Metabotropic glutamate receptor 2

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Metabotropic glutamate receptor 2
other names

GRM2, mGluR2

Properties of human protein
Mass / length primary structure 872 amino acids , 95,568 Da
Identifier
External IDs
Orthologue
human House mouse
Entrez 2912 108068
Ensemble ENSG00000164082 ENSMUSG00000023192
UniProt Q14416 Q14BI2
Refseq (mRNA) NM_000839.4 NM_001160353.1
Refseq (protein) NP_000830.2 NP_001153825.1
Gene locus
PubMed search 2912 108068

Metabotropic glutamate receptor 2 (GRM 2, mGluR2) is a protein from the group of metabotropic glutamate receptors .

properties

The metabotropic glutamate receptor 2 is a G protein-coupled receptor . Together with mGluR3 , it forms group II of the metabotropic glutamate receptors. After binding of glutamate , a change in conformation takes place , which causes signal transduction via G proteins (from the G i family ). As a result, adenylyl cyclase is inhibited. The metabotropic glutamate receptor 2 has disulfide bridges and is glycosylated .

Various psychedelics such as LSD-25 bind to oligomers made from 5HT2A and mGlu2R.

The development of positive allosteric modulators of the mGluR2 has increased since 2009. The allosteric enhancement of the activation of the mGluR2 is being investigated for the treatment of schizophrenia . In contrast, antagonists and negative allosteric modulators of mGluR2 and mGluR3 are being investigated for the treatment of depression .

Ligands

Agonists

  • Compound 1d

Positive allosteric modulators

Positive allosteric modulator of the mGluR2, analog of BINA
  • JNJ-46356479
  • JNJ-40411813
  • GSK-1331258
  • Imidazo [1,2- a ] pyridines
  • 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones
  • 3- (Imidazolylmethyl) -3-aza-bicyclo [3.1.0] hexan-6-yl) methyl ether: available orally
  • BINA : moderate ago- allosteric modulator , works in vivo .
  • LY-487,379
  • 3-pyridylmethylsulfonamides

