Metabotropic glutamate receptors as drug targets: what's new?

The question in the title: 'what's new?' has two facets. First, are 'clinical' expectations met with success? Second, is the number of CNS disorders targeted by mGlu drugs still increasing? The answer to the first question is 'no', because development program with promising drugs in the treatment of schizophrenia, Parkinson's disease, and Fragile X syndrome have been discontinued. Nonetheless, we continue to be optimistic because there is still the concrete hope that some of these drugs are beneficial in targeted subpopulations of patients. The answer to the second question is 'yes', because mGlu ligands are promising targets for 'new' disorders such as type-1 spinocerebellar ataxia and absence epilepsy. In addition, the increasing availability of pharmacological tools may push mGlu7 and mGlu8 receptors into the clinical scenario. After almost 30 years from their discovery, mGlu receptors are still alive.

[1]  M. Foster Olive,et al.  N-Acetylcysteine Reverses Cocaine Induced Metaplasticity , 2009, Nature Neuroscience.

[2]  Scott J. Russo,et al.  HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity , 2012, Nature Neuroscience.

[3]  D. Hoyer,et al.  Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse , 2013, Neuropharmacology.

[4]  S. Nakanishi,et al.  MGS0039: a potent and selective group II metabotropic glutamate receptor antagonist with antidepressant-like activity , 2004, Neuropharmacology.

[5]  P. Visscher,et al.  Deleterious GRM1 Mutations in Schizophrenia , 2012, PloS one.

[6]  F. S. Bersani,et al.  l-Acetylcarnitine in dysthymic disorder in elderly patients: A double-blind, multicenter, controlled randomized study vs. fluoxetine , 2013, European Neuropsychopharmacology.

[7]  Masahiko Watanabe,et al.  The Synaptic Targeting of mGluR1 by Its Carboxyl-Terminal Domain Is Crucial for Cerebellar Function , 2014, The Journal of Neuroscience.

[8]  P. Kammermeier.  Functional and Pharmacological Characteristics of Metabotropic Glutamate Receptors 2/4 Heterodimers , 2012, Molecular Pharmacology.

[9]  G. Fisone,et al.  Group III and subtype 4 metabotropic glutamate receptor agonists: Discovery and pathophysiological applications in Parkinson's disease , 2013, Neuropharmacology.

[10]  P. Visscher,et al.  Clustered Coding Variants in the Glutamate Receptor Complexes of Individuals with Schizophrenia and Bipolar Disorder , 2011, PloS one.

[11]  F. Nicoletti,et al.  Metabotropic glutamate receptors: From the workbench to the bedside , 2011, Neuropharmacology.

[12]  F. Nicoletti,et al.  L-acetylcarnitine causes rapid antidepressant effects through the epigenetic induction of mGlu2 receptors , 2013, Proceedings of the National Academy of Sciences.

[13]  G. Marek,et al.  The two faces of the pharmacological interaction of mGlu2 and 5-HT2A – Relevance of receptor heterocomplexes and interaction through functional brain pathways , 2013, Neuropharmacology.

[14]  P. Piazza,et al.  Increased locomotor response to novelty and propensity to intravenous amphetamine self-administration in adult offspring of stressed mothers , 1992, Brain Research.

[15]  R. Huganir,et al.  PICK1 uncoupling from mGluR7a causes absence-like seizures , 2008, Nature Neuroscience.

[16]  B. Oostra,et al.  A Reduced Number of Metabotropic Glutamate Subtype 5 Receptors Are Associated with Constitutive Homer Proteins in a Mouse Model of Fragile X Syndrome , 2005, The Journal of Neuroscience.

[17]  Mark F. Bear,et al.  Altered synaptic plasticity in a mouse model of fragile X mental retardation , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  Claire Williams,et al.  Neuroprotective and symptomatic effects of targeting group III mGlu receptors in neurodegenerative disease , 2014, Journal of neurochemistry.

