Target Information
| Target General Information | Top | |||||
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| Target ID |
T02719
(Former ID: TTDC00126)
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| Target Name |
Metabotropic glutamate receptor 3 (mGluR3)
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| Synonyms |
mGLUR3; Group III metabotropic glutamate receptor; GPRC1C
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| Gene Name |
GRM3
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | 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. Signaling inhibits adenylate cyclase activity. G-protein coupled receptor for glutamate.
Click to Show/Hide
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| BioChemical Class |
GPCR glutamate
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| UniProt ID | ||||||
| Sequence |
MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRI
NEDRGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKV DEAEYMCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSD KSRYDYFARTVPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNIC IATAEKVGRSNIRKSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVAS DGWGAQESIIKGSEHVAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQ CSLQNKRNHRRVCDKHLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCD AMKILDGKKLYKDYLLKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSY LKVGHWAETLSLDVNSIHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYL ADEFTCMDCGSGQWPTADLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIK HNNTPLVKASGRELCYILLFGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALL TKTNCIARIFDGVKNGAQRPKFISPSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLA EKRETVILKCNVKDSSMLISLTYDVILVILCTVYAFKTRKCPENFNEAKFIGFTMYTTCI IWLAFLPIFYVTSSDYRVQTTTMCISVSLSGFVVLGCLFAPKVHIILFQPQKNVVTHRLH LNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTTSSL Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 7 Clinical Trial Drugs | + | ||||
| 1 | LY404039 | Drug Info | Phase 3 | Schizophrenia | [2] | |
| 2 | MP-101 | Drug Info | Phase 2 | Alzheimer disease | [3] | |
| 3 | Oleoyl-estrone | Drug Info | Phase 2 | Obesity | [4] | |
| 4 | RO-4995819 | Drug Info | Phase 2 | Major depressive disorder | [5] | |
| 5 | BCI-632 | Drug Info | Phase 1 | Major depressive disorder | [6] | |
| 6 | BCI-838 | Drug Info | Phase 1 | Major depressive disorder | [7] | |
| 7 | Pomaglumetad | Drug Info | Phase 1 | Schizophrenia | [2] | |
| Discontinued Drug(s) | [+] 3 Discontinued Drugs | + | ||||
| 1 | LY-544344 | Drug Info | Discontinued in Phase 3 | Anxiety disorder | [8] | |
| 2 | LY354740 | Drug Info | Discontinued in Phase 2 | Anxiety disorder | [9], [10] | |
| 3 | R-1578 | Drug Info | Discontinued in Phase 2 | Mood disorder | [11] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Agonist | [+] 9 Agonist drugs | + | ||||
| 1 | LY404039 | Drug Info | [1], [12], [13] | |||
| 2 | MP-101 | Drug Info | [3] | |||
| 3 | Oleoyl-estrone | Drug Info | [14], [15] | |||
| 4 | LY-544344 | Drug Info | [22] | |||
| 5 | LY354740 | Drug Info | [23], [24], [25] | |||
| 6 | (1S,3R)-ACPD | Drug Info | [27] | |||
| 7 | L-CCG-I | Drug Info | [27] | |||
| 8 | NAAG | Drug Info | [28] | |||
| 9 | [3H]LY341495 | Drug Info | [28] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | RO-4995819 | Drug Info | [16] | |||
| 2 | BCI-632 | Drug Info | [17], [18] | |||
| 3 | BCI-838 | Drug Info | [19] | |||
| 4 | Pomaglumetad | Drug Info | [20] | |||
| Antagonist | [+] 7 Antagonist drugs | + | ||||
| 1 | PMID25435285-Compound-15 | Drug Info | [21] | |||
| 2 | PMID25435285-Compound-16 | Drug Info | [21] | |||
| 3 | PMID25435285-Compound-20 | Drug Info | [21] | |||
| 4 | PMID25435285-Compound-22 | Drug Info | [21] | |||
| 5 | R-1578 | Drug Info | [26] | |||
| 6 | (+)-MCPG | Drug Info | [27] | |||
| 7 | eGlu | Drug Info | [28] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | LY-379268 | Drug Info | [29] | |||
| 2 | LY-389795 | Drug Info | [29] | |||
| 3 | [3H]quisqualate | Drug Info | [33] | |||
| Modulator (allosteric modulator) | [+] 5 Modulator (allosteric modulator) drugs | + | ||||
| 1 | MNI-135 | Drug Info | [30] | |||
| 2 | MNI-136 | Drug Info | [30] | |||
| 3 | MNI-137 | Drug Info | [30] | |||
| 4 | Ro4491533 | Drug Info | [31] | |||
| 5 | VU0463597 | Drug Info | [32] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "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 | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Glutamatergic synapse | |||||
| 3 | Cocaine addiction | |||||
| Panther Pathway | [+] 4 Panther Pathways | + | ||||
| 1 | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | |||||
| 2 | Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway | |||||
| 3 | Ionotropic glutamate receptor pathway | |||||
| 4 | Metabotropic glutamate receptor group II pathway | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | G alpha (i) signalling events | |||||
| 2 | Class C/3 (Metabotropic glutamate/pheromone receptors) | |||||
| WikiPathways | [+] 3 WikiPathways | + | ||||
| 1 | GPCRs, Class C Metabotropic glutamate, pheromone | |||||
| 2 | GPCR ligand binding | |||||
| 3 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Expert Opin Ther Pat. 2009 Sep;19(9):1259-75. | |||||
| REF 2 | ClinicalTrials.gov (NCT01487083) A Long-Term Study in Schizophrenia. U.S. National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT03044249) A Study of MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT00449202) Phase 2a Obesity Study of Oral Doses of Oleoyl-Estrone (MP-101). U.S. National Institutes of Health. | |||||
| REF 5 | 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 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 | 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 9 | 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 10 | 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 11 | 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 12 | Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci. 2009 Mar;34(2):143-9. | |||||
| REF 13 | Glutamate 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 14 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 15 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 16 | Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112. | |||||
| REF 17 | 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 18 | Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41. | |||||
| REF 19 | Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010 | |||||
| REF 20 | 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 21 | 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 22 | Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17. | |||||
| REF 23 | Mutagenesis 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 24 | Effects 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 25 | Modulation 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. | |||||
| REF 26 | Clinical pipeline report, company report or official report of Roche. | |||||
| REF 27 | [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 28 | 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 29 | 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 30 | 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 31 | Synthesis 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 32 | Development 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 33 | 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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