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

DTT Name Metabotropic glutamate receptor 1 (mGluR1)
Synonyms mGLUR1; Glutamate receptor mGLU1; GPRC1A
Gene Name GRM1
DTT Type
Discontinued target
[1]
BioChemical Class
GPCR glutamate
UniProt ID
GRM1_HUMAN
TTD ID
T27137
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Sequence
MVGLLLFFFPAIFLEVSLLPRSPGRKVLLAGASSQRSVARMDGDVIIGALFSVHHQPPAE
KVPERKCGEIREQYGIQRVEAMFHTLDKINADPVLLPNITLGSEIRDSCWHSSVALEQSI
EFIRDSLISIRDEKDGINRCLPDGQSLPPGRTKKPIAGVIGPGSSSVAIQVQNLLQLFDI
PQIAYSATSIDLSDKTLYKYFLRVVPSDTLQARAMLDIVKRYNWTYVSAVHTEGNYGESG
MDAFKELAAQEGLCIAHSDKIYSNAGEKSFDRLLRKLRERLPKARVVVCFCEGMTVRGLL
SAMRRLGVVGEFSLIGSDGWADRDEVIEGYEVEANGGITIKLQSPEVRSFDDYFLKLRLD
TNTRNPWFPEFWQHRFQCRLPGHLLENPNFKRICTGNESLEENYVQDSKMGFVINAIYAM
AHGLQNMHHALCPGHVGLCDAMKPIDGSKLLDFLIKSSFIGVSGEEVWFDEKGDAPGRYD
IMNLQYTEANRYDYVHVGTWHEGVLNIDDYKIQMNKSGVVRSVCSEPCLKGQIKVIRKGE
VSCCWICTACKENEYVQDEFTCKACDLGWWPNADLTGCEPIPVRYLEWSNIESIIAIAFS
CLGILVTLFVTLIFVLYRDTPVVKSSSRELCYIILAGIFLGYVCPFTLIAKPTTTSCYLQ
RLLVGLSSAMCYSALVTKTNRIARILAGSKKKICTRKPRFMSAWAQVIIASILISVQLTL
VVTLIIMEPPMPILSYPSIKEVYLICNTSNLGVVAPLGYNGLLIMSCTYYAFKTRNVPAN
FNEAKYIAFTMYTTCIIWLAFVPIYFGSNYKIITTCFAVSLSVTVALGCMFTPKMYIIIA
KPERNVRSAFTTSDVVRMHVGDGKLPCRSNTFLNIFRRKKAGAGNANSNGKSVSWSEPGG
GQVPKGQHMWHRLSVHVKTNETACNQTAVIKPLTKSYQGSGKSLTFSDTSTKTLYNVEEE
EDAQPIRFSPPGSPSMVVHRRVPSAATTPPLPSHLTAEETPLFLAEPALPKGLPPPLQQQ
QQPPPQQKSLMDQLQGVVSNFSTAIPDFHAVLAGPGGPGNGLRSLYPPPPPPQHLQMLPL
QLSTFGEELVSPPADDDDDSERFKLLQEYVYEHEREGNTEEDELEEEEEDLQAASKLTPD
DSPALTPPSPFRDSVASGSSVPSSPVSESVLCTPPNVSYASVILRDYKQSSSTL
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. Signaling activates a phosphatidylinositol-calcium second messenger system. May participate in the central action of glutamate in the CNS, such as long-term potentiation in the hippocampus and long-term depression in the cerebellum. G-protein coupled receptor for glutamate.
