) were tested on LLC-PK1 cells transiently expressing the rat mGluR1a or mGluR5a receptors. As previously reported by others, (S)-3HPG and (RS)-DHPG were found to be partial agonists at mGluR1a, whereas (+)-MCPG, (S)-4CPG and (S)-4C3HPG competitively antagonized the effect of Glu. Surprisingly, the 4-carboxy derivatives of phenylglycine antagonized the effect of 1S,3R-ACPD on mGluR1a with lower KB values. On mGluR5a, (S)-3HPG and (RS)-DHPG are also partial agonists. However, in contrast to their effects on mGluR1a, (S)-4CPG did not inhibit the effect of Glu or 1S,3R-ACPD, and (S)-4C3HPG acted as an agonist at high concentration. Whereas no significant antagonism of the Glu effect on mGluR5a was observed with 1 mM (+)-MCPG, this compound was found to potently and competitively antagonize the effect of 1S,3R-ACPD. Finally, the effect of 4CPG was also examined on cultured cortical and cerebellar neurons that express mGluR5 and mGluR1 mRNA, respectively. 4CPG inhibited 1S,3R-ACPD-stimulated IP production in cerebellar neurons only. These results (1) demonstrate that phenylglycine derivatives can be used to discriminate between effects mediated by mGluR1 and mGluR5 and (2) suggest that the apparent potency of phenylglycine antagonists depends on the agonist used to activate these receptors.
Metabotropic glutamate receptors [A Special Issue of 32 papers]
1995, NeuropharmacologyGlutamate is known to produce many of its pre-and post-synaptic effects through interaction with at least three groups of G-protein-coupled metabotropic receptors. While molecular biological approaches have revealed a great deal about the nature of these receptors and their neuroanatomical localization, elucidation of their role in both physiological and pathological processes has been hampered by the lack of appropriate pharmacological agents. However, the situation is rapidly changing with the discovery of antagonist phenylglycine derivatives, and other compounds. Not only is it now possible to discriminate between the individual metabotropic glutamate receptor groups but, in several cases, between individual group members. The future development of potent and subtype-specific antagonists will greatly facilitate the advancement of our understanding of these receptors as well as providing the potential for novel therapeutic approaches in a variety of neuropathological states.