Metabotroper Glutamatrezeptor 3

Metabotroper Glutamatrezeptor 3 (GRM 3, mGluR3) ist ein Protein aus der Gruppe der metabotropen Glutamatrezeptoren.

Metabotropic glutamate receptor 3
nach PDB 2E4U
Eigenschaften des menschlichen Proteins
Masse/Länge Primärstruktur	879 Aminosäuren, 98.879 Da
Bezeichner
Externe IDs	GeneCards: GRM3 OMIM: 601115 UniProt Q14832
Vorkommen
Homologie-Familie	Hovergen
Orthologe (Mensch)
Entrez	2913
Ensembl	ENSG00000198822
UniProt	Q14832
Refseq (mRNA)	NM_000840.2
Refseq (Protein)	NP_000831.2
PubMed-Suche	2913

Eigenschaften

Der metabotrope Glutamatrezeptor 3 ist ein G-Protein-gekoppelter Rezeptor.^[1] Er wird in größeren Mengen in der Großhirnrinde, im Thalamus, Subthalamus, in der Substantia nigra, im Hypothalamus, Hippocampus, Corpus callosum und in der Amygdala gebildet.^[1] Gemeinsam mit mGluR2 bildet er die Gruppe II der metabotropen Glutamatrezeptoren. Nach Bindung von Glutamat erfolgt eine Konformationsänderung, die eine Signaltransduktion über G-Proteine (aus der Familie G_i) bewirkt. In Folge wird die Adenylylcyclase gehemmt.^[1] Der metabotrope Glutamatrezeptor 3 besitzt Disulfidbrücken und ist glykosyliert.^[1]

Liganden

Agonisten

• mit Bicyclo[3.1.0]hexanskelett:
  • MGS-0028^[2]
  • LY404040^[3]
  • LY379268^[4]
  • LY354740;^[5] das (+)-C4α-Methylanalogon ist ein GluR2-Agonist und GluR3 Antagonist^[6]
  • LY2794193^[7]
• (R)-2-amino-4-(4-hydroxy[1,2,5]thiadiazol-3-yl)buttersäure^[8]

Antagonisten

• CECXG – 38-fache Selektivität für mGluR₃ gegenüber mGluR₂
• LY-341,495 und sein 1-fluor-Analogon^[9]
• MGS-0039,^[10][11][12] HYDIA^[13]

D₃-ML337

Allosterische Modulatoren

• D₃-ML337: selektiver negativer allosterischer Modulator, IC50 = 450 nM für mGluR3, IC50 >30μM für mGluR2^[14]
• MNI-137:^[15] negativer allosterischer Modulator
• VU-0650786: NAM^[16]
• compound 7p:^[17] nichtkompetitiver Antagonist

Einzelnachweise

1. UniProt GRM3 - Metabotropic glutamate receptor 3 precursor - Homo sapiens (Human) - GRM3 gene & protein. Abgerufen am 6. November 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. Jahrgang, Nr. 25, 2000, S. 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. Jahrgang, Nr. 2, 2007, S. 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. Jahrgang, Nr. 6, 1999, S. 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. Jahrgang, Nr. 4, 1997, S. 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. Jahrgang, Nr. 10, 2005, S. 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. Jahrgang, Nr. 6, März 2018, S. 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. Jahrgang, Nr. 19, 2002, S. 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. Jahrgang, Nr. 8, 2008, S. 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. Jahrgang, Nr. 18, 2004, S. 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. Jahrgang, Nr. 12, 2006, S. 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. Jahrgang, Nr. 10, 2006, S. 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. Jahrgang, Nr. 2, 2008, S. 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. Jahrgang, Nr. 12, 2013, S. 5208–12, doi:10.1021/jm400439t, PMID 23718281, PMC 3769689 (freier Volltext).
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. Jahrgang, Nr. 1, 2007, S. 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. Jahrgang, Nr. 9, 2017, S. 925–930, doi:10.1021/acsmedchemlett.7b00249, PMID 28947938, PMC 5601378 (freier Volltext).
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. Jahrgang, Nr. 8, 2008, S. 2725–9, doi:10.1016/j.bmcl.2008.02.076, PMID 18374569.