Metabotropni glutamatni receptor 2
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
[уреди | уреди извор]PAM
[уреди | уреди извор]Razvoj podtip 2 selektivnih pozitivnih alosternih modulatora (PAM) je doživeo stabilan napredak zadnjih godina.[3] mGluR2 potencijacija je nov pristup tretiranju šizofrenije.[4]
- 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).
Vidi još
[уреди | уреди извор]Reference
[уреди | уреди извор]- ^ Flor PJ, Lindauer K, Puttner I, Ruegg D, Lukic S, Knopfel T, Kuhn R (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.
- ^ а б „Entrez Gene: GRM2 glutamate receptor, metabotropic 2”.
- ^ Fraley ME (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.
- ^ Conn PJ, Jones CK (2009). „Promise of mGluR2/3 activators in psychiatry”. Neuropsychopharmacology. 34 (1): 248—9. PMC 2907744 . PMID 19079073. doi:10.1038/npp.2008.156.
- ^ Dhanya RP; Sidique S; Sheffler DJ; et al. (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.
- ^ 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 (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.
- ^ 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 (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.
- ^ EJ Brnardic 2010
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Barda DA, Wang ZQ, Britton TC, et al. (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.
- ^ 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
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Spoljašnje veze
[уреди | уреди извор]- „Metabotropic Glutamate Receptors: mGlu2”. IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Архивирано из оригинала 19. 03. 2012. г.