KEGG Pathway
Calcium signaling pathway (hsa04020 )
FoxO signaling pathway (hsa04068 )
Neuroactive ligand-receptor interaction (hsa04080 )
Gap junction (hsa04540 )
Long-term potentiation (hsa04720 )
Retrograde endocannabinoid signaling (hsa04723 )
Glutamatergic synapse (hsa04724 )
Long-term depression (hsa04730 )
Estrogen signaling pathway (hsa04915 )
Reactome Pathway
Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499 )
G alpha (q) signalling events (R-HSA-416476 )

Molecular Interaction Atlas (MIA) of This DTT

Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DTT
4 Discontinued Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
PF-1913539 DMXEU14 Alzheimer disease 8A20 Discontinued in Phase 3 [2]
AZD8529 DMEQ2N1 Schizophrenia 6A20 Discontinued in Phase 2 [3]
AZD-9272 DMYSBN3 Neuropathic pain 8E43.0 Discontinued in Phase 1 [4]
LY-367385 DM98POQ Neurological disorder 6B60 Terminated [6]
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2 Preclinical Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
A-841720 DMSO8IE Pain MG30-MG3Z Preclinical [1]
NPS-2390 DMMRY0Z Cerebrovascular ischaemia 8B1Z Preclinical [5]
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84 Investigative Drug(s) Targeting This DTT
Drug Name Drug ID Indication ICD 11 Highest Status REF
(+)-MCPG DMG5QJB Discovery agent N.A. Investigative [7]
(1S,3R)-ACPD DM5DOAF Discovery agent N.A. Investigative [8]
(3,4-dimethylphenyl)(4-phenoxyphenyl)methanone DMAF43E Discovery agent N.A. Investigative [9]
(E)-1-Adamantan-1-yl-3-quinolin-3-yl-propenone DMQ9TWD Discovery agent N.A. Investigative [9]
(E)-4,4-Dimethyl-1-quinolin-3-yl-pent-1-en-3-one DMJGAFV Discovery agent N.A. Investigative [9]
(S)-(+)-CBPG DMPDOY8 Discovery agent N.A. Investigative [10]
(S)-3HPG DMQ0FVJ Discovery agent N.A. Investigative [8]
(S)-4C3HPG DMQK4I2 Discovery agent N.A. Investigative [8]
(S)-4CPG DMZ9UIL Discovery agent N.A. Investigative [7]
(S)-TBPG DM68XFZ Discovery agent N.A. Investigative [11]
2-methyl-6-(phenylethynyl)pyridine DMVQK4Y Discovery agent N.A. Investigative [12]
3,5-DHPG DMFEQ6S Discovery agent N.A. Investigative [7]
3,5-dimethyl PPP DM3E98I Discovery agent N.A. Investigative [13]
3-MATIDA DMRMF13 Discovery agent N.A. Investigative [14]
4-(cyclohexyloxy)quinazoline DMCDZ7E Discovery agent N.A. Investigative [15]
6-bromo-N-(3-chlorophenyl)quinazolin-4-amine DM0A3DB Discovery agent N.A. Investigative [16]
A-794278 DM6BRTF Discovery agent N.A. Investigative [17]
A-794282 DMU965M Discovery agent N.A. Investigative [17]
A-850002 DMJCPSD Discovery agent N.A. Investigative [17]
AIDA DM3LCDK Discovery agent N.A. Investigative [7]
BAY 367620 DMVP74I Discovery agent N.A. Investigative [18]
CFMMC DMN8B1S Discovery agent N.A. Investigative [19]
CFMTI DM9HMP4 Discovery agent N.A. Investigative [20]
CPCCOEt DMI4WVE Discovery agent N.A. Investigative [7]
DM-PPP DMUGPD1 Discovery agent N.A. Investigative [13]
FPTQ DMR2NBK Discovery agent N.A. Investigative [21]
FTIDC DM65VLB Discovery agent N.A. Investigative [22]
ibotenate DM8RZE0 Discovery agent N.A. Investigative [8]
JNJ-16567083 DMXNFU5 Discovery agent N.A. Investigative [23]
L-CCG-I DMPZ8XH Discovery agent N.A. Investigative [8]
LY-3390334 DMUXFZQ Discovery agent N.A. Investigative [24]
LY456066 DM86Y1V Discovery agent N.A. Investigative [19]
LY456236 DMROFX8 Discovery agent N.A. Investigative [25]
MK-5435 DMU8VRB Discovery agent N.A. Investigative [26]
N-(2,3-dihydro-1H-inden-2-yl)isoquinolin-1-amine DMTLPDZ Discovery agent N.A. Investigative [15]
N-(2,3-dihydro-1H-inden-2-yl)quinazolin-4-amine DMJ6LI8 Discovery agent N.A. Investigative [15]
