Target Information

Target General Information

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Target ID

T27137 (Former ID: TTDC00220)

Target Name

Metabotropic glutamate receptor 1 (mGluR1)

Synonyms

mGLUR1; Glutamate receptor mGLU1; GPRC1A

Gene Name

GRM1

Target Type

Discontinued target

[1]

Disease

[+] 6 Target-related Diseases

Alzheimer disease [ICD-11: 8A20]

Schizophrenia [ICD-11: 6A20]

General pain disorder [ICD-11: 8E43]

Cerebral ischaemia [ICD-11: 8B1Z]

Pain [ICD-11: MG30-MG3Z]

Dissociative neurological symptom disorder [ICD-11: 6B60]

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.

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BioChemical Class

GPCR glutamate

UniProt ID

GRM1_HUMAN

Sequence

MVGLLLFFFPAIFLEVSLLPRSPGRKVLLAGASSQRSVARMDGDVIIGALFSVHHQPPAE
KVPERKCGEIREQYGIQRVEAMFHTLDKINADPVLLPNITLGSEIRDSCWHSSVALEQSI
EFIRDSLISIRDEKDGINRCLPDGQSLPPGRTKKPIAGVIGPGSSSVAIQVQNLLQLFDI
PQIAYSATSIDLSDKTLYKYFLRVVPSDTLQARAMLDIVKRYNWTYVSAVHTEGNYGESG
MDAFKELAAQEGLCIAHSDKIYSNAGEKSFDRLLRKLRERLPKARVVVCFCEGMTVRGLL
SAMRRLGVVGEFSLIGSDGWADRDEVIEGYEVEANGGITIKLQSPEVRSFDDYFLKLRLD
TNTRNPWFPEFWQHRFQCRLPGHLLENPNFKRICTGNESLEENYVQDSKMGFVINAIYAM
AHGLQNMHHALCPGHVGLCDAMKPIDGSKLLDFLIKSSFIGVSGEEVWFDEKGDAPGRYD
IMNLQYTEANRYDYVHVGTWHEGVLNIDDYKIQMNKSGVVRSVCSEPCLKGQIKVIRKGE
VSCCWICTACKENEYVQDEFTCKACDLGWWPNADLTGCEPIPVRYLEWSNIESIIAIAFS
CLGILVTLFVTLIFVLYRDTPVVKSSSRELCYIILAGIFLGYVCPFTLIAKPTTTSCYLQ
RLLVGLSSAMCYSALVTKTNRIARILAGSKKKICTRKPRFMSAWAQVIIASILISVQLTL
VVTLIIMEPPMPILSYPSIKEVYLICNTSNLGVVAPLGYNGLLIMSCTYYAFKTRNVPAN
FNEAKYIAFTMYTTCIIWLAFVPIYFGSNYKIITTCFAVSLSVTVALGCMFTPKMYIIIA
KPERNVRSAFTTSDVVRMHVGDGKLPCRSNTFLNIFRRKKAGAGNANSNGKSVSWSEPGG
GQVPKGQHMWHRLSVHVKTNETACNQTAVIKPLTKSYQGSGKSLTFSDTSTKTLYNVEEE
EDAQPIRFSPPGSPSMVVHRRVPSAATTPPLPSHLTAEETPLFLAEPALPKGLPPPLQQQ
QQPPPQQKSLMDQLQGVVSNFSTAIPDFHAVLAGPGGPGNGLRSLYPPPPPPQHLQMLPL
QLSTFGEELVSPPADDDDDSERFKLLQEYVYEHEREGNTEEDELEEEEEDLQAASKLTPD
DSPALTPPSPFRDSVASGSSVPSSPVSESVLCTPPNVSYASVILRDYKQSSSTL

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

HIT2.0 ID

T02U6A

Drugs and Modes of Action

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Discontinued Drug(s)

[+] 4 Discontinued Drugs

PF-1913539

Drug Info

Discontinued in Phase 3

Alzheimer disease

[2]

AZD8529

Drug Info

Discontinued in Phase 2

Schizophrenia

[3], [4]