[19]  D. Umbricht,et al.  Cognitive impairment in major depression and the mGlu2 receptor as a therapeutic target , 2013, Neuropharmacology.

[20]  T. Wichmann,et al.  Metabotropic glutamate receptor 5 antagonist protects dopaminergic and noradrenergic neurons from degeneration in MPTP-treated monkeys. , 2011, Brain : a journal of neurology.

[21]  M. Grilli,et al.  Upregulation of mGlu2 Receptors via NF-κB p65 Acetylation Is Involved in the Proneurogenic and Antidepressant Effects of Acetyl-L-Carnitine , 2013, Neuropsychopharmacology.

[22]  A. Guidotti,et al.  Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice , 2013, Neuropharmacology.

[23]  Jens Meiler,et al.  Structure of a Class C GPCR Metabotropic Glutamate Receptor 1 Bound to an Allosteric Modulator , 2014, Science.

[24]  Eric Trinquet,et al.  A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[25]  R. Lefkowitz,et al.  Molecular mechanism of β-arrestin-biased agonism at seven-transmembrane receptors. , 2012, Annual review of pharmacology and toxicology.

[26]  O. Rascol,et al.  Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias. , 2014, Parkinsonism & related disorders.

[27]  F. Nicoletti,et al.  Changes in mGlu5 Receptor-Dependent Synaptic Plasticity and Coupling to Homer Proteins in the Hippocampus of Ube3A Hemizygous Mice Modeling Angelman Syndrome , 2014, The Journal of Neuroscience.

[28]  F. Nicoletti,et al.  Prenatal Restraint Stress Generates Two Distinct Behavioral and Neurochemical Profiles in Male and Female Rats , 2008, PloS one.

[29]  H. Geys,et al.  Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep-wake architecture. , 2009, European journal of pharmacology.

[30]  F. Nicoletti,et al.  Pharmacological Activation of mGlu4 Metabotropic Glutamate Receptors Reduces Nigrostriatal Degeneration in Mice Treated with 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine , 2006, The Journal of Neuroscience.

[31]  J. Lindenmayer,et al.  Pomaglumetad methionil: No significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo , 2013, Schizophrenia Research.

[32]  J. Huguenard,et al.  Modulation of Short-Term Plasticity in the Corticothalamic Circuit by Group III Metabotropic Glutamate Receptors , 2014, The Journal of Neuroscience.

[33]  B. Kinon,et al.  A Multicenter, Inpatient, Phase 2, Double-Blind, Placebo-Controlled Dose-Ranging Study of LY2140023 Monohydrate in Patients With DSM-IV Schizophrenia , 2011, Journal of clinical psychopharmacology.

[34]  R. Balice-Gordon,et al.  Antibodies to metabotropic glutamate receptor 5 in the Ophelia syndrome , 2011, Neurology.

[35]  S. Mosolov,et al.  Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial , 2007, Nature Medicine.

[36]  C. V. Rijn,et al.  Head-to head comparison of mGlu1 and mGlu5 receptor activation in chronic treatment of absence epilepsy in WAG/Rij rats , 2014, Neuropharmacology.

[37]  G. Marek,et al.  N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a Novel Metabotropic Glutamate 2 Potentiator with Potential Anxiolytic/Antidepressant Properties: In Vivo Profiling Suggests a Link between Behavioral and Central Nervous System Neu , 2011, Journal of Pharmacology and Experimental Therapeutics.

[38]  Paul J Carlson,et al.  A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. , 2006, Archives of general psychiatry.

[39]  M. Levite.  GLUTAMATE RECEPTOR ANTIBODIES IN NEUROLOGICAL DISEASES: Anti-AMPA-GluR3 antibodies, Anti-NMDA-NR1 antibodies, Anti-NMDA-NR2A/B antibodies, Anti-mGluR1 antibodies or Anti-mGluR5 antibodies are present in subpopulations of patients with either: Epilepsy, Encephalitis, Cerebellar Ataxia, Systemic Lupus , 2014, Journal of Neural Transmission.