N-(2-methyl-2-phenylpropyl)pyrazine-2-carboxamide DMXRSM1 Discovery agent N.A. Investigative [27]
N-(2-phenylpropyl)quinoxaline-2-carboxamide DMA1LRF Discovery agent N.A. Investigative [27]
N-(3-bromophenyl)-6-chloroquinazolin-4-amine DMEWQCN Discovery agent N.A. Investigative [16]
N-(3-bromophenyl)-6-fluoroquinazolin-4-amine DMRIK7P Discovery agent N.A. Investigative [16]
N-cyclohexylquinazolin-4-amine DMJ0T3W Discovery agent N.A. Investigative [15]
N-cyclohexylquinolin-4-amine DMJY2PA Discovery agent N.A. Investigative [15]
N-phenethylquinoxaline-2-carboxamide DM1ZPGY Discovery agent N.A. Investigative [27]
PHCCC DMNJY79 Discovery agent N.A. Investigative [25]
PMID12470711C3 DM1ISJU Discovery agent N.A. Investigative [13]
PMID16099654C3a DMIRSWL Discovery agent N.A. Investigative [28]
PMID16099654C4b DMV8UK1 Discovery agent N.A. Investigative [28]
PMID17064898C29 DMITDEB Discovery agent N.A. Investigative [27]
PMID17276684C22 DMWNYBV Discovery agent N.A. Investigative [29]
PMID17532216C2f DMX3CYG Discovery agent N.A. Investigative [30]
PMID17929793C11c DMDVW4K Discovery agent N.A. Investigative [31]
PMID17929793C23c DMIG308 Discovery agent N.A. Investigative [31]
PMID17929793C23e DMOB07W Discovery agent N.A. Investigative [31]
PMID17929793C23h DM83Z6M Discovery agent N.A. Investigative [31]
PMID17929793C23i DM07TVS Discovery agent N.A. Investigative [31]
PMID19289283C22 DMJRLB5 Discovery agent N.A. Investigative [15]
PMID19289283C32 DMSKGEJ Discovery agent N.A. Investigative [15]
PMID19433355C11q DMPXEIQ Discovery agent N.A. Investigative [32]
PMID19433355C11s DMBU0XJ Discovery agent N.A. Investigative [32]
PMID20346665C24 DMLKFTE Discovery agent N.A. Investigative [33]
PMID20346665C27 DMDKW6G Discovery agent N.A. Investigative [33]
PMID22266036C12e DM4NRG5 Discovery agent N.A. Investigative [34]
PMID22266036C9a DMFQHVL Discovery agent N.A. Investigative [34]
PMID23084894C10i DMURP5Y Discovery agent N.A. Investigative [35]
PMID23084894C9n DM4ATLM Discovery agent N.A. Investigative [35]
Pyrazine-2-carboxylic acid adamantan-1-ylamide DMIZB81 Discovery agent N.A. Investigative [5]
Quinoline-2-carboxylic acid adamantan-1-ylamide DMDY3I2 Discovery agent N.A. Investigative [5]
Quinoline-3-carboxylic acid adamantan-1-ylamide DM9BIVL Discovery agent N.A. Investigative [5]
R214127 DMX80BL Discovery agent N.A. Investigative [7]
Ro01-6128 DM0AC84 Discovery agent N.A. Investigative [36]
Ro0711401 DMZLUAK Discovery agent N.A. Investigative [37]
Ro67-4853 DMD93NP Discovery agent N.A. Investigative [36]
Ro67-7476 DMI95DP Discovery agent N.A. Investigative [36]
VU-71 DMHX1KJ Discovery agent N.A. Investigative [28]
VU0080241 DMUMOV1 Discovery agent N.A. Investigative [38]
VU0469650 DM1H5DL Discovery agent N.A. Investigative [39]
YM-202074 DM3IOLR Discovery agent N.A. Investigative [40]
YM298198 DMUYDXT Discovery agent N.A. Investigative [41]
[11C]MMTP DMQRSP7 Discovery agent N.A. Investigative [42]
[18F]FITM DM4VQNE Discovery agent N.A. Investigative [43]
[18F]FPIT DMRQ6XD Discovery agent N.A. Investigative [44]
[18F]MK-1312 DMQ6AR5 Discovery agent N.A. Investigative [26]
[3H]EM-TBPC DMM1KBW Discovery agent N.A. Investigative [45]
[3H]quisqualate DMDQBTX Discovery agent N.A. Investigative [45]
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⏷ Show the Full List of 84 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 2.31E-01 -0.05 -0.2
Schizophrenia 6A20 Superior temporal cortex 2.46E-02 0.11 0.74
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References

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2 Pfizer. Product Development Pipeline. March 31 2009.
