Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTXJ47W)

DTT Name Metabotropic glutamate receptor 2 (mGluR2)
Synonyms mGLUR2; Group II metabotropic glutamate receptor; Glutamate receptor mGLU2; GPRC1B
Gene Name GRM2
DTT Type
Clinical trial target
 [1]
Related Disease
Obesity [ICD-11: 5B80-5B81]
Psychotic disorder [ICD-11: 6A20-6A25]
Alzheimer disease [ICD-11: 8A20]
Bipolar disorder [ICD-11: 6A60]
Depression [ICD-11: 6A70-6A7Z]
Epilepsy/seizure [ICD-11: 8A61-8A6Z]
Mental/behavioural/neurodevelopmental disorder [ICD-11: 6E20-6E8Z]
Schizophrenia [ICD-11: 6A20]
BioChemical Class
GPCR glutamate
UniProt ID
GRM2_HUMAN
TTD ID
T62820
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQ
RLEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHI
CPDGSYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDY
FARTVPPDFFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEK
VGRAMSRAAFEGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGAL
ESVVAGSEGAAEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQR
DCAAHSLRAVPFEQESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYK
DFVLNVKFDAPFRPADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTL
DTSLIPWASPSAGPLPASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADC
GLGYWPNASLTGCFELPQEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKA
SGRELCYILLGGVFLCYCMTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARI
FGGAREGAQRPRFISPASQVAICLALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLR
CNHRDASMLGSLAYNVLLIALCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIF
YVTSSDYRVQTTTMCVSVSLSGSVVLGCLFAPKLHIILFQPQKNVVSHRAPTSRFGSAAA
RASSSLGQGSGSQFVPTVCNGREVVDSTTSSL
Function
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. G-protein coupled receptor for glutamate.
KEGG Pathway
Neuroactive ligand-receptor interaction (hsa04080 )
Glutamatergic synapse (hsa04724 )
Cocaine addiction (hsa05030 )
Reactome Pathway
Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499 )
G alpha (i) signalling events (R-HSA-418594 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
9 Clinical Trial Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
MP-101 DMYCITZ Alzheimer disease 8A20 Phase 2 [2]
Oleoyl-estrone DM0RA8F Alzheimer disease 8A20 Phase 2 [3], [4]
RO-4995819 DMNTC7O Major depressive disorder 6A70.3 Phase 2 [5]
ADX71149 DMBUOX4 Epilepsy 8A60-8A68 Phase 1 [6]
BCI-632 DMZYCWT Alzheimer disease 8A20 Phase 1 [7]
BCI-838 DMRXDN3 Major depressive disorder 6A70.3 Phase 1 [8]
JNJ-42491293 DMOL9JR Psychiatric disorder 6E8Z Phase 1 [9]
LY-2979165 DM16IX2 Bipolar disorder 6A60 Phase 1 [10]
Pomaglumetad DMTOLI5 Schizophrenia 6A20 Phase 1 [1]
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⏷ Show the Full List of 9 Clinical Trial Drug(s)
49 Patented Agent(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
Ethinyl-pyrazole derivative 1 DMLOBAQ N. A. N. A. Patented [11]
Ethinyl-pyrazole derivative 2 DMA3PE7 N. A. N. A. Patented [11]
Ethinyl-pyrazole derivative 3 DM87DOX N. A. N. A. Patented [11]
Heteroaryl-pyrazole derivative 1 DM9LQCH N. A. N. A. Patented [11]
Heteroaryl-pyrazole derivative 2 DMIG0TQ N. A. N. A. Patented [11]
Heteroaryl-pyrazole derivative 3 DMO45G3 N. A. N. A. Patented [11]
N-substituted pyrazole derivative 1 DMHTVGM N. A. N. A. Patented [11]
N-substituted pyrazole derivative 2 DMQWODI N. A. N. A. Patented [11]
N-substituted pyrazole derivative 3 DM5TIFH N. A. N. A. Patented [11]
PMID25435285-Compound-10 DM12QO7 N. A. N. A. Patented [11]
PMID25435285-Compound-15 DMHBWNS N. A. N. A. Patented [11]
PMID25435285-Compound-16 DMKFX2G N. A. N. A. Patented [11]
PMID25435285-Compound-20 DMG9FYH N. A. N. A. Patented [11]
PMID25435285-Compound-22 DM27U1F N. A. N. A. Patented [11]
PMID25435285-Compound-25 DMIVJMO N. A. N. A. Patented [11]
PMID25435285-Compound-26 DMTJHAK N. A. N. A. Patented [11]
PMID25435285-Compound-37 DMTYHCU N. A. N. A. Patented [11]
PMID25435285-Compound-38 DMSIKM2 N. A. N. A. Patented [11]
PMID25435285-Compound-39 DMG2ES1 N. A. N. A. Patented [11]
PMID25435285-Compound-40 DMW2C19 N. A. N. A. Patented [11]
