Target Information

Target General Infomation
Target ID
T27137
Former ID
TTDC00220
Target Name
Metabotropicglutamate receptor 1
Gene Name
GRM1
Synonyms
Glutamate receptor mGLU1; mGLUR1; GRM1
Target Type
Research
Disease Alzheimer disease; Huntington's disease [ICD9:331, 294.1, 333.4; ICD10: G30, F02.2, G10]
Neuropathic pain [ICD9: 356.0, 356.8; ICD10: G64, G90.0]
Neurological disease [ICD9: 338, 338.2, 410, 782.3,780; ICD10: I21, I22, R52, R52.1-R52.2, R60.9, G89]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Schizophrenia [ICD9: 295; ICD10: F20]
Unspecified [ICD code not available]
Function
Receptor forglutamate. The activity of this receptor is mediated by a g-protein that activates a phosphatidylinositol- calcium second messenger system. May participate in the central action of glutamate in the cns, such as long-term potentiation.
BioChemical Class
GPCR glutamate
Target Validation
T27137
UniProt ID
Q13255
Sequence
MVGLLLFFFPAIFLEVSLLPRSPGRKVLLAGASSQRSVARMDGDVIIGALFSVHHQPPAE
KVPERKCGEIREQYGIQRVEAMFHTLDKINADPVLLPNITLGSEIRDSCWHSSVALEQSI
EFIRDSLISIRDEKDGINRCLPDGQSLPPGRTKKPIAGVIGPGSSSVAIQVQNLLQLFDI
PQIAYSATSIDLSDKTLYKYFLRVVPSDTLQARAMLDIVKRYNWTYVSAVHTEGNYGESG
MDAFKELAAQEGLCIAHSDKIYSNAGEKSFDRLLRKLRERLPKARVVVCFCEGMTVRGLL
SAMRRLGVVGEFSLIGSDGWADRDEVIEGYEVEANGGITIKLQSPEVRSFDDYFLKLRLD
TNTRNPWFPEFWQHRFQCRLPGHLLENPNFKRICTGNESLEENYVQDSKMGFVINAIYAM
AHGLQNMHHALCPGHVGLCDAMKPIDGSKLLDFLIKSSFIGVSGEEVWFDEKGDAPGRYD
IMNLQYTEANRYDYVHVGTWHEGVLNIDDYKIQMNKSGVVRSVCSEPCLKGQIKVIRKGE
VSCCWICTACKENEYVQDEFTCKACDLGWWPNADLTGCEPIPVRYLEWSNIESIIAIAFS
CLGILVTLFVTLIFVLYRDTPVVKSSSRELCYIILAGIFLGYVCPFTLIAKPTTTSCYLQ
RLLVGLSSAMCYSALVTKTNRIARILAGSKKKICTRKPRFMSAWAQVIIASILISVQLTL
VVTLIIMEPPMPILSYPSIKEVYLICNTSNLGVVAPLGYNGLLIMSCTYYAFKTRNVPAN
FNEAKYIAFTMYTTCIIWLAFVPIYFGSNYKIITTCFAVSLSVTVALGCMFTPKMYIIIA
KPERNVRSAFTTSDVVRMHVGDGKLPCRSNTFLNIFRRKKAGAGNANSNGKSVSWSEPGG
GQVPKGQHMWHRLSVHVKTNETACNQTAVIKPLTKSYQGSGKSLTFSDTSTKTLYNVEEE
EDAQPIRFSPPGSPSMVVHRRVPSAATTPPLPSHLTAEETPLFLAEPALPKGLPPPLQQQ
QQPPPQQKSLMDQLQGVVSNFSTAIPDFHAVLAGPGGPGNGLRSLYPPPPPPQHLQMLPL
QLSTFGEELVSPPADDDDDSERFKLLQEYVYEHEREGNTEEDELEEEEEDLQAASKLTPD
DSPALTPPSPFRDSVASGSSVPSSPVSESVLCTPPNVSYASVILRDYKQSSSTL
Drugs and Mode of Action
Drug(s) A-841720 Drug Info Preclinical Pain [1], [2]
PF-1913539 Drug Info Discontinued in Phase 3 Alzheimer disease; Huntington's disease [3]
AZD8529 Drug Info Discontinued in Phase 2 Schizophrenia [4], [5]
AZD-9272 Drug Info Discontinued in Phase 1 Neuropathic pain [6], [7]
LY-367385 Drug Info Terminated Neurological disease [8], [9]
Antagonist (+)-MCPG Drug Info [10]
(S)-(+)-CBPG Drug Info [11]
(S)-4C3HPG Drug Info [12]
(S)-4CPG Drug Info [10]
(S)-TBPG Drug Info [13]
3-MATIDA Drug Info [14]
A-841720 Drug Info [15]
AIDA Drug Info [10]
PF-1913539 Drug Info [16], [17]
Agonist (1S,3R)-ACPD Drug Info [12]
(S)-3HPG Drug Info [12]
3,5-DHPG Drug Info [10]
AZD8529 Drug Info [18]
ibotenate Drug Info [12]
L-CCG-I Drug Info [12]
LY-367385 Drug Info [19]
[3H]quisqualate Drug Info [20]
Inhibitor (3,4-dimethylphenyl)(4-phenoxyphenyl)methanone Drug Info [21]
(E)-1-Adamantan-1-yl-3-quinolin-3-yl-propenone Drug Info [21]
(E)-4,4-Dimethyl-1-quinolin-3-yl-pent-1-en-3-one Drug Info [21]
2-methyl-6-(phenylethynyl)pyridine Drug Info [22]
4-(1-Amino-1-Carboxy-Ethyl)-Benzoic Acid Drug Info [23]
4-(cyclohexyloxy)quinazoline Drug Info [24]
6-bromo-N-(3-chlorophenyl)quinazolin-4-amine Drug Info [25]
GLUTAMATE Drug Info [26]
N-(2,3-dihydro-1H-inden-2-yl)isoquinolin-1-amine Drug Info [24]
N-(2,3-dihydro-1H-inden-2-yl)quinazolin-4-amine Drug Info [24]