Antagonists

Negative allosteric modulators

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

Individual evidence

  1. ↑ a b c d GRM2 - Metabotropic glutamate receptor 2 precursor - Homo sapiens (Human) - GRM2 gene & protein. In: uniprot.org. September 27, 2005, accessed October 11, 2018 .
  2. ↑ Moreno JL, Miranda-Azpiazu P, García-Bea A, Younkin J, Cui M, Kozlenkov A, Ben-Ezra A, Voloudakis G, Fakira AK, Baki L, Ge Y, Georgakopoulos A, Morón JA, Milligan G, López -Giménez JF, Robakis NK, Logothetis DE, Meana JJ, González-Maeso J: Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia . In: Science Signaling . 9, No. 410, January 2016, p. Ra5. doi : 10.1126 / scisignal.aab0467 . PMID 26758213 . PMC 4819166 (free full text).
  3. ↑ Baki L, Friborg M, Younkin J, Eltit JM, Moreno JL, Park G, Vysotskaya Z, Narahari A, Sealfon SC, Gonzalez-Maeso J, Logothetis DE: Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells . In: Pflüger's archive . 468, No. 5, May 2016, pp. 775-93. doi : 10.1007 / s00424-015-1780-7 . PMID 26780666 .
  4. ^ Fraley ME: Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia . In: Expert Opinion on Therapeutic Patents . 19, No. 9, September 2009, pp. 1259-75. doi : 10.1517 / 13543770903045009 . PMID 19552508 .
  5. ^ Conn PJ, Jones CK: Promise of mGluR2 / 3 activators in psychiatry . In: Neuropsychopharmacology . 34, No. 1, January 2009, pp. 248-9. doi : 10.1038 / npp.2008.156 . PMID 19079073 . PMC 2907744 (free full text).
  6. ↑ Muguruza C, Meana JJ, Callado LF: Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs . In: Frontiers in Pharmacology . 7, 2016, p. 130. doi : 10.3389 / fphar.2016.00130 . PMID 27242534 . PMC 4873505 (free full text).
  7. ↑ Kawashima N, Karasawa J, Shimazaki T, Chaki S, Okuyama S, Yasuhara A, Nakazato A: Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors . In: Neuroscience Letters . 378, No. 3, April 2005, pp. 131-4. doi : 10.1016 / j.neulet.2004.12.021 . PMID 15781145 .
  8. ↑ Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G: Behavioral characterization of the mGlu group II / III receptor antagonist, LY-341495, in animal models of anxiety and depression . In: European Journal of Pharmacology . 592, No. 1-3, September 2008, pp. 96-102. doi : 10.1016 / j.ejphar.2008.06.089 . PMID 18634781 .
  9. ↑ Dwyer JM, Lepack AE, Duman RS: mTOR activation is required for the antidepressant effects of mGluR₂ / ₃ blockade . In: The International Journal of Neuropsychopharmacology . 15, No. 4, May 2012, pp. 429-34. doi : 10.1017 / S1461145711001702 . PMID 22114864 . PMC 3580765 (free full text).
  10. ↑ Koike H, Fukumoto K, Iijima M, Chaki S: Role of BDNF / TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression . In: Behavioral Brain Research . 238, February 2013, pp. 48-52. doi : 10.1016 / j.bbr.2012.10.023 . PMID 23098797 .
  11. ↑ Fukumoto K, Iijima M, Funakoshi T, Chaki S: 5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2 / 3 receptor antagonist in mice . In: Neuropharmacology . 137, May 2018, pp. 96-103. doi : 10.1016 / j.neuropharm.2018.05.001 . PMID 29738849 .
  12. ↑ Huynh TH, Erichsen MN, Tora AS, Goudet C, Sagot E, Assaf Z, Thomsen C, Brodbeck R, Stensbøl TB, Bjørn-Yoshimoto WE, Nielsen B, Pin JP, Gefflaut T, Bunch L: New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III . In: Journal of Medicinal Chemistry . 59, No. 3, February 2016, pp. 914-24. doi : 10.1021 / acs.jmedchem.5b01333 . PMID 26814576 .
  13. ↑ Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND: Design and synthesis of an orally active metabotropic glutamate receptor subtype-2 (mGluR2) positive allosteric modulator (PAM) that decreases cocaine self-administration in rats . In: Journal of Medicinal Chemistry . 54, No. 1, January 2011, pp. 342-53. doi : 10.1021 / jm1012165 . PMID 21155570 . PMC 3071440 (free full text).
  14. ↑ Cid JM, Tresadern G, Vega JA, de Lucas AI, Del Cerro A, Matesanz E, Linares ML, García A, Iturrino L, Pérez-Benito L, Macdonald GJ, Oehlrich D, Lavreysen H, Peeters L, Ceusters M, Ahnaou A, Drinkenburg W, Mackie C, Somers M, Trabanco AA: Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7 - [(4- (2,4-difluorophenyl) -1-piperazinyl) methyl] -1.2, 4-triazolo [4,3-a] pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM) . In: Journal of Medicinal Chemistry . 59, No. 18, September 2016, pp. 8495-507. doi : 10.1021 / acs.jmedchem.6b00913 . PMID 27579727 .
