Metabotropic glutamate receptor 3

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Metabotropic glutamate receptor 3
Metabotropic glutamate receptor 3
according to PDB  2E4U
Properties of human protein
Mass / length primary structure 879 amino acids , 98,879 Da
Identifier
External IDs
Orthologue (human)
Entrez 2913
Ensemble ENSG00000198822
UniProt Q14832
Refseq (mRNA) NM_000840.2
Refseq (protein) NP_000831.2
PubMed search 2913

Metabotropic glutamate receptor 3 (GRM 3, mGluR3) is a protein from the group of metabotropic glutamate receptors .

properties

The metabotropic glutamate receptor 3 is a G protein-coupled receptor . It is formed in large quantities in the cerebral cortex , thalamus , subthalamus , substantia nigra , hypothalamus , hippocampus , corpus callosum and in the amygdala . Together with mGluR2 , it forms group II of the metabotropic glutamate receptors. After binding of glutamate , a change in conformation takes place , which causes signal transduction via G proteins (from the G i family ). As a result, adenylyl cyclase is inhibited. The metabotropic glutamate receptor 3 has disulfide bridges and is glycosylated .

Ligands

Agonists

  • with bicyclo [3.1.0] hexane skeleton:
    • MGS-0028
    • LY404040
    • LY379268
    • LY354740 ; the (+) - C4α-methyl analog is a GluR2 agonist and GluR3 antagonist
    • LY2794193
  • ( R ) -2-amino-4- (4-hydroxy [1,2,5] thiadiazol-3-yl) butyric acid

Antagonists

D 3 -ML337

Allosteric modulators

  • D 3 -ML337: selective negative allosteric modulator, IC50 = 450 nM for mGluR3, IC50> 30μM for mGluR2
  • MNI-137: negative allosteric modulator
  • VU-0650786: NAM
  • compound 7p: non-competitive antagonist