PMID25435285-Compound-41 DMJ5LGA N. A. N. A. Patented [11]
PMID25435285-Compound-42 DMTN79G N. A. N. A. Patented [11]
PMID25435285-Compound-43 DMEGJ73 N. A. N. A. Patented [11]
PMID25435285-Compound-44 DM4K3AU N. A. N. A. Patented [11]
PMID25435285-Compound-45 DM74WSJ N. A. N. A. Patented [11]
PMID25435285-Compound-46 DMC6HPV N. A. N. A. Patented [11]
PMID25435285-Compound-47 DM92F1C N. A. N. A. Patented [11]
PMID25435285-Compound-49 DM7G51M N. A. N. A. Patented [11]
PMID25435285-Compound-50 DML48NA N. A. N. A. Patented [11]
PMID25435285-Compound-51 DM2VZG6 N. A. N. A. Patented [11]
PMID25435285-Compound-52 DMXD8L1 N. A. N. A. Patented [11]
PMID25435285-Compound-53 DMSRYIP N. A. N. A. Patented [11]
Pyrazole derivative 76 DM6Y27J N. A. N. A. Patented [11]
Pyrazole derivative 77 DM5E1ZJ N. A. N. A. Patented [11]
Pyrazole derivative 78 DMMCHOW N. A. N. A. Patented [11]
Pyrazole derivative 79 DM9JHYL N. A. N. A. Patented [11]
Quinoline derivative 3 DMDV6EY N. A. N. A. Patented [11]
Quinoline derivative 4 DMPB4L6 N. A. N. A. Patented [11]
Quinoline derivative 5 DMS1TOX N. A. N. A. Patented [11]
Quinoline derivative 6 DMVBPGI N. A. N. A. Patented [11]
Quinoline derivative 7 DM56I8H N. A. N. A. Patented [11]
Quinoline derivative 8 DMLIW1X N. A. N. A. Patented [11]
Quinoline derivative 9 DMIC86N N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 1 DM3W5SM N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 2 DMB1T6S N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 3 DM71LVY N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 4 DMLMXT6 N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 5 DM7C0R8 N. A. N. A. Patented [11]
Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 6 DMCE3J0 N. A. N. A. Patented [11]
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⏷ Show the Full List of 49 Patented Agent(s)
6 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
LY-544344 DMSC4K1 Anxiety disorder 6B00-6B0Z Discontinued in Phase 3 [12]
LY-2300559 DMTS1X5 Migraine 8A80 Discontinued in Phase 2 [13]
LY354740 DM08BIZ Anxiety disorder 6B00-6B0Z Discontinued in Phase 2 [14]
R-1578 DMAPRGQ Mood disorder 6A60-6E23 Discontinued in Phase 2 [15]
RG1578 DM3TU7D Major depressive disorder 6A70.3 Discontinued in Phase 2 [16]
TS-032 DMOHEYU Schizophrenia 6A20 Discontinued in Phase 1 [17]
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⏷ Show the Full List of 6 Discontinued Drug(s)
37 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(+)-MCPG DMG5QJB Discovery agent N.A. Investigative [18]
(1S,3R)-ACPD DM5DOAF Discovery agent N.A. Investigative [19]
(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate DMYW40T Discovery agent N.A. Investigative [20], [21]
(S)-4C3HPG DMQK4I2 Discovery agent N.A. Investigative [18]
3-MPPTS DMCDLG4 Discovery agent N.A. Investigative [22]
4-APPES DM1UXHE Discovery agent N.A. Investigative [22]
4-MPPTS DM4E6HW Discovery agent N.A. Investigative [23]
alpha-methylserine-O-phosphate DMCIH1X Discovery agent N.A. Investigative [18]
biphenylindanone A DM2MYKC Discovery agent N.A. Investigative [24]
CBiPES DMALVY7 Discovery agent N.A. Investigative [22]
cyPPTS DME9LPO Discovery agent N.A. Investigative [22]
DCG IV DM9HG1Y Discovery agent N.A. Investigative [21]
DT-2228 DMCKQF7 Major depressive disorder 6A70.3 Investigative [25]
eGlu DMKW0Q3 Discovery agent N.A. Investigative [14]
GSK1331268 DMIWY7Q Discovery agent N.A. Investigative [26]
JNJ-42153605 DMLOQ92 Discovery agent N.A. Investigative [27]
L-CCG-I DMPZ8XH Discovery agent N.A. Investigative [19]
LY-379268 DMME40U Discovery agent N.A. Investigative [28]
LY-389795 DM6Y2XG Discovery agent N.A. Investigative [28]
MGS0028 DMIMKFZ Discovery agent N.A. Investigative [29]
MNI-135 DMBJFH9 Discovery agent N.A. Investigative [30]
MNI-136 DM5C9VI Discovery agent N.A. Investigative [30]
MNI-137 DMKRI1J Discovery agent N.A. Investigative [30]
PCCG-4 DMD9KYN Discovery agent N.A. Investigative [31]
PMID20409708C34 DMA2Y74 Discovery agent N.A. Investigative [32]
PMID21155570C14 DM7I341 Discovery agent N.A. Investigative [33]
