Metabotropni glutamatni receptor 3

Из Википедије, слободне енциклопедије
Metabotropni glutamatni receptor 3
PDB prikaz baziran na 2e4u.
Dostupne strukture
3SM9
Identifikatori
Simboli GRM3; GLUR3; GPRC1C; MGLUR3; mGlu3
Vanjski ID OMIM601115 MGI1351340 HomoloGene651 IUPHAR: mGlu3 GeneCards: GRM3 Gene
Pregled RNK izražavanja
PBB GE GRM3 205814 at tn.png
podaci
Ortolozi
Vrsta Čovek Miš
Entrez 2913 108069
Ensembl ENSG00000198822 ENSMUSG00000003974
UniProt Q14832 Q9QYS2
RefSeq (mRNA) NM_000840.2 NM_181850.2
RefSeq (protein) NP_000831.2 NP_862898.1
Lokacija (UCSC) Chr 7:
86.27 - 86.49 Mb
Chr 5:
9.49 - 9.73 Mb
PubMed pretraga [1] [2]

Metabotropni glutamatni receptor 3 je protein koji je kod ljudi kodiran GRM3 genom.[1][2]

L-glutamat je jedan od glavnih ekscitatornih neurotransmitera centralnog nervnog sistema. On aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalne moždane funkcije. Ona može da bude modifikovana mnogim neuropatološkim uslovima. Metabotropini glutamatni receptori su familija G protein spregnutih receptora, koji se dele u tri grupe na bazi homologije sekvenci, mehanizama prenosa signala, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5. Za njih je pokazano da aktiviraju fosfolipazu C. Grupa II obuhvata GRM2 i GRM3, dok su grupi III GRM4, GRM6, GRM7 i GRM8. Grupe II i III receptora su povezane sa inhibicijom kaskade cikličnog AMP-a, ali se razlikuju u selektivnost na agoniste.[2]

Ligandi[уреди]

Potpuno mGluR3 selektivni agensi nisu dostupni. Poznati su mešoviti mGluR2/3 (grupa II) ligandi sa selektivnošću u odnosu na druge mGluR podtipove. Neki od njih imaju nisku oralnu biodostupnost, ali postoji mogućnost njihove upotrebe u obliku proleka.[3]

Agonisti[уреди]

  • sa biciklo[3.1.0]heksanskom osnovom
    • MGS-0028[4]
    • LY404040[5]
    • LY379268[6]
    • LY354740[7]; njegov (+)-C4α-metil analog je GluR2 agonist / GluR3 antagonist[8]
  • (R)-2-amino-4-(4-hidroksi[1,2,5]tiadiazol-3-il)buterna kiselina[9]

Antagonist[уреди]

Alosterni modulatori[уреди]

  • MNI-137[13]: inhibitor
  • jedinjenje 7p[14]: nekompetitivni antagonist

Interakcije[уреди]

Metabotropni glutamatni receptor 3 formira interakcije sa GRIP1,[15] PICK1[15] i PPM1A.[16]

Reference[уреди]

  1. Scherer SW, Duvoisin RM, Kuhn R, Heng HH, Belloni E, Tsui LC (1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q”. Genomics. 31 (2): 230—3. PMID 8824806. doi:10.1006/geno.1996.0036. 
  2. 2,0 2,1 „Entrez Gene: GRM3 glutamate receptor, metabotropic 3”. 
  3. Rorick-Kehn LM; Perkins EJ; Knitowski KM; et al. (2006). „Improved bioavailability of the mGlu2/3 receptor agonist LY354740 using a prodrug strategy: in vivo pharmacology of LY544344”. J. Pharmacol. Exp. Ther. 316 (2): 905—13. PMID 16223873. doi:10.1124/jpet.105.091926. 
  4. Nakazato A; Kumagai T; Sakagami K; et al. (2000). „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”. J. Med. Chem. 43 (25): 4893—909. PMID 11123999. doi:10.1021/jm000346k. 
  5. Monn JA; Massey SM; Valli MJ; et al. (2007). „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”. J. Med. Chem. 50 (2): 233—40. PMID 17228865. doi:10.1021/jm060917u. 
  6. Monn JA; Valli MJ; Massey SM; et al. (1999). „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”. J. Med. Chem. 42 (6): 1027—40. PMID 10090786. doi:10.1021/jm980616n. 
  7. Monn JA; Valli MJ; Massey SM; et al. (1997). „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”. J. Med. Chem. 40 (4): 528—37. PMID 9046344. doi:10.1021/jm9606756. 
  8. Dominguez C; Prieto L; Valli MJ; et al. (2005). „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”. J. Med. Chem. 48 (10): 3605—12. PMID 15887967. doi:10.1021/jm040222y. 
  9. Clausen RP; Bräuner-Osborne H; Greenwood JR; et al. (2002). „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”. J. Med. Chem. 45 (19): 4240—5. PMID 12213064. doi:10.1021/jm020122x. 
  10. Sakagami K; Yasuhara A; Chaki S; et al. (2008). „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”. Bioorg. Med. Chem. 16 (8): 4359—66. PMID 18348906. doi:10.1016/j.bmc.2008.02.066. 
  11. a) Nakazato A; Sakagami K; Yasuhara A; et al. (2004). „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. 47 (18): 4570—87. PMID 15317467. doi:10.1021/jm0400294. ,
    b) Yasuhara A; Nakamura M; Sakagami K; et al. (2006). „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”. Bioorg. Med. Chem. 14 (12): 4193—207. PMID 16487713. doi:10.1016/j.bmc.2006.01.060. ,
    c) Yasuhara A, Sakagami K, Yoshikawa R, Chaki S, Nakamura M, Nakazato A (2006). „Synthesis, in vitro pharmacology, and structure-activity relationships of 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as mGluR2 antagonists”. Bioorg. Med. Chem. 14 (10): 3405—20. PMID 16431115. doi:10.1016/j.bmc.2005.12.061. 
  12. Woltering TJ; Adam G; Huguenin P; et al. (2008). „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”. ChemMedChem. 3 (2): 323—35. PMID 18058780. doi:10.1002/cmdc.200700226. 
  13. Hemstapat K; Da Costa H; Nong Y; et al. (2007). „A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors”. J. Pharmacol. Exp. Ther. 322 (1): 254—64. PMID 17416742. doi:10.1124/jpet.106.117093. 
  14. Woltering TJ; Wichmann J; Goetschi E; et al. (2008). „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”. Bioorg. Med. Chem. Lett. 18 (8): 2725—9. PMID 18374569. doi:10.1016/j.bmcl.2008.02.076. 
  15. 15,0 15,1 Hirbec, Hélène; Perestenko Olga; et al. (2002). „The PDZ proteins PICK1, GRIP, and syntenin bind multiple glutamate receptor subtypes. Analysis of PDZ binding motifs”. J. Biol. Chem. United States. 277 (18): 15221—4. ISSN 0021-9258. PMID 11891216. doi:10.1074/jbc.C200112200. 
  16. Flajolet, Marc; Rakhilin Sergey; et al. (2003). „Protein phosphatase 2C binds selectively to and dephosphorylates metabotropic glutamate receptor 3”. Proc. Natl. Acad. Sci. U.S.A. United States. 100 (26): 16006—11. ISSN 0027-8424. PMC 307683Слободан приступ. PMID 14663150. doi:10.1073/pnas.2136600100. 

Literatura[уреди]

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