Metabotropic Glutamate Receptors as Drug Targets

Abstract

L-glutamate (Glu), the main excitatory amino acid neurotransmitter in the mammalian central nervous system, is involved in many physiological functions, including learning and memory, but also in toxic phenomena occurring in numerous degenerative or neurological diseases. These functions mainly result from its interaction with Glu receptors (GluRs). The broad spectrum of roles played by glutamate derived from the large number of membrane receptors, which are currently classified in two main categories, ionotropic (iGluRs) and metabotropic (mGluRs) receptors. The iGluRs are ion channels, permeant to Na(+) (Ca(2+)) while the mGluRs belongs to the superfamily of G-protein coupled receptors (GPCRs). Despite continuous efforts over more than two decades, the use of iGluR agonists or antagonists to improve or inhibit excitatory transmission in pathological states still remains a major challenge, though the discovery and development of recent molecules may prove it worthwhile. This probably results form the vital role of fast excitatory transmission in many fundamental physiological functions. Since the discovery of mGluRs, hope has emerged. Indeed, mGluRs are mainly involved in the regulation of fast excitatory transmission. Consequently, it was logically thought that modulating mGluRs with agonists or antagonists might lead to more subtle regulation of fast excitatory transmission than by directly blocking iGluRs. As a result of intensive investigation, new drugs permitting to discriminate between these receptors have emerged. Moreover, a new class of molecules acting as negative or positive allosteric modulators or mGluRs is now available and appears to be promising. In the following, we will review the classification of mGluRs and the functions in which mGluRs are involved. We will focus on their potential as therapeutic targets for improving numerous physiological functions and for different neurodegenerative and neuropsychiatric disorders, which are related to malfunction of Glu signaling in human beings.

A Virtual Screening Hit Reveals New Possibilities for Developing Group III Metabotropic Glutamate Receptor Agonists

“…Constraining the carboxyethyl chain in an extended conformation (6) affords the most potent agonist of the series, suggesting that PCEP and derivatives may bind to the receptor in a similarly extended form (see below). We then investigated the effect of various substitutions on that chain (8)(9)(10)(11)(12)(13)(17)(18)(19)(20)(21)(22). PCEP derivatives substituted at the 1 0 or 2 0 position were tested as mixtures of diastereoisomers in a preliminary evaluation.…”

Tyrosine Phosphorylation of the NMDA Receptor Following Cerebral Ischaemia

“…The metabotropic receptors are coupled to G-proteins, and, while structurally related to one another, do vary appreciably in their distribution and signal transduction mechanisms [175,193]. The ionotropic receptors are non-specific cation channels that possess a common general structure, but vary considerably in both distribution and function [153,175,236].…”

Resveratrol and Ischemic Preconditioning in the Brain

“…These receptors are grouped into 2 classes: metabotropic and ionotropic. Metabotropic receptors are G-protein coupled receptors (GPCRs) that can activate cell signaling pathways discussed in previous sections [78]. Ionotropic receptors are ligand-gated ion channels [79].…”