AZD-9272

Drug Info

Discontinued in Phase 1

Neuropathic pain

[5], [6]

LY-367385

Drug Info

Terminated

Neurological disorder

[11], [12]

Preclinical Drug(s)

[+] 2 Preclinical Drugs

A-841720

Drug Info

Preclinical

Pain

[7], [8]

NPS-2390

Drug Info

Preclinical

Cerebrovascular ischaemia

[9], [10]

Mode of Action

[+] 5 Modes of Action

Antagonist

[+] 9 Antagonist drugs

PF-1913539

Drug Info

[13], [14]

A-841720

Drug Info

[1]

(+)-MCPG

Drug Info

[18], [19]

(S)-(+)-CBPG

Drug Info

[22]

(S)-4C3HPG

Drug Info

[20]

(S)-4CPG

Drug Info

[18]

(S)-TBPG

Drug Info

[23]

3-MATIDA

Drug Info

[26]

AIDA

Drug Info

[18]

Agonist

[+] 8 Agonist drugs

AZD8529

Drug Info

[15]

LY-367385

Drug Info

[17]

(1S,3R)-ACPD

Drug Info

[20]

(S)-3HPG

Drug Info

[20]

3,5-DHPG

Drug Info

[18]

ibotenate

Drug Info

[20]

L-CCG-I

Drug Info

[20]

[3H]quisqualate

Drug Info

[57], [58]

Modulator

[+] 2 Modulator drugs

AZD-9272

Drug Info

[6]

LY-3390334

Drug Info

[36]

Inhibitor

[+] 20 Inhibitor drugs

NPS-2390

Drug Info

[16]

(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

[24]

4-(cyclohexyloxy)quinazoline

Drug Info

[27]

6-bromo-N-(3-chlorophenyl)quinazolin-4-amine

Drug Info

[28]

N-(2,3-dihydro-1H-inden-2-yl)isoquinolin-1-amine

Drug Info

[27]

N-(2,3-dihydro-1H-inden-2-yl)quinazolin-4-amine

Drug Info

[27]

N-(2-methyl-2-phenylpropyl)pyrazine-2-carboxamide

Drug Info

[39]

N-(2-phenylpropyl)quinoxaline-2-carboxamide

Drug Info

[39]

N-(3-bromophenyl)-6-chloroquinazolin-4-amine

Drug Info

[28]

N-(3-bromophenyl)-6-fluoroquinazolin-4-amine

Drug Info

[28]

N-cyclohexylquinazolin-4-amine

Drug Info

[27]

N-cyclohexylquinolin-4-amine

Drug Info

[27]

N-phenethylquinoxaline-2-carboxamide

Drug Info

[39]

Pyrazine-2-carboxylic acid adamantan-1-ylamide

Drug Info

[16]

Quinoline-2-carboxylic acid adamantan-1-ylamide

Drug Info

[16]

Quinoline-3-carboxylic acid adamantan-1-ylamide

Drug Info

[16]

VU0080241

Drug Info

[50]

Modulator (allosteric modulator)

[+] 51 Modulator (allosteric modulator) drugs

3,5-dimethyl PPP

Drug Info

[25]

A-794278

Drug Info

[29]

A-794282

Drug Info

[29]

A-850002

Drug Info

[29]

BAY 367620

Drug Info

[30]

CFMMC

Drug Info

[31]

CFMTI

Drug Info

[32]

CPCCOEt

Drug Info

[18]

DM-PPP

Drug Info

[25]

FPTQ

Drug Info

[33]

FTIDC

Drug Info

[34]

JNJ-16567083

Drug Info

[35]

LY456066

Drug Info

[31]

LY456236

Drug Info

[37]

MK-5435

Drug Info

[38]

PHCCC

Drug Info

[37]

PMID12470711C3

Drug Info

[25]

PMID16099654C3a

Drug Info

[40]

PMID16099654C4b

Drug Info

[40]

PMID17064898C29

Drug Info

[39]

PMID17276684C22

Drug Info

[41]

PMID17532216C2f

Drug Info

[42]

PMID17929793C11c

Drug Info

[43]

