Metabotropic glutamate receptor 2

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Glutamate receptor, metabotropic 2
Identifiers
Symbols GRM2 ; GLUR2; GPRC1B; MGLUR2; mGlu2
External IDs OMIM604099 MGI1351339 HomoloGene20229 IUPHAR: mGlu2 ChEMBL: 5137 GeneCards: GRM2 Gene
RNA expression pattern
PBB GE GRM2 208465 at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2912 108068
Ensembl ENSG00000164082 ENSMUSG00000023192
UniProt Q14416 Q14BI2
RefSeq (mRNA) NM_000839 NM_001160353
RefSeq (protein) NP_000830 NP_001153825
Location (UCSC) Chr 3:
51.74 – 51.75 Mb
Chr 9:
106.64 – 106.66 Mb
PubMed search [1] [2]

Metabotropic glutamate receptor 2 is a protein that in humans is encoded by the GRM2 gene.[1][2]

Function[edit]

L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 (this receptor) and GRM3 while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.[2]

Ligands[edit]

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.[3] mGluR2 potentiation is a new approach for the treatment of schizophrenia.[4] On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.[5][6][7][8]

PAMs[edit]

Highly selective mGluR2 PAM (2010),[9] analog of BINA
  • ADX-71149[10]
  • GSK1331258[11]
  • Imidazo[1,2-a]pyridines[12]
  • 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones[13]
  • 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable[14]
  • BINA:[15][16] potent; modest ago-allosteric modulator; robust in-vivo activity.
  • LY-487,379:[17][18][19] devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides[20][21] the first subtype-2-selective potentiator published (2003).

Antagonists[edit]

NAMs[edit]

  • 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.[22]
  • MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one[23]
  • RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one[24]

Protein-protein interactions[edit]

The metabotropic glutamate receptor 2 is able to form a heteromeric complex with its isoform mGluR4. This heteromer exhibits a pharmacological profile distinct from the parent receptor monomers.[25]

See also[edit]

References[edit]

  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. doi:10.1111/j.1460-9568.1995.tb00666.x. PMID 7620613. 
  2. ^ a b "Entrez Gene: GRM2 glutamate receptor, metabotropic 2". 
  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. doi:10.1517/13543770903045009. PMID 19552508. 
  4. ^ Conn PJ, Jones CK (January 2009). "Promise of mGluR2/3 activators in psychiatry". Neuropsychopharmacology 34 (1): 248–9. doi:10.1038/npp.2008.156. PMC 2907744. PMID 19079073. 
  5. ^ Kawashima N, Karasawa J, Shimazaki T, Chaki S, Okuyama S, Yasuhara A, Nakazato A (April 2005). "Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors". Neurosci. Lett. 378 (3): 131–4. doi:10.1016/j.neulet.2004.12.021. PMID 15781145. 
  6. ^ Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G (September 2008). "Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression". Eur. J. Pharmacol. 592 (1-3): 96–102. doi:10.1016/j.ejphar.2008.06.089. PMID 18634781. 
  7. ^ Dwyer JM, Lepack AE, Duman RS (May 2012). "mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade". Int. J. Neuropsychopharmacol. 15 (4): 429–34. doi:10.1017/S1461145711001702. PMC 3580765. PMID 22114864. 
  8. ^ Koike H, Fukumoto K, Iijima M, Chaki S (February 2013). "Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression". Behav. Brain Res. 238: 48–52. doi:10.1016/j.bbr.2012.10.023. PMID 23098797. 
  9. ^ 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". Journal of Medicinal Chemistry 54 (1): 342–53. doi:10.1021/jm1012165. PMC 3071440. PMID 21155570. 
  10. ^ addextherapeutics – ADX71149 for schizophrenia
  11. ^ 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. doi:10.1016/j.bmcl.2009.11.032. PMID 20005096. 
  12. ^ 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. doi:10.1016/j.bmcl.2009.11.008. PMID 19932615. 
  13. ^ EJ Brnardic 2010
  14. ^ Zhang L, Rogers BN, Duplantier AJ, McHardy SF, Efremov I, Berke H, Qian W, Zhang AQ, Maklad N, Candler J, Doran AC, Lazzaro JT, Ganong AH (October 2008). "3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators". Bioorg. Med. Chem. Lett. 18 (20): 5493–6. doi:10.1016/j.bmcl.2008.09.026. PMID 18812259. 
  15. ^ Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de Paulis T, Conn PJ (July 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. doi:10.1124/jpet.106.102046. PMID 16608916. 
  16. ^ Bonnefous C, Vernier JM, Hutchinson JH, Gardner MF, Cramer M, James JK, Rowe BA, Daggett LP, Schaffhauser H, Kamenecka TM (October 2005). "Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor". Bioorg. Med. Chem. Lett. 15 (19): 4354–8. doi:10.1016/j.bmcl.2005.06.062. PMID 16046122. 
  17. ^ Johnson MP, Baez M, Jagdmann GE, Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD (July 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". Journal of Medicinal Chemistry 46 (15): 3189–92. doi:10.1021/jm034015u. PMID 12852748. 
  18. ^ Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, Schoepp DD (April 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. doi:10.1007/s00213-004-2099-9. PMID 15717213. 
  19. ^ Schaffhauser H, Rowe BA, Morales S, Chavez-Noriega LE, Yin R, Jachec C, Rao SP, Bain G, Pinkerton AB, Vernier JM, Bristow LJ, Varney MA, Daggett LP (October 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. doi:10.1124/mol.64.4.798. PMID 14500736. 
  20. ^ Barda DA, Wang ZQ, Britton TC, Henry SS, Jagdmann GE, Coleman DS, Johnson MP, Andis SL, Schoepp DD (June 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. doi:10.1016/j.bmcl.2004.04.017. PMID 15149652. 
  21. ^ Pinkerton AB, Vernier JM, Schaffhauser H, Rowe BA, Campbell UC, Rodriguez DE, Lorrain DS, Baccei CS, Daggett LP, Bristow LJ (August 2004). "Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor". Journal of Medicinal Chemistry 47 (18): 4595–9. doi:10.1021/jm040088h. PMID 15317469. 
  22. ^ Zhang MQ, Zhang XL, Li Y, Fan WJ, Wang YH, Hao M, Zhang SW, Ai CZ (2011). "Investigation on Quantitative Structure Activity Relationships and Pharmacophore Modeling of a Series of mGluR2 Antagonists". Int J Mol Sci 12 (9): 5999–6023. doi:10.3390/ijms12095999. PMC 3189765. PMID 22016641. 
  23. ^ Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, Conn PJ (July 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. 
  24. ^ Campo B, Kalinichev M, Lambeng N, El Yacoubi M, Royer-Urios I, Schneider M, Legrand C, Parron D, Girard F, Bessif A, Poli S, Vaugeois JM, Le Poul E, Celanire S (December 2011). "Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression". J. Neurogenet. 25 (4): 152–66. doi:10.3109/01677063.2011.627485. PMID 22091727. 
  25. ^ Yin S, Noetzel MJ, Johnson KA, et al. (2014). "Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS". J. Neurosci. 34 (1): 79–94. doi:10.1523/JNEUROSCI.1129-13.2014. PMID 24381270. 

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.