N-(2-methyl-2-phenylpropyl)pyrazine-2-carboxamide Drug Info [27]
N-(2-phenylpropyl)quinoxaline-2-carboxamide Drug Info [27]
N-(3-bromophenyl)-6-chloroquinazolin-4-amine Drug Info [25]
N-(3-bromophenyl)-6-fluoroquinazolin-4-amine Drug Info [25]
N-cyclohexylquinazolin-4-amine Drug Info [24]
N-cyclohexylquinolin-4-amine Drug Info [24]
N-phenethylquinoxaline-2-carboxamide Drug Info [27]
Pyrazine-2-carboxylic acid adamantan-1-ylamide Drug Info [28]
Quinoline-2-carboxylic acid adamantan-1-ylamide Drug Info [28]
Quinoline-3-carboxylic acid adamantan-1-ylamide Drug Info [28]
Quinoxaline-2-carboxylic acid adamantan-1-ylamide Drug Info [28]
QUISQUALATE Drug Info [29]
VU0080241 Drug Info [30]
Modulator (allosteric modulator) 3,5-dimethyl PPP Drug Info [31]
A-794278 Drug Info [32]
A-794282 Drug Info [32]
A-850002 Drug Info [32]
BAY 367620 Drug Info [33]
CFMMC Drug Info [34]
CFMTI Drug Info [35]
cis-10 Drug Info [36]
compound 10i Drug Info [37]
compound 11c Drug Info [38]
compound 11q Drug Info [39]
compound 11s Drug Info [39]
compound 12e Drug Info [40]
compound 22 Drug Info [41]
compound 22 Drug Info [24]
compound 23c Drug Info [38]
compound 23e Drug Info [38]
compound 23h Drug Info [38]
compound 23i Drug Info [38]
compound 24 Drug Info [42]
compound 27 Drug Info [42]
compound 29 Drug Info [27]
compound 2f Drug Info [43]
compound 3 Drug Info [31]
compound 32 Drug Info [24]
compound 3a Drug Info [44]
compound 4b Drug Info [44]
compound 9a Drug Info [40]
compound 9n Drug Info [37]
CPCCOEt Drug Info [10]
DM-PPP Drug Info [31]
EM-TBPC Drug Info [20]
FPTQ Drug Info [45]
FTIDC Drug Info [46]
JNJ-16567083 Drug Info [47]
LY456066 Drug Info [34]
LY456236 Drug Info [48]
MK-5435 Drug Info [49]
PHCCC Drug Info [48]
R214127 Drug Info [10]
Ro01-6128 Drug Info [50]
Ro0711401 Drug Info [51]
Ro67-4853 Drug Info [50]
Ro67-7476 Drug Info [50]
VU-71 Drug Info [44]
VU0469650 Drug Info [52]
YM-202074 Drug Info [53]
YM298198 Drug Info [54]
[11C]MMTP Drug Info [55]
[18F]FITM Drug Info [56]
[18F]FPIT Drug Info [57]
[18F]MK-1312 Drug Info [49]
[3H]EM-TBPC Drug Info [20]
[3H]R214127 Drug Info [10]
[3H]YM298198 Drug Info [54]
Modulator AZD-9272 Drug Info [6]
LY-3390334 Drug Info
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Calcium signaling pathway
FoxO signaling pathway
Neuroactive ligand-receptor interaction
Gap junction
Long-term potentiation
Retrograde endocannabinoid signaling
Glutamatergic synapse
Long-term depression
Estrogen signaling pathway
PANTHER Pathway Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Metabotropic glutamate receptor group III pathway
Metabotropic glutamate receptor group I pathway
Endogenous cannabinoid signaling
Reactome G alpha (q) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
WikiPathways Hypothetical Network for Drug Addiction
GPCRs, Class C Metabotropic glutamate, pheromone
Gastrin-CREB signalling pathway via PKC and MAPK
GPCR ligand binding
GPCR downstream signaling
GPCRs, Other
References
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REF 2Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024545)
REF 3Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021875)
REF 4(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: 7678).
REF 5Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029661)
REF 6Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.
REF 7(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: 6439).
REF 8(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: 1379).
