Target Information

Target General Information

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Target ID

T62820 (Former ID: TTDR00321)

Target Name

Metabotropic glutamate receptor 2 (mGluR2)

Synonyms

mGLUR2; Group II metabotropic glutamate receptor; Glutamate receptor mGLU2; GPRC1B

Gene Name

GRM2

Target Type

Clinical trial target

[1]

Disease

[+] 8 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Obesity [ICD-11: 5B80-5B81]

Psychotic disorder [ICD-11: 6A20-6A25]

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]

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.

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BioChemical Class

GPCR glutamate

UniProt ID

GRM2_HUMAN

Sequence

MGSLLALLALLLLWGAVAEGPAKKVLTLEGDLVLGGLFPVHQKGGPAEDCGPVNEHRGIQ
RLEAMLFALDRINRDPHLLPGVRLGAHILDSCSKDTHALEQALDFVRASLSRGADGSRHI
CPDGSYATHGDAPTAITGVIGGSYSDVSIQVANLLRLFQIPQISYASTSAKLSDKSRYDY
FARTVPPDFFQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFELEARARNICVATSEK
VGRAMSRAAFEGVVRALLQKPSARVAVLFTRSEDARELLAASQRLNASFTWVASDGWGAL
ESVVAGSEGAAEGAITIELASYPISDFASYFQSLDPWNNSRNPWFREFWEQRFRCSFRQR
DCAAHSLRAVPFEQESKIMFVVNAVYAMAHALHNMHRALCPNTTRLCDAMRPVNGRRLYK
DFVLNVKFDAPFRPADTHNEVRFDRFGDGIGRYNIFTYLRAGSGRYRYQKVGYWAEGLTL
DTSLIPWASPSAGPLPASRCSEPCLQNEVKSVQPGEVCCWLCIPCQPYEYRLDEFTCADC
GLGYWPNASLTGCFELPQEYIRWGDAWAVGPVTIACLGALATLFVLGVFVRHNATPVVKA
SGRELCYILLGGVFLCYCMTFIFIAKPSTAVCTLRRLGLGTAFSVCYSALLTKTNRIARI
FGGAREGAQRPRFISPASQVAICLALISGQLLIVVAWLVVEAPGTGKETAPERREVVTLR
CNHRDASMLGSLAYNVLLIALCTLYAFKTRKCPENFNEAKFIGFTMYTTCIIWLAFLPIF
YVTSSDYRVQTTTMCVSVSLSGSVVLGCLFAPKLHIILFQPQKNVVSHRAPTSRFGSAAA
RASSSLGQGSGSQFVPTVCNGREVVDSTTSSL

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 9 Clinical Trial Drugs

MP-101

Drug Info

Phase 2

Alzheimer disease

[2]

Oleoyl-estrone

Drug Info

Phase 2

Obesity

[3]

RO-4995819

Drug Info

Phase 2

Major depressive disorder

[4]

ADX71149

Drug Info

Phase 1

Epilepsy

[5]

BCI-632

Drug Info

Phase 1

Major depressive disorder

[6]

BCI-838

Drug Info

Phase 1

Major depressive disorder

[7]

JNJ-42491293

Drug Info

Phase 1

Psychiatric disorder

[8]

LY-2979165

Drug Info

Phase 1

Bipolar disorder

[9]

Pomaglumetad

Drug Info

Phase 1

Schizophrenia

[10]

Discontinued Drug(s)

[+] 6 Discontinued Drugs

LY-544344

Drug Info

Discontinued in Phase 3

Anxiety disorder

[11]

LY-2300559

Drug Info

Discontinued in Phase 2

Migraine

[12]

LY354740

Drug Info

Discontinued in Phase 2

Anxiety disorder

[13], [14]

R-1578

Drug Info

Discontinued in Phase 2

Mood disorder

[15]

RG1578

Drug Info

Discontinued in Phase 2

Major depressive disorder

[15]

TS-032

Drug Info

Discontinued in Phase 1

Schizophrenia

[16]

Mode of Action

[+] 6 Modes of Action

Agonist

[+] 11 Agonist drugs

MP-101

Drug Info

[2]

Oleoyl-estrone

Drug Info

[5], [17]

LY-544344

Drug Info

[25]

LY354740

Drug Info

[27]

TS-032

Drug Info

[30]

