Target Information

Target General Infomation
Target ID
T62820
Former ID
TTDR00321
Target Name
Metabotropic glutamate receptor 2
Gene Name
GRM2
Synonyms
Glutamate receptor mGLU2; Group II metabotropic glutamate receptor; mGLUR2; GRM2
Target Type
Clinical Trial
Disease Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Alzheimer disease; Major depressive disorder [ICD9:331, 296.2, 296.3, 710.0; ICD10: G30, F32, F33, M32]
Bipolar disorder [ICD9: 296.0, 296.1, 296.4, 296.5, 296.6, 296.7, 296.8, 300; ICD10: F31, F40-F42]
Central nervous system disease [ICD10: G00-G99]
Major depressive disorder [ICD9: 296.2, 296.3, 710.0; ICD10: F32, F33, M32]
Mood disorder [ICD10: F30-F39]
Migraine [ICD9: 346; ICD10: G43]
Psychiatric disorder [ICD9: 290-319; ICD10: F01-F99]
Schizophrenia [ICD9: 295; ICD10: F20]
Function
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase activity. May mediate suppression of neurotransmission or may be involved in synaptogenesis or synaptic stabilization.
BioChemical Class
GPCR glutamate
Target Validation
T62820
UniProt ID
Q14416
Sequence
MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQ
RLEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHI
CPDGSYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDY
FARTVPPDFFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEK
VGRAMSRAAFEGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGAL
ESVVAGSEGAAEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQR
DCAAHSLRAVPFEQESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYK
DFVLNVKFDAPFRPADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTL
DTSLIPWASPSAGPLPASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADC
GLGYWPNASLTGCFELPQEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKA
SGRELCYILLGGVFLCYCMTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARI
FGGAREGAQRPRFISPASQVAICLALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLR
CNHRDASMLGSLAYNVLLIALCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIF
YVTSSDYRVQTTTMCVSVSLSGSVVLGCLFAPKLHIILFQPQKNVVSHRAPTSRFGSAAA
RASSSLGQGSGSQFVPTVCNGREVVDSTTSSL
Drugs and Mode of Action
Drug(s) Pomaglumetad Drug Info Phase 1 Schizophrenia [1]
LY-544344 Drug Info Discontinued in Phase 3 Anxiety disorder [2]
ADX71149 Drug Info Discontinued in Phase 2 Psychiatric disorder [3]
JNJ-40411813 Drug Info Discontinued in Phase 2 Anxiety disorder [4]
LY-2300559 Drug Info Discontinued in Phase 2 Migraine [5]
R-1578 Drug Info Discontinued in Phase 2 Mood disorder [6]
RG1578 Drug Info Discontinued in Phase 2 Major depressive disorder [6]
RO-4995819 Drug Info Discontinued in Phase 2 Major depressive disorder [7]
BCI-838 Drug Info Discontinued in Phase 1 Alzheimer disease; Major depressive disorder [8]
JNJ-42491293 Drug Info Discontinued in Phase 1 Psychiatric disorder [9]
LY-2979165 Drug Info Discontinued in Phase 1 Bipolar disorder [10]
TS-032 Drug Info Discontinued in Phase 1 Schizophrenia [11]
Antagonist (+)-MCPG Drug Info [12]
alpha-methylserine-O-phosphate Drug Info [12]
eGlu Drug Info [13]
LY341495 Drug Info [14]
MGS0039 Drug Info [15]
PCCG-4 Drug Info [16]
R-1578 Drug Info [17]
[3H]LY341495 Drug Info [18]
Agonist (1S,3R)-ACPD Drug Info [18]
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate Drug Info [14]
(S)-4C3HPG Drug Info [12]
2R,4R-APDC Drug Info [19]
DCG IV Drug Info [19]
L-CCG-I Drug Info [18]
LY-544344 Drug Info [20]
MGS0028 Drug Info [21]
TS-032 Drug Info [22]
[3H]eglumegad Drug Info [13]
Modulator (allosteric modulator) 2,2,2-TEMPS Drug Info [23]
3-MPPTS Drug Info [24]
