Metabotropni glutamatni receptor 3

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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 (Mar 1997). „Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q“. Genomics 31 (2): 230–3. DOI:10.1006/geno.1996.0036. PMID 8824806. 
  2. ^ а б „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. DOI:10.1124/jpet.105.091926. PMID 16223873. 
  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. DOI:10.1021/jm000346k. PMID 11123999. 
  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. DOI:10.1021/jm060917u. PMID 17228865. 
  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. DOI:10.1021/jm980616n. PMID 10090786. 
  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. DOI:10.1021/jm9606756. PMID 9046344. 
  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. DOI:10.1021/jm040222y. PMID 15887967. 
  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. DOI:10.1021/jm020122x. PMID 12213064. 
  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. DOI:10.1016/j.bmc.2008.02.066. PMID 18348906. 
  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. DOI:10.1021/jm0400294. PMID 15317467. ,
    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. DOI:10.1016/j.bmc.2006.01.060. PMID 16487713. ,
    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. DOI:10.1016/j.bmc.2005.12.061. PMID 16431115. 
  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. DOI:10.1002/cmdc.200700226. PMID 18058780. 
  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. DOI:10.1124/jpet.106.117093. PMID 17416742. 
  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. DOI:10.1016/j.bmcl.2008.02.076. PMID 18374569. 
  15. ^ а б Hirbec, Hélène; Perestenko Olga, Nishimune Atsushi, Meyer Guido, Nakanishi Shigetada, Henley Jeremy M, Dev Kumlesh K (May. 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. DOI:10.1074/jbc.C200112200. ISSN 0021-9258. PMID 11891216. 
  16. ^ Flajolet, Marc; Rakhilin Sergey, Wang Hong, Starkova Natalia, Nuangchamnong Nina, Nairn Angus C, Greengard Paul (Dec. 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. DOI:10.1073/pnas.2136600100. ISSN 0027-8424. PMC 307683. PMID 14663150. 

Literatura[уреди]

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