(1S,3R)-ACPD

Drug Info

[32]

(2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate

Drug Info

[33], [34]

(S)-4C3HPG

Drug Info

[31]

DCG IV

Drug Info

[34]

L-CCG-I

Drug Info

[32]

MGS0028

Drug Info

[42]

Modulator

[+] 8 Modulator drugs

RO-4995819

Drug Info

[18]

ADX71149

Drug Info

[19]

BCI-838

Drug Info

[21]

LY-2979165

Drug Info

[23]

Pomaglumetad

Drug Info

[1]

LY-2300559

Drug Info

[26]

RG1578

Drug Info

[29]

DT-2228

Drug Info

[38]

Antagonist

[+] 56 Antagonist drugs

BCI-632

Drug Info

[20]

Ethinyl-pyrazole derivative 1

Drug Info

[24]

Ethinyl-pyrazole derivative 2

Drug Info

[24]

Ethinyl-pyrazole derivative 3

Drug Info

[24]

Heteroaryl-pyrazole derivative 1

Drug Info

[24]

Heteroaryl-pyrazole derivative 2

Drug Info

[24]

Heteroaryl-pyrazole derivative 3

Drug Info

[24]

N-substituted pyrazole derivative 1

Drug Info

[24]

N-substituted pyrazole derivative 2

Drug Info

[24]

N-substituted pyrazole derivative 3

Drug Info

[24]

PMID25435285-Compound-10

Drug Info

[24]

PMID25435285-Compound-15

Drug Info

[24]

PMID25435285-Compound-16

Drug Info

[24]

PMID25435285-Compound-20

Drug Info

[24]

PMID25435285-Compound-22

Drug Info

[24]

PMID25435285-Compound-25

Drug Info

[24]

PMID25435285-Compound-26

Drug Info

[24]

PMID25435285-Compound-37

Drug Info

[24]

PMID25435285-Compound-38

Drug Info

[24]

PMID25435285-Compound-39

Drug Info

[24]

PMID25435285-Compound-40

Drug Info

[24]

PMID25435285-Compound-41

Drug Info

[24]

PMID25435285-Compound-42

Drug Info

[24]

PMID25435285-Compound-43

Drug Info

[24]

PMID25435285-Compound-44

Drug Info

[24]

PMID25435285-Compound-45

Drug Info

[24]

PMID25435285-Compound-46

Drug Info

[24]

PMID25435285-Compound-47

Drug Info

[24]

PMID25435285-Compound-49

Drug Info

[24]

PMID25435285-Compound-50

Drug Info

[24]

PMID25435285-Compound-51

Drug Info

[24]

PMID25435285-Compound-52

Drug Info

[24]

PMID25435285-Compound-53

Drug Info

[24]

Pyrazole derivative 76

Drug Info

[24]

Pyrazole derivative 77

Drug Info

[24]

Pyrazole derivative 78

Drug Info

[24]

Pyrazole derivative 79

Drug Info

[24]

Quinoline derivative 3

Drug Info

[24]

Quinoline derivative 4

Drug Info

[24]

Quinoline derivative 5

Drug Info

[24]

Quinoline derivative 6

Drug Info

[24]

Quinoline derivative 7

Drug Info

[24]

Quinoline derivative 8

Drug Info

[24]

Quinoline derivative 9

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 1

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 2

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 3

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 4

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 5

Drug Info

[24]

Tetra-hydro-imidazo[1,5-d][1,4]oxazepin-3-yl derivative 6

Drug Info

[24]

R-1578

Drug Info

[28]

(+)-MCPG

Drug Info

[31]

alpha-methylserine-O-phosphate

Drug Info

[31]

eGlu

Drug Info

[27]

PCCG-4

Drug Info

[44]

[3H]LY341495

Drug Info

[32], [33]

Binder

[+] 1 Binder drugs

JNJ-42491293

Drug Info

[22]

Modulator (allosteric modulator)

[+] 22 Modulator (allosteric modulator) drugs

3-MPPTS

Drug Info

[35]

4-APPES

Drug Info

[35]

4-MPPTS

Drug Info

[36]

biphenylindanone A

Drug Info

[37]

CBiPES

Drug Info

[35]

cyPPTS

Drug Info

[35]

GSK1331268

Drug Info

[39]

