Target Information

Target General Infomation
Target ID
T02719
Former ID
TTDC00126
Target Name
Metabotropic glutamate receptor3
Gene Name
GRM3
Synonyms
Group III metabotropic glutamate receptor; mGLUR3; GRM3
Target Type
Clinical Trial
Disease Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Alzheimer disease; Major depressive disorder [ICD9:331, 296.2, 296.3, 710.0; ICD10: G30, F32, F33, M32]
Mood disorder [ICD10: F30-F39]
Major depressive disorder [ICD9: 296.2, 296.3, 710.0; ICD10: F32, F33, M32]
Schizophrenia [ICD9: 295; ICD10: F20]
Function
G-protein coupled receptor for glutamate. 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 inhibits adenylate cyclase activity.
BioChemical Class
GPCR glutamate
Target Validation
T02719
UniProt ID
Q14832
Sequence
MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRI
NEDRGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKV
DEAEYMCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSD
KSRYDYFARTVPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNIC
IATAEKVGRSNIRKSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVAS
DGWGAQESIIKGSEHVAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQ
CSLQNKRNHRRVCDKHLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCD
AMKILDGKKLYKDYLLKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSY
LKVGHWAETLSLDVNSIHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYL
ADEFTCMDCGSGQWPTADLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIK
HNNTPLVKASGRELCYILLFGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALL
TKTNCIARIFDGVKNGAQRPKFISPSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLA
EKRETVILKCNVKDSSMLISLTYDVILVILCTVYAFKTRKCPENFNEAKFIGFTMYTTCI
IWLAFLPIFYVTSSDYRVQTTTMCISVSLSGFVVLGCLFAPKVHIILFQPQKNVVTHRLH
LNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTTSSL
Drugs and Mode of Action
Drug(s) BCI-632 Drug Info Phase 1 Alzheimer disease; Major depressive disorder [523828]
Pomaglumetad Drug Info Phase 1 Schizophrenia [523714]
LY-544344 Drug Info Discontinued in Phase 3 Anxiety disorder [547724]
LY354740 Drug Info Discontinued in Phase 2 Anxiety disorder [538869], [546477]
R-1578 Drug Info Discontinued in Phase 2 Mood disorder [549263]
RO-4995819 Drug Info Discontinued in Phase 2 Major depressive disorder [524135]
BCI-838 Drug Info Discontinued in Phase 1 Alzheimer disease; Major depressive disorder [523820]
Antagonist (+)-MCPG Drug Info [525619]
eGlu Drug Info [525820]
MGS0039 Drug Info [527175]
R-1578 Drug Info [551608]
Agonist (1S,3R)-ACPD Drug Info [525619]
L-CCG-I Drug Info [525619]
LY-544344 Drug Info [536166]
LY354740 Drug Info [536959], [537037], [537272]
NAAG Drug Info [525820]
[3H]LY341495 Drug Info [525820]
Modulator BCI-632 Drug Info [1572591]
BCI-838 Drug Info [551197]
Pomaglumetad Drug Info [530986]
RO-4995819 Drug Info [544330]
Modulator (allosteric modulator) compound 2 Drug Info [531276]
compound 3 Drug Info [531276]
compound 4 Drug Info [531276]
MNI-135 Drug Info [528775]
MNI-136 Drug Info [528775]
MNI-137 Drug Info [528775]
Ro4491533 Drug Info [531231]
VU0463597 Drug Info [531911]
Inhibitor LY-379268 Drug Info [528620]
LY-389795 Drug Info [528620]
QUISQUALATE Drug Info [534590]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Glutamatergic synapse
Cocaine addiction
PANTHER Pathway 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 G alpha (i) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
WikiPathways GPCRs, Class C Metabotropic glutamate, pheromone
GPCR ligand binding
GPCR downstream signaling
References
Ref 523714ClinicalTrials.gov (NCT01487083) A Long-Term Study in Schizophrenia. U.S. National Institutes of Health.
Ref 523820ClinicalTrials.gov (NCT01546051) A Study of BCI-838 and Several BCI-632 Prodrugs in Healthy Volunteers. U.S. National Institutes of Health.
Ref 523828ClinicalTrials.gov (NCT01548703) A Multiple Ascending Dose Study of BCI-838 in Healthy Volunteers. U.S. National Institutes of Health.
Ref 524135ClinicalTrials.gov (NCT01733654) Investigate Efficacy & Safety of RO4995819 vs. Placebo as Adjunct Tx in Patients w/Major Depressive Disorder. U.S. National Institutes of Health.
Ref 538869(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 546477Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008428)
Ref 547724Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018821)
Ref 549263Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800034342)
Ref
Ref 525619[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 525820Characterization 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 527175Synthesis, 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 528620J Med Chem. 2007 Jan 25;50(2):233-40.Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identification of potent, selective, and orally bioavailable agonists for mGlu2/3 receptors.
Ref 528775A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):254-64. Epub 2007 Apr 6.
Ref 530986LY-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 531231Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6969-74.
Ref 531276Chemical switch of a metabotropic glutamate receptor 2 silent allosteric modulator into dual metabotropic glutamate receptor 2/3 negative/positive allosteric modulators. J Med Chem. 2010 Dec 23;53(24):8775-9.
Ref 531911Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg Med Chem Lett. 2012 Jun 15;22(12):3921-5.
Ref 534590J 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 536166Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
Ref 536959Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep-wake architecture. Eur J Pharmacol. 2009 Jan 28;603(1-3):62-72. Epub 2008 Nov 17.
Ref 536982Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(High) receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse. 2009 Mar;63(3):247-51.
Ref 537037Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav Pharmacol. 2009 Feb;20(1):56-66.
Ref 537133Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci. 2009 Mar;34(2):143-9.
Ref 537272Mutagenesis and molecular modeling of the orthosteric binding site of the mGlu2 receptor determining interactions of the group II receptor antagonist (3)H-HYDIA. ChemMedChem. 2009 Jul;4(7):1086-94.
Ref 537518Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Expert Opin Ther Pat. 2009 Jun 24.
Ref 544330Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112.
Ref 551197Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010
Ref 551608Clinical pipeline report, company report or official report of Roche.
Ref 1572591Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.

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