Metabotropni glutamatni receptor 2

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Metabotropni glutamatni receptor 2 je protein je protein koji je kod ljudi kodiran GRM2 genom.[1][2]

L-glutamat je jedan od glavnih ekscitatornih neurotransmitera u centralnom nervnom sistemu i aktivira jonotropne i metabotropne glutamatne receptore. Glutamatergična neurotransmisija učestvuje u većini aspekata normalnih moždanih funkcija i može da bude poremećena u slučaju neuropatoloških poremećaja. Metabotropni glutamatni receptori su familija G protein spregnutih receptora, koji se dele u 3 grupe na bazi homologije sekvenci, signalno transdukcionih mehanizama, i farmakoloških svojstava. Grupa I obuhvata GRM1 i GRM5 i ti receptori aktiviraju fosfolipazu C. Grupa II uključuje GRM2 i GRM3, dok su u grupi III GRM4, GRM6, GRM7 i GRM8. Receptori grupe II i III su vezani za inhibiciju kaskade cikličnog AMP-a, ali se razlikuju u njihovim selektivnostima za agoniste.[2]

Ligandi[uredi - уреди | uredi izvor]

PAM[uredi - уреди | uredi izvor]

Razvoj podtip 2 selektivnih pozitivnih alosternih modulatora (PAM) je doživeo stabilan napredak zadnjih godina.[3] mGluR2 potencijacija je nov pristup tretiranju šizofrenije.[4]

Visoko selektivni mGluR2 PAM (2010)[5], BINA analog
  • GSK1331258[6]
  • Imidazo[1,2-a]piridini[7]
  • 3-Aril-5-fenoksimetil-1,3-oksazolidin-2-oni[8]
  • 3-(Imidazolil metil)-3-aza-biciklo[3.1.0]heksan-6-il)metil etri: potentni, oralno stabilni[9]
  • BINA:[10][11] potentan, umereni ago-alosterni modulator sa robustno in-vivo aktivnošću.
  • LY487379:[12][13][14] bez ortosterne aktivnosti; zajedno sa srodnim 3-piridilmetilsulfonamidima[15][16] je prvi objavljeni selektivni potencijator za podtip 2 (2003).

Reference[uredi - уреди | uredi izvor]

  1. Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R (Aug 1995). "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2". Eur J Neurosci 7 (4): 622–9. PMID 7620613. doi:10.1111/j.1460-9568.1995.tb00666.x.  Check date values in: |date= (help)
  2. 2,0 2,1 "Entrez Gene: GRM2 glutamate receptor, metabotropic 2". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2912. 
  3. Fraley ME (September 2009). "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opin Ther Pat 19 (9): 1259–75. PMID 19552508. doi:10.1517/13543770903045009. 
  4. Conn PJ, Jones CK (January 2009). "Promise of mGluR2/3 activators in psychiatry". Neuropsychopharmacology 34 (1): 248–9. PMC 2907744. PMID 19079073. doi:10.1038/npp.2008.156. 
  5. Dhanya RP, Sidique S, Sheffler DJ et al. (January 2011). "Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats". J. Med. Chem. 54 (1): 342–53. PMC 3071440. PMID 21155570. doi:10.1021/jm1012165. 
  6. D'Alessandro PL, Corti C, Roth A, Ugolini A, Sava A, Montanari D, Bianchi F, Garland SL, Powney B, Koppe EL, Rocheville M, Osborne G, Perez P, de la Fuente J, De Los Frailes M, Smith PW, Branch C, Nash D, Watson SP (January 2010). "The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2". Bioorg. Med. Chem. Lett. 20 (2): 759–62. PMID 20005096. doi:10.1016/j.bmcl.2009.11.032. 
  7. Tresadern G, Cid JM, Macdonald GJ, Vega JA, de Lucas AI, García A, Matesanz E, Linares ML, Oehlrich D, Lavreysen H, Biesmans I, Trabanco AA (January 2010). "Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor". Bioorg. Med. Chem. Lett. 20 (1): 175–9. PMID 19932615. doi:10.1016/j.bmcl.2009.11.008. 
  8. EJ Brnardic 2010
  9. Zhang L, Rogers BN, Duplantier AJ et al. (2008). "3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators". Bioorganic & Medicinal Chemistry Letters 18 (20): 5493–6. PMID 18812259. doi:10.1016/j.bmcl.2008.09.026. 
  10. Galici R, Jones CK, Hemstapat K et al. (2006). "Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice". J. Pharmacol. Exp. Ther. 318 (1): 173–85. PMID 16608916. doi:10.1124/jpet.106.102046. 
  11. Bonnefous C, Vernier JM, Hutchinson JH et al. (2005). "Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor". Bioorg. Med. Chem. Lett. 15 (19): 4354–8. PMID 16046122. doi:10.1016/j.bmcl.2005.06.062. 
  12. Johnson MP, Baez M, Jagdmann GE et al. (2003). "Discovery of allosteric potentiators for the metabotropic glutamate 2 receptor: synthesis and subtype selectivity of N-(4-(2-methoxyphenoxy)phenyl)-N-(2,2,2- trifluoroethylsulfonyl)pyrid-3-ylmethylamine". J. Med. Chem. 46 (15): 3189–92. PMID 12852748. doi:10.1021/jm034015u. 
  13. Johnson MP, Barda D, Britton TC et al. (2005). "Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s)". Psychopharmacology (Berl.) 179 (1): 271–83. PMID 15717213. doi:10.1007/s00213-004-2099-9. 
  14. Schaffhauser H, Rowe BA, Morales S et al. (2003). "Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2". Mol. Pharmacol. 64 (4): 798–810. PMID 14500736. doi:10.1124/mol.64.4.798. 
  15. Barda DA, Wang ZQ, Britton TC et al. (2004). (2004). "SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide". Bioorg. Med. Chem. Lett. 14 (12): 3099–102. PMID 15149652. doi:10.1016/j.bmcl.2004.04.017. 
  16. Pinkerton AB, Vernier JM, Schaffhauser H et al. (2004). "Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor". J. Med. Chem. 47 (18): 4595–9. PMID 15317469. doi:10.1021/jm040088h. 

Literatura[uredi - уреди | uredi izvor]

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