REF 9Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011092)
REF 10[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.
REF 11Biochemical 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.
REF 12Characterization 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.
REF 13Synthesis 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.
REF 14The novel and systemically active metabotropic glutamate 1 (mGlu1) receptor antagonist 3-MATIDA reduces post-ischemic neuronal death. Neuropharmacology. 2002 May;42(6):741-51.
REF 15Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition. Behav Pharmacol. 2007 Jul;18(4):273-81.
REF 16Comparative study of action mechanisms of dimebon and memantine on AMPA- and NMDA-subtypes glutamate receptors in rat cerebral neurons. Bull Exp Biol Med. 2003 Nov;136(5):474-7.
REF 17Pfizer. Product Development Pipeline. March 31 2009.
REF 18Clinical pipeline report, company report or official report of AstraZeneca (2009).
REF 19Anticonvulsant 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.
REF 20Mutational analysis and molecular modeling of the allosteric binding site of a novel, selective, noncompetitive antagonist of the metabotropic glutamate 1 receptor. J Biol Chem. 2003 Mar 7;278(10):8340-7. Epub 2002 Dec 30.
REF 21Bioorg Med Chem. 2009 Aug 1;17(15):5708-15. Epub 2009 Jun 23.Synergism of virtual screening and medicinal chemistry: identification and optimization of allosteric antagonists of metabotropic glutamate receptor 1.
REF 22Bioorg Med Chem Lett. 2010 Aug 1;20(15):4371-5. Epub 2010 Jun 17.Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists.
REF 23How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6.
REF 24Bioorg Med Chem Lett. 2009 Apr 15;19(8):2190-4. Epub 2009 Mar 3.In vitro and in vivo SAR of pyrido[3,4-d]pyramid-4-ylamine based mGluR1 antagonists.
REF 25Bioorg Med Chem Lett. 2009 Dec 1;19(23):6623-6. Epub 2009 Oct 9.Discovery and SAR of 6-substituted-4-anilinoquinazolines as non-competitive antagonists of mGlu5.
REF 26J 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 27Bioorg Med Chem Lett. 2007 Jan 15;17(2):486-90. Epub 2006 Oct 11.Structure-activity relationships of novel non-competitive mGluR1 antagonists: a potential treatment for chronic pain.
REF 28J Med Chem. 2008 Feb 14;51(3):634-47. Epub 2008 Jan 4.Positive and negative modulation of group I metabotropic glutamate receptors.
REF 29J 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 30Bioorg Med Chem Lett. 2008 Oct 15;18(20):5626-30. Epub 2008 Aug 29.Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4): Part I. Discovery of pyrazolo[3,4-d]pyrimidines as novel mGluR4 positive allosteric modulators.
REF 31Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists. Bioorg Med Chem. 2003 Jan 17;11(2):171-83.
REF 32Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists. J Med Chem. 2005 Nov 17;48(23):7374-88.
REF 33BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol. 2001 May;59(5):965-73.
REF 34Identification 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.
REF 35Unique 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.
REF 36Synthesis, structure-activity relationship, and receptor pharmacology of a new series of quinoline derivatives acting as selective, noncompetitive mGlu1 antagonists. J Med Chem. 2005 Mar 24;48(6):2134-53.
REF 37Synthesis and SAR development of novel mGluR1 antagonists for the treatment of chronic pain. Bioorg Med Chem Lett. 2012 Dec 1;22(23):7223-6.
REF 38Discovery 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. Epub 2007 Oct 11.
REF 39Tricyclic thienopyridine-pyrimidones/thienopyrimidine-pyrimidones as orally efficacious mGluR1 antagonists for neuropathic pain. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3199-203.
REF 40Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1575-8.
REF 41From 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. Epub 2007 Jan 25.
REF 42A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2474-7.
REF 43Rapid 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. Epub 2007 May 16.
REF 449H-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.
REF 45Synthesis 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.
REF 46Pharmacological characterization of a new, orally active and potent allosteric metabotropic glutamate receptor 1 antagonist, 4-[1-(2-fluoropyridin-3-yl)-5-methyl-1H-1,2,3-triazol-4-yl]-N-isopropyl-N-methyl-3,6-dihydropyridine-1(2H)-carboxamide (FTIDC). J Pharmacol Exp Ther. 2007 Jun;321(3):1144-53. Epub 2007 Mar 14.
REF 47A 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.
REF 48(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).
REF 49Synthesis, 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.
REF 50Positive 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. Epub 2001 Oct 23.
REF 51Fluorinated 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.
REF 52N-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.
REF 53Neuroprotective effects of the selective type 1 metabotropic glutamate receptor antagonist YM-202074 in rat stroke models. Brain Res. 2008 Jan 29;1191:168-79.
REF 54Radioligand binding properties and pharmacological characterization of 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-carboxamide (YM-298198), a high-affinity, selective, and noncompetitive antagonist of metabotropic glutamate receptor type 1. J Pharmacol Exp Ther. 2005 Oct;315(1):163-9. Epub 2005 Jun 23.
REF 55Synthesis, 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.
REF 56Radiosynthesis 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.
REF 57Characterization 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.

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