3 Clinical pipeline report, company report or official report of AstraZeneca (2009).
4 Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
5 Positive and negative modulation of group I metabotropic glutamate receptors. J Med Chem. 2008 Feb 14;51(3):634-47.
6 Anticonvulsant actions of LY 367385 ((+)-2-methyl-4-carboxyphenylglycine) and AIDA ((RS)-1-aminoindan-1,5-dicarboxylic acid). Eur J Pharmacol. 1999 Feb 26;368(1):17-24.
7 [3H]R214127: a novel high-affinity radioligand for the mGlu1 receptor reveals a common binding site shared by multiple allosteric antagonists. Mol Pharmacol. 2003 May;63(5):1082-93.
8 Characterization of [(3)H]Quisqualate binding to recombinant rat metabotropic glutamate 1a and 5a receptors and to rat and human brain sections. J Neurochem. 2000 Dec;75(6):2590-601.
9 Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate recepto... Bioorg Med Chem. 2009 Aug 1;17(15):5708-15.
10 Biochemical and electrophysiological studies on (S)-(+)-2-(3'-carboxybicyclo(1.1.1)pentyl)-glycine (CBPG), a novel mGlu5 receptor agonist endowed with mGlu1 receptor antagonist activity. Neuropharmacology. 1999 Jul;38(7):917-26.
11 Synthesis and biological evaluation of 2-(3'-(1H-tetrazol-5-yl) bicyclo[1.1.1]pent-1-yl)glycine (S-TBPG), a novel mGlu1 receptor antagonist. Bioorg Med Chem. 2001 Feb;9(2):221-7.
12 Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4371-5.
13 Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists. Bioorg Med Chem. 2003 Jan 17;11(2):171-83.
14 The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death. Neuropharmacology. 2002 May;42(6):741-51.
15 In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists. Bioorg Med Chem Lett. 2009 Apr 15;19(8):2190-4.
16 Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5. Bioorg Med Chem Lett. 2009 Dec 1;19(23):6623-6.
17 Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists. J Med Chem. 2005 Nov 17;48(23):7374-88.
18 BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol. 2001 May;59(5):965-73.
19 Identification of a novel transmembrane domain involved in the negative modulation of mGluR1 using a newly discovered allosteric mGluR1 antagonist, 3-cyclohexyl-5-fluoro-6-methyl-7-(2-morpholin-4-ylethoxy)-4H-chromen-4-one. Neuropharmacology. 2009 Sep;57(4):438-45.
20 Unique antipsychotic activities of the selective metabotropic glutamate receptor 1 allosteric antagonist 2-cyclopropyl-5-[1-(2-fluoro-3-pyridinyl)-5-methyl-1H-1,2,3-triazol-4-yl]-2,3-dihydro-1H-isoindol-1-one. J Pharmacol Exp Ther. 2009 Jul;330(1):179-90.
21 Synthesis and evaluation of 6-[1-(2-[(18)F]fluoro-3-pyridyl)-5-methyl-1H-1,2,3-triazol-4-yl]quinoline for positron emission tomography imaging of the metabotropic glutamate receptor type 1 in brain. Bioorg Med Chem. 2011 Jan 1;19(1):102-10.