  15. ↑ addextherapeutics - ADX71149 for schizophrenia ( Memento of the original from December 16, 2017 in the Internet Archive ) Info: The archive link was automatically inserted and not yet checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.addextherapeutics.com
  16. ↑ 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: The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2 . In: Bioorganic & Medicinal Chemistry Letters . 20, No. 2, January 2010, pp. 759-62. doi : 10.1016 / j.bmcl.2009.11.032 . PMID 20005096 .
  17. ↑ 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: Scaffold hopping from pyridones to imidazo [1,2-a ] pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor . In: Bioorganic & Medicinal Chemistry Letters . 20, No. 1, January 2010, pp. 175-9. doi : 10.1016 / j.bmcl.2009.11.008 . PMID 19932615 .
  18. ↑ Brnardic EJ, Fraley ME, Garbaccio RM, Layton ME, Sanders JM, Culberson C, Jacobson MA, Magliaro BC, Hutson PH, O'Brien JA, Huszar SL, Uslaner JM, Fillgrove KL, Tang C, Kuo Y, Sur SM , Hartman GD: 3-Aryl-5-phenoxymethyl-1,3-oxazolidine-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts . In: Bioorganic & Medicinal Chemistry Letters . 20, No. 10, May 2010, pp. 3129-33. doi : 10.1016 / j.bmcl.2010.03.089 . PMID 20409708 .
  19. ↑ 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: 3- (imidazolyl methyl) -3-aza -bicyclo [3.1.0] hexan-6-yl) methyl ethers: a novel series of mGluR2 positive allosteric modulators . In: Bioorganic & Medicinal Chemistry Letters . 18, No. 20, October 2008, pp. 5493-6. doi : 10.1016 / j.bmcl.2008.09.026 . PMID 18812259 .
  20. ↑ Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de Paulis T, Conn PJ: Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice . In: The Journal of Pharmacology and Experimental Therapeutics . 318, No. 1, July 2006, pp. 173-85. doi : 10.1124 / jpet.106.102046 . PMID 16608916 .
  21. ↑ Bonnefous C, Vernier JM, Hutchinson JH, Gardner MF, Cramer M, James JK, Rowe BA, Daggett LP, Schaffhauser H, Kamenecka TM: Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor . In: Bioorganic & Medicinal Chemistry Letters . 15, No. 19, October 2005, pp. 4354-8. doi : 10.1016 / j.bmcl.2005.06.062 . PMID 16046122 .
  22. ↑ Johnson MP, Baez M, Jagdmann GE, Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD: 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 . In: Journal of Medicinal Chemistry . 46, No. 15, July 2003, pp. 3189-92. doi : 10.1021 / jm034015u . PMID 12852748 .
  23. ↑ Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, Schoepp DD: Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model (s) . In: Psychopharmacology . 179, No. 1, April 2005, pp. 271-83. doi : 10.1007 / s00213-004-2099-9 . PMID 15717213 .
  24. ↑ 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: Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2 . In: Molecular Pharmacology . 64, No. 4, October 2003, pp. 798-810. doi : 10.1124 / mol.64.4.798 . PMID 14500736 .
  25. ↑ Barda DA, Wang ZQ, Britton TC, Henry SS, Jagdmann GE, Coleman DS, Johnson MP, Andis SL, Schoepp DD: SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N- (4-phenoxyphenyl) - N- (3-pyridinylmethyl) ethanesulfonamides . In: Bioorganic & Medicinal Chemistry Letters . 14, No. 12, June 2004, pp. 3099-102. doi : 10.1016 / j.bmcl.2004.04.017 . PMID 15149652 .
  26. ↑ Pinkerton AB, Vernier JM, Schaffhauser H, Rowe BA, Campbell UC, Rodriguez DE, Lorrain DS, Baccei CS, Daggett LP, Bristow LJ: Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor . In: Journal of Medicinal Chemistry . 47, No. 18, August 2004, pp. 4595-9. doi : 10.1021 / jm040088h . PMID 15317469 .
  27. ↑ Zhang MQ, Zhang XL, Li Y, Fan WJ, Wang YH, Hao M, Zhang SW, Ai CZ: Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists . In: International Journal of Molecular Sciences . 12, No. 9, 2011, pp. 5999-6023. doi : 10.3390 / ijms12095999 . PMID 22016641 . PMC 3189765 (free full text).
  28. ↑ Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, Conn PJ: A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors . In: The Journal of Pharmacology and Experimental Therapeutics . 322, No. 1, July 2007, pp. 254-64. doi : 10.1124 / jpet.106.117093 . PMID 17416742 .
  29. ↑ 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: Characterization of an mGluR2 / 3 negative allosteric modulator in rodent models of depression . In: Journal of Neurogenetics . 25, No. 4, December 2011, pp. 152-66. doi : 10.3109 / 01677063.2011.627485 . PMID 22091727 .