4-APPES Drug Info [24]
4-MPPTS Drug Info [23]
biphenylindanone A Drug Info [25]
CBiPES Drug Info [24]
compound 14 Drug Info [26]
compound 14a Drug Info [27]
compound 14c Drug Info [27]
compound 19 Drug Info [27]
compound 2 Drug Info [28]
compound 3 Drug Info [28]
compound 34 Drug Info [29]
compound 4 Drug Info [28]
compound 48 Drug Info [30]
cyPPTS Drug Info [24]
GSK1331268 Drug Info [31]
JNJ-40068782 Drug Info [32]
JNJ-42153605 Drug Info [33]
MNI-135 Drug Info [34]
MNI-136 Drug Info [34]
MNI-137 Drug Info [34]
PTBE Drug Info [35]
Ro4491533 Drug Info [36]
RO4988546 Drug Info [37]
RO5488608 Drug Info [37]
Ro64-5229 Drug Info [38]
THIIC Drug Info [39]
[3H]2,2,2-TEMPS Drug Info [37]
[3H]JNJ-40068782 Drug Info [32]
Modulator ADX71149 Drug Info [40]
BCI-838 Drug Info [41]
DT-2228 Drug Info [42]
JNJ-40411813 Drug Info [43]
LY-2300559 Drug Info
LY-2979165 Drug Info [44]
MGluR2 PAMs Drug Info [42]
Pomaglumetad Drug Info [45]
RG1578 Drug Info
RO-4995819 Drug Info [46]
Inhibitor GLUTAMATE Drug Info [47]
LY-379268 Drug Info [48]
LY-389795 Drug Info [48]
QUISQUALATE Drug Info [49]
Binder JNJ-42491293 Drug Info [50]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Glutamatergic synapse
Cocaine addiction
PANTHER Pathway Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Ionotropic glutamate receptor pathway
Metabotropic glutamate receptor group II pathway
Reactome G alpha (i) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
WikiPathways GPCRs, Class C Metabotropic glutamate, pheromone
GPCR ligand binding
GPCR downstream signaling
References
REF 1ClinicalTrials.gov (NCT01487083) A Long-Term Study in Schizophrenia. U.S. National Institutes of Health.
REF 2Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018821)
REF 3Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030424)
REF 4ClinicalTrials.gov (NCT01323205) Investigation of the Safety, Tolerability and Potential Therapeutic Effects of JNJ-40411813 in Patients With Schizophrenia. U.S. National Institutes of Health.
REF 5ClinicalTrials.gov (NCT01184508) A Study in Migraine Prevention. U.S. National Institutes of Health.
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034342)
REF 7ClinicalTrials.gov (NCT01733654) Investigate Efficacy & Safety of RO4995819 vs. Placebo as Adjunct Tx in Patients w/Major Depressive Disorder. U.S. National Institutes of Health.
REF 8ClinicalTrials.gov (NCT01546051) A Study of BCI-838 and Several BCI-632 Prodrugs in Healthy Volunteers. U.S. National Institutes of Health.
REF 9ClinicalTrials.gov (NCT01359852) A Study of [11C]JNJ-42491293, a Possible PET Ligand for the mGlu2 Receptor, in Healthy Adult Volunteers. U.S. National Institutes of Health.
REF 10ClinicalTrials.gov (NCT01524237) A Study of LY2979165 and LY2140023 in Healthy Volunteers. U.S. National Institutes of Health.
REF 11ClinicalTrials.gov (NCT00876304) Multiple Dose Safety Study of PF-04802540 in Subjects With Schizophrenia. U.S. National Institutes of Health.
REF 12Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes. Br J Pharmacol. 1998 Feb;123(3):497-504.
REF 13Characterization of [(3)H]-LY354740 binding to rat mGlu2 and mGlu3 receptors expressed in CHO cells using semliki forest virus vectors. Neuropharmacology. 2000 Jul 24;39(10):1700-6.
REF 14Group II metabotropic glutamate receptors within the amygdala regulate fear as assessed with potentiated startle in rats. Behav Neurosci. 2002 Dec;116(6):1075-83.
REF 15Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists. J Med Chem. 2004 Aug 26;47(18):4570-87.
