Target Information
Target General Infomation | |||||
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Target ID |
T62820
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Former ID |
TTDR00321
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Target Name |
Metabotropic glutamate receptor 2
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Gene Name |
GRM2
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Synonyms |
Glutamate receptor mGLU2; Group II metabotropic glutamate receptor; mGLUR2; GRM2
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Target Type |
Clinical Trial
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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.
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BioChemical Class |
GPCR glutamate
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Target Validation |
T62820
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UniProt ID | |||||
Sequence |
MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQ
RLEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHI CPDGSYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDY FARTVPPDFFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEK VGRAMSRAAFEGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGAL ESVVAGSEGAAEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQR DCAAHSLRAVPFEQESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYK DFVLNVKFDAPFRPADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTL DTSLIPWASPSAGPLPASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADC GLGYWPNASLTGCFELPQEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKA SGRELCYILLGGVFLCYCMTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARI FGGAREGAQRPRFISPASQVAICLALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLR CNHRDASMLGSLAYNVLLIALCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIF YVTSSDYRVQTTTMCVSVSLSGSVVLGCLFAPKLHIILFQPQKNVVSHRAPTSRFGSAAA RASSSLGQGSGSQFVPTVCNGREVVDSTTSSL |
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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 1 | ClinicalTrials.gov (NCT01487083) A Long-Term Study in Schizophrenia. U.S. National Institutes of Health. | ||||
REF 2 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018821) | ||||
REF 3 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030424) | ||||
REF 4 | ClinicalTrials.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 5 | ClinicalTrials.gov (NCT01184508) A Study in Migraine Prevention. U.S. National Institutes of Health. | ||||
REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034342) | ||||
REF 7 | ClinicalTrials.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 8 | ClinicalTrials.gov (NCT01546051) A Study of BCI-838 and Several BCI-632 Prodrugs in Healthy Volunteers. U.S. National Institutes of Health. | ||||
REF 9 | ClinicalTrials.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 10 | ClinicalTrials.gov (NCT01524237) A Study of LY2979165 and LY2140023 in Healthy Volunteers. U.S. National Institutes of Health. | ||||
REF 11 | ClinicalTrials.gov (NCT00876304) Multiple Dose Safety Study of PF-04802540 in Subjects With Schizophrenia. U.S. National Institutes of Health. | ||||
REF 12 | Characterization 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 13 | Characterization 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 14 | Group 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 15 | Synthesis, 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 16 | Synthesis 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 17 | Clinical 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 19 | Attenuation 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 20 | Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17. | ||||
REF 21 | Synthesis, 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 22 | Metabotropic 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 23 | SAR 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 24 | Metabotropic 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 25 | Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg Med Chem Lett. 2005 Oct 1;15(19):4354-8. | ||||
REF 26 | Design 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 27 | 3-(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 28 | Chemical 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 29 | 3-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 30 | Discovery 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 31 | The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2. Bioorg Med Chem Lett. 2010 Jan 15;20(2):759-62. | ||||
REF 32 | Pharmacological 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 33 | Discovery 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 34 | A 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 35 | Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor. J Med Chem. 2004 Aug 26;47(18):4595-9. | ||||
REF 36 | Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet. 2011 Dec;25(4):152-66. | ||||
REF 37 | Structural 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 38 | Synthesis 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 39 | 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 neurochemical changes. J Pharmacol Exp Ther. 2011 Jan;336(1):165-77. | ||||
REF 40 | MGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats. European journal of pharmacology. 01/2014; 727(1). | ||||
REF 41 | Metabotropic 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 43 | Pharmacokinetic 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 44 | Annual Reports in Medicinal Chemistry. Volume 47, 2012, Page(78). | ||||
REF 45 | LY-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 46 | Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112. | ||||
REF 47 | J 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 48 | J 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 49 | J 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 50 | Opportunities 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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