22 Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-... J Pharmacol Exp Ther. 2007 Jun;321(3):1144-53.
23 A positron emission tomography radioligand for the in vivo labeling of metabotropic glutamate 1 receptor: (3-ethyl-2-[11C]methyl-6-quinolinyl)(cis- 4-methoxycyclohexyl)methanone. J Med Chem. 2005 Aug11;48(16):5096-9.
24 Inhibition of group I metabotropic glutamate receptor responses in vivo in rats by a new generation of carboxyphenylglycine-like amino acid antagon... Neurosci Lett. 2002 Sep 20;330(2):127-30.
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: 289).
26 Synthesis, characterization, and monkey PET studies of [ ]MK-1312, a PET tracer for quantification of mGluR1 receptor occupancy by MK-5435. Synapse. 2011 Feb;65(2):125-35.
27 Structure-activity relationships of novel non-competitive mGluR1 antagonists: a potential treatment for chronic pain. Bioorg Med Chem Lett. 2007 Jan 15;17(2):486-90.
28 9H-Xanthene-9-carboxylic acid [1,2,4]oxadiazol-3-yl- and (2H-tetrazol-5-yl)-amides as potent, orally available mGlu1 receptor enhancers. Bioorg Med Chem Lett. 2005 Oct 15;15(20):4628-31.
29 From pyrroles to 1-oxo-2,3,4,9-tetrahydro-1H-beta-carbolines: a new class of orally bioavailable mGluR1 antagonists. Bioorg Med Chem Lett. 2007 Apr 15;17(8):2254-9.
30 Rapid hit to lead evaluation of pyrazolo[3,4-d]pyrimidin-4-one as selective and orally bioavailable mGluR1 antagonists. Bioorg Med Chem Lett. 2007 Aug 1;17(15):4303-7.
31 Discovery of orally efficacious tetracyclic metabotropic glutamate receptor 1 (mGluR1) antagonists for the treatment of chronic pain. J Med Chem. 2007 Nov 15;50(23):5550-3.
32 Tricyclic thienopyridine-pyrimidones/thienopyrimidine-pyrimidones as orally efficacious mGluR1 antagonists for neuropathic pain. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3199-203.
33 A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2474-7.
34 Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1575-8.
35 Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7223-6.
36 Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):13402-7.
37 Fluorinated 9H-xanthene-9-carboxylic acid oxazol-2-yl-amides as potent, orally available mGlu1 receptor enhancers. Bioorg Med Chem Lett. 2009 Mar 15;19(6):1666-9.
38 Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel ... Bioorg Med Chem Lett. 2008 Oct 15;18(20):5626-30.
39 N-Acyl-N'-arylpiperazines as negative allosteric modulators of mGlu1: identification of VU0469650, a potent and selective tool compound with CNS exposure in rats. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3713-8.
40 Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models. Brain Res. 2008 Jan 29;1191:168-79.
41 Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide ... J Pharmacol Exp Ther. 2005 Oct;315(1):163-9.
42 Synthesis, in vitro and in vivo evaluation of [11C]MMTP: a potential PET ligand for mGluR1 receptors. Bioorg Med Chem Lett. 2010 Jun 15;20(12):3499-501.
43 Radiosynthesis and preliminary evaluation of 4-[18F]fluoro-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide as a new positron emission tomography ligand for metabotropic glutamate receptor subtype 1. Bioorg Med Chem Lett. 2011 May 15;21(10):2998-3001.
44 Characterization of 1-(2-[18F] fluoro-3-pyridyl)-4-(2-isopropyl-1-oxo- isoindoline-5-yl)-5-methyl-1H-1,2,3-triazole, a PET ligand for imaging the metabotropic glutamate receptor type 1 in rat and monkey brains. J Neurochem. 2012 Apr;121(1):115-24.
45 Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, noncompetitive antagonist of the metabotropic glut... J Biol Chem. 2003 Mar 7;278(10):8340-7.