PMID22364337C48 DMRLG7Z Discovery agent N.A. Investigative [34]
PTBE DMY02IR Discovery agent N.A. Investigative [35]
Ro4491533 DMJLSX0 Discovery agent N.A. Investigative [36]
RO4988546 DM6SQ9A Discovery agent N.A. Investigative [37]
RO5488608 DMHXGCO Discovery agent N.A. Investigative [37]
Ro64-5229 DMXOTHC Discovery agent N.A. Investigative [38]
THIIC DM3KU46 Discovery agent N.A. Investigative [39]
[3H]2,2,2-TEMPS DMQO8AF Discovery agent N.A. Investigative [37], [23]
[3H]JNJ-40068782 DMSE56B Discovery agent N.A. Investigative [40]
[3H]LY341495 DMGX0Y8 Discovery agent N.A. Investigative [19], [20]
[3H]quisqualate DMDQBTX Discovery agent N.A. Investigative [41]
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⏷ Show the Full List of 37 Investigative Drug(s)

Molecular Expression Atlas (MEA) of This DTT

Molecular Expression Atlas (MEA) Jump to Detail Molecular Expression Atlas of This DTT
Disease Name ICD 11 Studied Tissue p-value Fold-Change Z-score
Schizophrenia 6A20 Pre-frontal cortex 1.09E-01 -0.11 -0.2
Schizophrenia 6A20 Superior temporal cortex 3.19E-01 -0.06 -0.34
Bipolar disorder 6A20 Pre-frontal cortex 1.04E-01 -0.13 -0.51
Major depressive disorder 6A20 Pre-frontal cortex 6.83E-01 -0.06 -0.25
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References

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3 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
4 Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
5 Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112.
6 MGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats. European journal of pharmacology. 01/2014; 727(1).
7 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.
8 Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010
9 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.
10 Annual Reports in Medicinal Chemistry. Volume 47, 2012, Page(78).
11 Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 - present).Expert Opin Ther Pat. 2015 Jan;25(1):69-90.
12 Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
13 Annual Reports in Medicinal Chemistry. Elsevier (ISBN: 9780123964922). 2012, p78
14 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.
15 Clinical pipeline report, company report or official report of Roche.
16 Company report (Roche pipeline: 15 April 2014)
17 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
18 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.
19 [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.
20 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.
21 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.
22 Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and... Psychopharmacology (Berl). 2005 Apr;179(1):271-83.
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.
24 Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg Med Chem Lett. 2005 Oct 1;15(19):4354-8.
25 URL: 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).
26 The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2. Bioorg Med Chem Lett. 2010 Jan 15;20(2):759-62.
27 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.
28 Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identif... J Med Chem. 2007 Jan 25;50(2):233-40.
29 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.
30 A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):254-64.
31 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.
32 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.
33 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.
34 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.
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.
36 Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet. 2011 Dec;25(4):152-66.
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.
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.
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.
40 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.
41 Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)... J Med Chem. 1998 Mar 12;41(6):930-9.