Metabotropic glutamate receptors as targets for neuroprotective drugs (original) (raw)
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Metabotropic Glutamate Receptor Ligands as Novel Therapeutic Agents
The Receptors, 2008
Metabotropic glutamate receptors comprise a diverse family of G proteincoupled receptors that are critical for regulating normal neuronal function in the central nervous system (CNS). The heterogeneous distribution and diverse physiologic roles of the various mGluR subtypes make them highly attractive targets for the treatment of a number of neurologic and psychiatric disorders. The discovery of subtype-selective ligands for these receptors has provided the tools to support a number of preclinical studies, suggesting the tremendous therapeutic potential that lies in the ability selectively to modulate a specific mGluR subtype. In the last few years, a major milestone in the field was achieved with the first selective mGluR ligands entering into clinical development and demonstrating efficacy in the treatment of anxiety disorders. In addition to the discovery of selective, direct-acting mGluR ligands, a novel class of mGluR-selective ligands has recently emerged. These allosteric modulators, which act through nontraditional binding sites on the mGluRs, may exhibit even greater subtype selectivity than orthosteric ligands. Furthermore, because they modulate mGluRs in an activity-dependent manner, it is possible that allosteric activators of mGluRs will be less likely to induce adverse effects or promote receptor desensitization. This chapter summarizes the critical studies that have contributed to the validation of mGluRs as therapeutic targets for the treatment of a number of CNS disorders and describes progress thus far in identifying and developing novel mGluR subtype-selective compounds.
Neuropharmacology, 1999
Despite there being a lot of biochemical data about metabotropic glutamate (mGlu) receptors, our knowledge of the behavioural effects of mGlu receptor agonists/antagonists is still inadequate. LY 354740 is a systemically active agonist of group II mGlu receptors. After peripheral administration, LY 354740 produced anxiolytic-like effects in the conflict drinking test in rats and a four-plate test in mice. It was also found that LY 354740 decreased spontaneous locomotor activity in mice, but did not disturb motor coordination. In behavioural models of depression including the despair test and a tail suspension test, LY 354740 did not produce antidepressant-like effects. LY 354740 inhibited the naloxone-induced symptoms of morphine withdrawal in morphine-dependent mice. The above results indicate that agonists of group II mGlu receptors may play a role in the therapy of anxiety and/or drug-dependence states. The brain sites of action of LY 354740 need to be identified and the mechanism of both the above described effects remains to be elucidated.
European Neuropsychopharmacology, 2004
Although glutamate is a simple molecule, its actions in the limbic system and areas concerning anxiety are complex and widespread. These actions are mediated through different combinations of ionotropic and metabotropic glutamate receptors. Preclinical studies have shown that compounds active at NMDA, AMPA/kaïnate and metabotropic receptors might have anxiolytic properties. The major research effort so far has been directed towards the development of compounds which modulate the function of NMDA receptors. In general, the utility of NMDA and AMPA/kaïnate antagonists is greatly hampered by adverse effects. For the treatment of clinical anxiety disorder a more delicate regulation of the glutaminergic system is required. It is encouraging that different ways to fine-tune the glutaminergic system are emerging, e.g., modulators of the glycine site and compounds acting at the AMPA receptor. Metabotropic glutamate receptor agonists and antagonists are in particular promising in this respect. It can be expected that selective modulators of glutamate activity will be of great clinical significance for the treatment of anxiety disorders.
Metabotropic glutamate 2/3 receptors as drug targets
Current Opinion in Pharmacology, 2004
Metabotropic glutamate receptors are a family of class III Gprotein-coupled receptors comprising eight members (mGluR1-8), which are an attractive target in the central nervous system because of the widespread use of glutamate as the principal excitatory amino acid transmitter. The unique pharmacology of class III G-protein coupled receptors, their forebrain localization in key limbic-related cortical/thalamic/striatal/amygdaloid circuits, and the promise of subtle modulation of glutamatergic neurotransmission make these receptors intriguing targets for a wide variety of neuropsychiatric disorders. Abbreviations GAD generalized anxiety disorder GPCR G-protein-coupled receptor mGluR metabotropic glutamate receptor NMDA N-methyl-D-aspartate PCP phencyclidine 24. Lorrain DS, Baccei CS, Bristow LJ, Anderson JJ, Varney MA: Effects of ketamine and N-methyl-D-aspartate on glutamate and dopamine release in the rat prefrontal cortex: modulation by a group II selective metabotropic glutamate receptor agonist LY379268. Neuroscience 2003, 117:697-706. 25. Moghaddam B, Adams BW: Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonists in rats. Science 1998, 281:1349-1352. 26. Klodzinska A, Bijak M, Tokarski K, Pilc A: Group II mGlu receptor agonists inhibit behavioral and electrophysiological effects of DOI in mice.
Therapeutic potential of metabotropic glutamate receptor modulators
Current Neuropharmacology, 2012
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.
Psychopharmacology, 2008
Rationale The increasing awareness of the need to align clinical and preclinical research to facilitate rapid development of new drug therapies is reflected in the recent introduction of the term "translational medicine". This review examines the implications of translational medicine for psychiatric disorders, focusing on metabotropic glutamate (mGlu) receptor biology in anxiety disorders and on anxiety-related biomarkers. Objectives This review aims to (1) examine recent progress in translational medicine, emphasizing the role that translational research has played in understanding of the potential of mGlu receptor agonists and antagonists as anxiolytics, (2) identify lacunas where animal and human research have yet to be connected, and (3) suggest areas where translational research can be further developed.