[40]  Bita Moghaddam,et al.  From Revolution to Evolution: The Glutamate Hypothesis of Schizophrenia and its Implication for Treatment , 2012, Neuropsychopharmacology.

[41]  T. Salt,et al.  Metabotropic glutamate receptors in the thalamocortical network: Strategic targets for the treatment of absence epilepsy , 2011, Epilepsia.

[42]  E. Smeraldi,et al.  A double-blind, randomised, controlled clinical trial of acetyl-l-carnitine vs. amisulpride in the treatment of dysthymia , 2006, European Neuropsychopharmacology.

[43]  S. Chaki,et al.  mGlu2/3 and mGlu5 receptors: Potential targets for novel antidepressants , 2013, Neuropharmacology.

[44]  F. Biagioni,et al.  Pharmacological enhancement of mGlu1 metabotropic glutamate receptors causes a prolonged symptomatic benefit in a mouse model of spinocerebellar ataxia type 1 , 2013, Molecular Brain.

[45]  L. Prézeau,et al.  The complexity of their activation mechanism opens new possibilities for the modulation of mGlu and GABAB class C G protein-coupled receptors , 2011, Neuropharmacology.

[46]  B. Mcewen,et al.  Mind the gap: glucocorticoids modulate hippocampal glutamate tone underlying individual differences in stress susceptibility , 2014, Molecular Psychiatry.

[47]  A. Coenen,et al.  The WAG/Rij rat model for absence epilepsy: age and sex factors , 1987, Epilepsy Research.

[48]  A. Doré,et al.  Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain , 2014, Nature.

[49]  P. Jeffrey Conn,et al.  Development of allosteric modulators of GPCRs for treatment of CNS disorders , 2014, Neurobiology of Disease.

[50]  C. Lindsley,et al.  Chemical Modulation of Mutant mGlu1 Receptors Derived from Deleterious GRM1 Mutations Found in Schizophrenics , 2014, ACS chemical biology.

[51]  T. Dinan,et al.  Regulation of the brain-gut axis by group III metabotropic glutamate receptors. , 2013, European journal of pharmacology.

[52]  Kari A. Johnson,et al.  Selective Actions of Novel Allosteric Modulators Reveal Functional Heteromers of Metabotropic Glutamate Receptors in the CNS , 2014, The Journal of Neuroscience.

[53]  Manfred Schneider,et al.  Characterization of an mGluR2/3 Negative Allosteric Modulator in Rodent Models of Depression , 2011, Journal of neurogenetics.

[54]  Masahiko Watanabe,et al.  Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain , 2014, Science.

[55]  C. Lindsley,et al.  Potentiation of mGlu5 receptors with the novel enhancer, VU0360172, reduces spontaneous absence seizures in WAG/Rij rats , 2013, Neuropharmacology.

[56]  P. Worley,et al.  Disrupted mGluR5-Homer scaffolds mediate abnormal mGluR5 signaling, circuit function and behavior in a mouse model of Fragile X Syndrome , 2012, Nature Neuroscience.

[57]  D. Lovinger,et al.  Loss of metabotropic glutamate receptor 2 escalates alcohol consumption , 2013, Proceedings of the National Academy of Sciences.

[58]  E. Aronica,et al.  Switch in the expression of mGlu1 and mGlu5 metabotropic glutamate receptors in the cerebellum of mice developing experimental autoimmune encephalomyelitis and in autoptic cerebellar samples from patients with multiple sclerosis , 2008, Neuropharmacology.

[59]  Giuseppe Battaglia,et al.  Endogenous Activation of mGlu5 Metabotropic Glutamate Receptors Contributes to the Development of Nigro-Striatal Damage Induced by 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine in Mice , 2004, The Journal of Neuroscience.