PMID17929793C23c

Drug Info

[43]

PMID17929793C23e

Drug Info

[43]

PMID17929793C23h

Drug Info

[43]

PMID17929793C23i

Drug Info

[43]

PMID19289283C22

Drug Info

[27]

PMID19289283C32

Drug Info

[27]

PMID19433355C11q

Drug Info

[44]

PMID19433355C11s

Drug Info

[44]

PMID20346665C24

Drug Info

[45]

PMID20346665C27

Drug Info

[45]

PMID22266036C12e

Drug Info

[46]

PMID22266036C9a

Drug Info

[46]

PMID23084894C10i

Drug Info

[47]

PMID23084894C9n

Drug Info

[47]

R214127

Drug Info

[18]

Ro01-6128

Drug Info

[48]

Ro0711401

Drug Info

[49]

Ro67-4853

Drug Info

[48]

Ro67-7476

Drug Info

[48]

VU-71

Drug Info

[40]

VU0469650

Drug Info

[51]

YM-202074

Drug Info

[52]

YM298198

Drug Info

[53]

[11C]MMTP

Drug Info

[54]

[18F]FITM

Drug Info

[55]

[18F]FPIT

Drug Info

[56]

[18F]MK-1312

Drug Info

[38]

[3H]EM-TBPC

Drug Info

[57]

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

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 9 KEGG Pathways

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

[+] 4 Panther Pathways

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

[+] 2 Reactome Pathways

G alpha (q) signalling events

Class C/3 (Metabotropic glutamate/pheromone receptors)

WikiPathways

[+] 6 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

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

Top

REF 1

Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition. Behav Pharmacol. 2007 Jul;18(4):273-81.

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 800021875)

REF 3

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: 7678).

REF 4

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800029661)

REF 5

REF 6

Emerging drugs in neuropathic pain. Expert Opin Emerg Drugs. 2007 Mar;12(1):113-26.

REF 7

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024545)

REF 9

REF 10

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800014988)

REF 11

REF 12

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800011092)

REF 13

Pfizer. Product Development Pipeline. March 31 2009.

REF 14

Comparative 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 15

Clinical pipeline report, company report or official report of AstraZeneca (2009).

REF 16

Positive and negative modulation of group I metabotropic glutamate receptors. J Med Chem. 2008 Feb 14;51(3):634-47.

REF 17

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.

REF 18

[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 19

How many drug targets are there Nat Rev Drug Discov. 2006 Dec;5(12):993-6.

REF 20

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.

REF 21

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.

REF 22

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.

REF 23

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.

REF 24

Carbamoyloximes as novel non-competitive mGlu5 receptor antagonists. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4371-5.

REF 25

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.

REF 26

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.

REF 27

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.

REF 28

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.

REF 29

Structure-activity relationship of triazafluorenone derivatives as potent and selective mGluR1 antagonists. J Med Chem. 2005 Nov 17;48(23):7374-88.

REF 30

BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol. 2001 May;59(5):965-73.

REF 31

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.

REF 32

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.

REF 33

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.

REF 34

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.

REF 35

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.

REF 36

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.

REF 37

REF 38

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.

REF 39

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.

REF 40

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.

REF 41

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.

REF 42

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.

REF 43

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.

REF 44

Tricyclic thienopyridine-pyrimidones/thienopyrimidine-pyrimidones as orally efficacious mGluR1 antagonists for neuropathic pain. Bioorg Med Chem Lett. 2009 Jun 15;19(12):3199-203.

REF 45

A-ring modifications on the triazafluorenone core structure and their mGluR1 antagonist properties. Bioorg Med Chem Lett. 2010 Apr 15;20(8):2474-7.

REF 46

Fused tricyclic mGluR1 antagonists for the treatment of neuropathic pain. Bioorg Med Chem Lett. 2012 Feb 15;22(4):1575-8.

REF 47

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.

REF 48

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.

REF 49

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.

REF 50

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.

REF 51

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.

REF 52

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.

REF 53

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.

REF 54

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.

REF 55

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.

REF 56

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.

REF 57

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.

REF 58

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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