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
Click to Show/Hide
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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) | [+] 6 Clinical Trial Drugs | + | ||||
| 1 | LY404039 | Drug Info | Phase 3 | Schizophrenia | [2] | |
| 2 | Oleoyl-estrone | Drug Info | Phase 2 | Obesity | [4] | |
| 3 | RO-4995819 | Drug Info | Phase 2 | Major depressive disorder | [5] | |
| 4 | BCI-632 | Drug Info | Phase 1 | Major depressive disorder | [6] | |
| 5 | BCI-838 | Drug Info | Phase 1 | Major depressive disorder | [7] | |
| 6 | Pomaglumetad | Drug Info | Phase 1 | Schizophrenia | [2] | |
| Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
| 1 | LY-544344 | Drug Info | Discontinued in Phase 3 | Anxiety disorder | [8] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Agonist | [+] 6 Agonist drugs | + | ||||
| 1 | LY404039 | Drug Info | [1], [12], [13] | |||
| 2 | Oleoyl-estrone | Drug Info | [14], [15] | |||
| 3 | LY-544344 | Drug Info | [22] | |||
| 4 | (1S,3R)-ACPD | Drug Info | [23] | |||
| 5 | NAAG | Drug Info | [24] | |||
| 6 | [3H]LY341495 | Drug Info | [24] | |||
| 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 | [+] 6 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 | (+)-MCPG | Drug Info | [23] | |||
| 6 | eGlu | Drug Info | [24] | |||
| Inhibitor | [+] 3 Inhibitor drugs | + | ||||
| 1 | LY-379268 | Drug Info | [25] | |||
| 2 | LY-389795 | Drug Info | [25] | |||
| 3 | [3H]quisqualate | Drug Info | [29] | |||
| Modulator (allosteric modulator) | [+] 5 Modulator (allosteric modulator) drugs | + | ||||
| 1 | MNI-135 | Drug Info | [26] | |||
| 2 | MNI-136 | Drug Info | [26] | |||
| 3 | MNI-137 | Drug Info | [26] | |||
| 4 | Ro4491533 | Drug Info | [27] | |||
| 5 | VU0463597 | Drug Info | [28] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: LY354740 | Ligand Info | |||||
| Structure Description | mGluR2 ECD and mGluR3 ECD complex with ligands | PDB:4XAR | ||||
| Method | X-ray diffraction | Resolution | 2.26 Å | Mutation | Yes | [30] |
| PDB Sequence |
RREIKIEGDL
39 VLGGLFPINE49 KGTGTEECGR59 INEDRGIQRL69 EAMLFAIDEI79 NKDDYLLPGV 89 KLGVHILDTC99 SRDTYALEQS109 LEFVRASLLL141 IAGVIGGSYS151 SVSIQVANLL 161 RLFQIPQISY171 ASTSAKLSDK181 SRYDYFARTV191 PPDFYQAKAM201 AEILRFFNWT 211 YVSTVASEGD221 YGETGIEAFE231 QEARLRNISI241 ATAEKVGRSN251 IRKSYDSVIR 261 ELLQKPNARV271 VVLFMRSDDS281 RELIAAASRA291 NASFTWVASD301 GWGAQESIIK 311 GSEHVAYGAI321 TLELASQPVR331 QFDRYFQSLN341 PYNNHRNPWF351 RDFWEQKFQC 361 SLRVCDKHLA378 IDSSNYEQES388 KIMFVVNAVY398 AMAHALHKMQ408 RTLCPNTTKL 418 CDAMKILDGK428 KLYKDYLLKI438 NFTAPDADSI453 VKFDTFGDGM463 GRYNVFNFQN 473 VGGKYSYLKV483 GHWAETLSLD493 VNSIHWSRNS503 VPTSE
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| Ligand Name: [3H]LY341495 | Ligand Info | |||||
| Structure Description | Crystal Structure of Metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist | PDB:3SM9 | ||||
| Method | X-ray diffraction | Resolution | 2.26 Å | Mutation | No | [31] |
| PDB Sequence |
RREIKIEGDL
14 VLGGLFPINE24 KGTTEECGRI35 NEDRGIQRLE45 AMLFAIDEIN55 KDDYLLPGVK 65 LGVHILDTCS75 RDTYALEQSL85 EFVRASLLIA118 GVIGGSYSSV128 SIQVANLLRL 138 FQIPQISYAS148 TSAKLSDKSR158 YDYFARTVPP168 DFYQAKAMAE178 ILRFFNWTYV 188 STVASEGDYG198 ETGIEAFEQE208 ARLRNISIAT218 AEKVGRIRKS230 YDSVIRELLQ 240 KPNARVVVLF250 MRSDDSRELI260 AAASRANASF270 TWVASDGWGA280 QESIIKGSEH 290 VAYGAITLEL300 ASQPVRQFDR310 YFQSLNPYNN320 HRNPWFRDFW330 EQKFQCSLQN 343 HRRVCDKHLA353 IDSSNYEQES363 KIMFVVNAVY373 AMAHALHKMQ383 RTLCPNTTKL 393 CDAMKILDGK403 KLYKDYLLKI413 NFTAPFNDSI428 VKFDTFGDGM438 GRYNVFNFQN 448 VGGKYSYLKV458 GHWAETLSLD468 VNSIHWS
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
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There is no similarity protein (E value < 0.005) for this target
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Phospholipase D signaling pathway | hsa04072 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Glutamatergic synapse | hsa04724 | Affiliated Target |
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| Class: Organismal Systems => Nervous system | Pathway Hierarchy | ||
| 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 | |||||
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| 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 | [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 24 | 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 25 | 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 26 | 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 27 | 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 28 | 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 29 | 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. | |||||
| REF 30 | Synthesis and pharmacological characterization of C4-disubstituted analogs of 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate: identification of a potent, selective metabotropic glutamate receptor agonist and determination of agonist-bound human mGlu2 and mGlu3 amino terminal domain structures. J Med Chem. 2015 Feb 26;58(4):1776-94. | |||||
| REF 31 | Crystal Structure of Metabotropic glutamate receptor 3 precursor in presence of LY341495 antagonist | |||||
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