Therapeutic Potential of Metabotropic Glutamate Receptor Modulators

Abstract

Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson’s disease, Alzheimer’s disease and pain.

Maternal inflammation leads to impaired glutamate homeostasis and up-regulation of glutamate carboxypeptidase II in activated microglia in the fetal/newborn rabbit brain

“…Although it is possible that glutamate formation from NAAG hydrolysis alone may not be enough to lead to the substantial increase in glutamate concentration noted here, increased GCPII expression may worsen the injury in multiple ways, one of which may be by decreasing the levels of neuroprotective NAAG. NAAG activates mGluR3 which plays a strong role in inhibiting presynaptic glutamate release (Hovelso et al, 2012). Since we have measured total glutamate in this study, we do not know what fraction of this glutamate is extracellular.…”

Metabotropic Glutamate Receptors for Parkinson's Disease Therapy

“…Glutamate receptors modulate glutamatergic neurotransmission in the brain and play a role in memory, learning and motor control; glutamatergic dysfunction is implicated in a range of neurological disorders [25–27]. Two classes of glutamate receptor have been described: ionotropic glutamate receptors (iGlu receptors) [28], and metabotropic glutamate receptors (mGlu receptors) [26].…”

Synthesis and Preliminary Studies of a Novel Negative Allosteric Modulator, 7-((2,5-Dioxopyrrolidin-1-yl)methyl)-4-(2-fluoro-4-[11C]methoxyphenyl) quinoline-2-carboxamide, for Imaging of Metabotropic Glutamate Receptor 2

“…10–14 It has been reported that mGlu 2 is involved in the pathogenesis of numerous brain dysfunctions, including psychiatric disorders and neurodegenerative diseases. 7,15–19 Therefore pharmacological modulation of mGlu 2 represents a promising therapeutic approach for the treatment of several CNS diseases, 20 including drug dependence, 21–23 chronic pain, 24 anxiety, 17 depression, 25,26 schizophrenia, 27 Parkinson’s disease 28,29 and Alzheimer’s disease. 30 Initial drug discovery efforts focused on non-selective mGlu 2/3 agonists and antagonists that bind to the mGlu orthosteric binding site (evolutionarily conserved glutamate binding site); 31 however, in recent years there has been a shift towards allosteric modulation strategies (consisting of positive and negative allosteric modulators; abbreviated as PAM and NAM, respectively) that offer the potential for improved selectivity for mGlu 2 or mGlu 3 .…”