JNJ-42153605

Drug Info

[40]

MNI-135

Drug Info

[43]

MNI-136

Drug Info

[43]

MNI-137

Drug Info

[43]

PMID20409708C34

Drug Info

[45]

PMID21155570C14

Drug Info

[46]

PMID22364337C48

Drug Info

[47]

PTBE

Drug Info

[48]

Ro4491533

Drug Info

[49]

RO4988546

Drug Info

[50]

RO5488608

Drug Info

[50]

Ro64-5229

Drug Info

[51]

THIIC

Drug Info

[52]

[3H]2,2,2-TEMPS

Drug Info

[36], [50]

[3H]JNJ-40068782

Drug Info

[53]

Inhibitor

[+] 3 Inhibitor drugs

LY-379268

Drug Info

[41]

LY-389795

Drug Info

[41]

[3H]quisqualate

Drug Info

[54]

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 3 KEGG Pathways

Neuroactive ligand-receptor interaction

Glutamatergic synapse

Cocaine addiction

Panther Pathway

[+] 4 Panther Pathways

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

[+] 2 Reactome Pathways

G alpha (i) signalling events

Class C/3 (Metabotropic glutamate/pheromone receptors)

WikiPathways

[+] 3 WikiPathways

GPCRs, Class C Metabotropic glutamate, pheromone

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

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 2

ClinicalTrials.gov (NCT03044249) A Study of MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression. U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT00449202) Phase 2a Obesity Study of Oral Doses of Oleoyl-Estrone (MP-101). U.S. National Institutes of Health.

REF 4

ClinicalTrials.gov (NCT01457677) ARTDeCo Study: A Study of RO4995819 in Patients With Major Depressive Disorder And Inadequate Response to Ongoing Antidepressant Treatment in Hoffmann-La Roche.

REF 5

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 6

ClinicalTrials.gov (NCT01548703) A Multiple Ascending Dose Study of BCI-838 in Healthy Volunteers. U.S. National Institutes of Health.

REF 7

ClinicalTrials.gov (NCT01548703) A Multiple Ascending Dose Study of BCI-838 in Healthy Volunteers in BrainCells Inc.

REF 8

ClinicalTrials.gov (NCT01359852) A Study of [11C]JNJ-42491293, a Possible PET Ligand for the mGlu2 Receptor, in Healthy Adult Volunteers in Healthy Volunteers in Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

REF 9

ClinicalTrials.gov (NCT01248052) A First Human Dose Study to Investigate Safety and Tolerability of LY2979165 in Healthy Volunteers in Eli Lilly and Company.

REF 10

ClinicalTrials.gov (NCT01487083) A Long-Term Study in Schizophrenia. U.S. National Institutes of Health.

REF 11

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 12

ClinicalTrials.gov (NCT01184508) A Study in Migraine Prevention. U.S. National Institutes of Health.

REF 13

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. (Ligand id: 1393).

REF 14

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008428)

REF 15

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 16

ClinicalTrials.gov (NCT00876304) Multiple Dose Safety Study of PF-04802540 in Subjects With Schizophrenia. U.S. National Institutes of Health.

REF 17

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 18

Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112.

REF 19

MGlu2 receptor-mediated modulation of conditioned avoidance behavior in rats. European journal of pharmacology. 01/2014; 727(1).

REF 20

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 21

Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010

REF 22

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.

REF 23

Annual Reports in Medicinal Chemistry. Volume 47, 2012, Page(78).

REF 24

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.

REF 25

Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.

REF 26

Annual Reports in Medicinal Chemistry. Elsevier (ISBN: 9780123964922). 2012, p78

REF 27

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 28

Clinical pipeline report, company report or official report of Roche.

REF 29

Company report (Roche pipeline: 15 April 2014)

REF 30

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 31

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 32

[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 33

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 34

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 35

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.

REF 36

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 37

Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor. Bioorg Med Chem Lett. 2005 Oct 1;15(19):4354-8.

REF 38

REF 39

The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2. Bioorg Med Chem Lett. 2010 Jan 15;20(2):759-62.

REF 40

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 41

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.

REF 42

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 43

A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):254-64.

REF 44

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 45

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 46

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 47

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 48

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 49

Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression. J Neurogenet. 2011 Dec;25(4):152-66.

REF 50

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 51

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 52

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 53

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 54

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.

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