Individual evidence

  1. ↑ a b c d GRM3 - Metabotropic glutamate receptor 3 precursor - Homo sapiens (Human) - GRM3 gene & protein. In: uniprot.org. September 27, 2005, accessed November 6, 2018 .
  2. ↑ Nakazato A, Kumagai T, Sakagami K, Yoshikawa R, Suzuki Y, Chaki S, Ito H, Taguchi T, Nakanishi S, Okuyama S: Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo [3.1 .0] hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists . In: Journal of Medicinal Chemistry . 43, No. 25, 2000, pp. 4893-909. doi : 10.1021 / jm000346k . PMID 11123999 .
  3. ↑ Monn JA, Massey SM, Valli MJ, Henry SS, Stephenson GA, Bures M, Hérin M, Catlow J, Giera D, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD: 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 . In: Journal of Medicinal Chemistry . 50, No. 2, 2007, pp. 233-40. doi : 10.1021 / jm060917u . PMID 17228865 .
  4. ↑ Monn JA, Valli MJ, Massey SM, Hansen MM, Kress TJ, Wepsiec JP, Harkness AR, Grutsch JL, Wright RA, Johnson BG, Andis SL, Kingston A, Tomlinson R, Lewis R, Griffey KR, Tizzano JP, Schoepp DD: Synthesis, pharmacological characterization, and molecular modeling of heterobicyclic amino acids related to (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY354740): identification of two new potent, selective, and systemically active agonists for group II metabotropic glutamate receptors . In: Journal of Medicinal Chemistry . 42, No. 6, 1999, pp. 1027-40. doi : 10.1021 / jm980616n . PMID 10090786 .
  5. ↑ Monn JA, Valli MJ, Massey SM, Wright RA, Salhoff CR, Johnson BG, Howe T, Alt CA, Rhodes GA, Robey RL, Griffey KR, Tizzano JP, Kallman MJ, Helton DR, Schoepp DD: Design, synthesis, and pharmacological characterization of (+) - 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties . In: Journal of Medicinal Chemistry . 40, No. 4, 1997, pp. 528-37. doi : 10.1021 / jm9606756 . PMID 9046344 .
  6. ↑ Dominguez C, Prieto L, Valli MJ, Massey SM, Bures M, Wright RA, Johnson BG, Andis SL, Kingston A, Schoepp DD, Monn JA: Methyl substitution of 2-aminobicyclo [3.1.0] hexane 2,6- dicarboxylate (LY354740) determines functional activity at metabotropic glutamate receptors: identification of a subtype selective mGlu2 receptor agonist . In: Journal of Medicinal Chemistry . 48, No. 10, 2005, pp. 3605-12. doi : 10.1021 / jm040222y . PMID 15887967 .
  7. ↑ Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Atwell S, Lu F, Wang J, Russell M, Heinz BA, Wang XS, Carter JH, Getman BG, Adragni K, Broad LM, Sanger HE, Ursu D, Catlow JT, Swanson S, Johnson BG, Shaw DB, McKinzie DL, Hao J: Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo [3.1.0] hexane-2,6- dicarboxylates. Identification of (1 S, 2 S, 4 S, 5 R, 6 S) -2-Amino-4 - [(3-methoxybenzoyl) amino] bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (LY2794193) , a Highly Potent and Selective mGlu3Receptor Agonist . In: J. Med. Chem. . 61, No. 6, March 2018, pp. 2303–2328. doi : 10.1021 / acs.jmedchem.7b01481 . PMID 29350927 .
  8. ↑ Clausen RP, Bräuner-Osborne H, Greenwood JR, Hermit MB, Stensbøl TB, Nielsen B, Krogsgaard-Larsen P: Selective agonists at group II metabotropic glutamate receptors: synthesis, stereochemistry, and molecular pharmacology of (S) - and (R ) -2-amino-4- (4-hydroxy [1,2,5] thiadiazol-3-yl) butyric acid . In: Journal of Medicinal Chemistry . 45, No. 19, 2002, pp. 4240-5. doi : 10.1021 / jm020122x . PMID 12213064 .
  9. ↑ Sakagami K, Yasuhara A, Chaki S, Yoshikawa R, Kawakita Y, Saito A, Taguchi T, Nakazato A: Synthesis, in vitro pharmacology, and pharmacokinetic profiles of 2- [1-amino-1-carboxy-2- (9H -xanthen-9-yl) -ethyl] -1-fluorocyclopropanecarboxylic acid and its 6-heptyl ester, a potent mGluR2 antagonist . In: Bioorg. Med. Chem . 16, No. 8, 2008, pp. 4359-66. doi : 10.1016 / j.bmc.2008.02.066 . PMID 18348906 .
  10. ↑ Nakazato A, Sakagami K, Yasuhara A, Ohta H, Yoshikawa R, Itoh M, Nakamura M, Chaki S: 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 . In: Journal of Medicinal Chemistry . 47, No. 18, 2004, pp. 4570-87. doi : 10.1021 / jm0400294 . PMID 15317467 .
  11. ↑ Yasuhara A, Nakamura M, Sakagami K, Shimazaki T, Yoshikawa R, Chaki S, Ohta H, Nakazato A: Prodrugs of 3- (3,4-dichlorobenzyloxy) -2-amino-6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic acid (MGS0039): a potent and orally active group II mGluR antagonist with antidepressant-like potential . In: Bioorg. Med. Chem . 14, No. 12, 2006, pp. 4193-207. doi : 10.1016 / j.bmc.2006.01.060 . PMID 16487713 .
  12. ↑ Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A: Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists . In: Bioorg. Med. Chem . 14, No. 10, 2006, pp. 3405-20. doi : 10.1016 / j.bmc.2005.12.061 . PMID 16431115 .
  13. ↑ Woltering TJ, Adam G, Huguenin P, Wichmann J, Kolczewski S, Gatti S, Bourson A, Kew JN, Richards G, Kemp JA, Mutel V, Knoflach F: Asymmetric synthesis and receptor pharmacology of the group II mGlu receptor ligand ( 1S, 2R, 3R, 5R, 6S) -2-amino-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid-HYDIA . In: ChemMedChem . 3, No. 2, 2008, pp. 323-35. doi : 10.1002 / cmdc.200700226 . PMID 18058780 .
  14. ↑ Wenthur CJ, Morrison R, Felts AS, Smith KA, Engers JL, Byers FW, Daniels JS, Emmitte KA, Conn PJ, Lindsley CW: Discovery of (R) - (2-fluoro-4 - ((- 4-methoxyphenyl ) ethynyl) phenyl) (3-hydroxypiperidin-1-yl) methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM) . In: J. Med. Chem. . 56, No. 12, 2013, pp. 5208-12. doi : 10.1021 / jm400439t . PMID 23718281 . PMC 3769689 (free full text).
  15. ↑ Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, Conn PJ: A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors . In: J. Pharmacol. Exp. Ther. . 322, No. 1, 2007, pp. 254-64. doi : 10.1124 / jpet.106.117093 . PMID 17416742 .
  16. ↑ Engers JL, Bollinger KA, Weiner RL, Rodriguez AL, Long MF, Breiner MM, Chang S, Bollinger SR, Bubser M, Jones CK, Morrison RD, Bridges TM, Blobaum AL, Niswender CM, Conn PJ, Emmitte KA, Lindsley CW: Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs . In: ACS Med Chem Lett . 8, No. 9, 2017, pp. 925–930. doi : 10.1021 / acsmedchemlett.7b00249 . PMID 28947938 . PMC 5601378 (free full text).
  17. ↑ Woltering TJ, Wichmann J, Goetschi E, Adam G, Kew JN, Knoflach F, Ballard TM, Huwyler J, Mutel V, Gatti S: Synthesis and characterization of 1,3-dihydro-benzo [b] [1,4] diazepin-2-one derivatives: Part 3. New potent non-competitive metabotropic glutamate receptor 2/3 antagonists . In: Bioorg. Med. Chem. Lett. . 18, No. 8, 2008, pp. 2725-9. doi : 10.1016 / j.bmcl.2008.02.076 . PMID 18374569 .