REF 16Synthesis and pharmacological characterization of all sixteen stereoisomers of 2-(2'-carboxy-3'-phenylcyclopropyl)glycine. Focus on (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, a novel and selective group II metabotropic glutamate receptors antagonist. J Med Chem. 1996 May 24;39(11):2259-69.
REF 17Clinical pipeline report, company report or official report of Roche.
REF 18[3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Neuropharmacology. 1999 Oct;38(10):1519-29.
REF 19Attenuation of seizures induced by homocysteic acid in immature rats by metabotropic glutamate group II and group III receptor agonists. Brain Res. 2001 Jul 27;908(2):120-9.
REF 20Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
REF 21Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. J Med Chem. 2000 Dec 14;43(25):4893-909.
REF 22Metabotropic glutamate receptor subtype 2/3 (mGluR2/3); serotonin receptor (5-HT2A receptor). SciBX 1(6); doi:10.1038/scibx.2008.145. March 6 2008
REF 23SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide. Bioorg Med Chem Lett. 2004 Jun 21;14(12):3099-102.
REF 24Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s). Psychopharmacology (Berl). 2005Apr;179(1):271-83. Epub 2005 Feb 17.
REF 25Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg Med Chem Lett. 2005 Oct 1;15(19):4354-8.
REF 26Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats. J Med Chem. 2011 Jan 13;54(1):342-53.
REF 273-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5493-6.
REF 28Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators. J Med Chem. 2010 Dec 23;53(24):8775-9.
REF 293-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts. Bioorg Med Chem Lett. 2010 May 15;20(10):3129-33.
REF 30Discovery of 1,4-disubstituted 3-cyano-2-pyridones: a new class of positive allosteric modulators of the metabotropic glutamate 2 receptor. J Med Chem. 2012 Mar 8;55(5):2388-405.
REF 31The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2. Bioorg Med Chem Lett. 2010 Jan 15;20(2):759-62.
REF 32Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782. J Pharmacol Exp Ther. 2013 Sep;346(3):514-27.
REF 33Discovery of 3-cyclopropylmethyl-7-(4-phenylpiperidin-1-yl)-8-trifluoromethyl[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605): a positive allosteric modulator of the metabotropic glutamate 2 receptor. JMed Chem. 2012 Oct 25;55(20):8770-89.
REF 34A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):254-64. Epub 2007 Apr 6.
REF 35Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor. J Med Chem. 2004 Aug 26;47(18):4595-9.
REF 36Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet. 2011 Dec;25(4):152-66.
REF 37Structural determinants of allosteric antagonism at metabotropic glutamate receptor 2: mechanistic studies with new potent negative allosteric modulators. Br J Pharmacol. 2011 Sep;164(2b):521-37.
REF 38Synthesis of heterocyclic enol ethers and their use as group 2 metabotropic glutamate receptor antagonists. Bioorg Med Chem Lett. 1999 Aug 2;9(15):2173-6.
REF 39N-(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 neurochemical changes. J Pharmacol Exp Ther. 2011 Jan;336(1):165-77.
REF 40MGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats. European journal of pharmacology. 01/2014; 727(1).
REF 41Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010
REF 42(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 290).
REF 43Pharmacokinetic and pharmacodynamic characterisation of JNJ-40411813, a positive allosteric modulator of mGluR2, in two randomised, double-blind phase-I studies. J Psychopharmacol. 2015 Apr;29(4):414-25.
REF 44Annual Reports in Medicinal Chemistry. Volume 47, 2012, Page(78).
REF 45LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr Opin Investig Drugs. 2010 Jul;11(7):833-45.
REF 46Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112.
REF 47J Med Chem. 2007 Sep 20;50(19):4630-41. Epub 2007 Aug 29.Synthesis, molecular modeling studies, and preliminary pharmacological characterization of all possible 2-(2'-sulfonocyclopropyl)glycine stereoisomers as conformationally constrained L-homocysteic acid analogs.
REF 48J Med Chem. 2007 Jan 25;50(2):233-40.Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors.
REF 49J Med Chem. 1998 Mar 12;41(6):930-9.Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)propionic acid.
REF 50Opportunities and challenges in the discovery of allosteric modulators of GPCRs for treating CNS disorders. Nat Rev Drug Discov. 2014 Sep;13(9):692-708. doi: 10.1038/nrd4308.

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