Metabotropic glutamate receptor 2

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Metabotropic glutamate receptor 2 (mGluR2) is a protein that, in humans, is encoded by the GRM2 gene.[1][2] mGluR2 is a G protein-coupled receptor (GPCR) that couples with the Gi alpha subunit.[3] The receptor functions as an autoreceptor for glutamate, that upon activation, inhibits the emptying of vesicular contents at the presynaptic terminal of glutamatergic neurons.

Structure

In humans, mGluR2 is encoded by the GRM2 gene on chromosome 3. At least three protein-coding isoforms are predicted based on genomic information, as well as numerous non-coding isoforms. The mGluR2 protein is a seven-pass transmembrane protein.

Function

In humans, mGluR2 is only expressed in the brain, and not in any other tissue.[4] In the brain, mGluR2 is expressed in neurons as well as astrocytes. Subcellularly, mGluR2 is predominantly positioned at the presynaptic terminal, although it is also expressed at the postsynaptic terminal.[5]

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 mGluR2 (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]

Protein–protein interactions

mGluR2 is able to form a heteromeric complex with various other different GPCRs. One example is with isoform mGluR4. The mGluR2-mGluR4 heteromer exhibits a pharmacological profile distinct from the parent receptor monomers.[6] Another example is with serotonin receptor 2A (5HT2A); see below.

Pharmacology

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.[7] mGluR2 potentiation is a new approach for the treatment of schizophrenia.[8][9] On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.[10][11][12][13][14]

Agonists

  • Compound 1d (see reference)[15]

PAMs

File:Dhanya 2010.svg
Highly selective mGluR2 PAM (2010),[16] analog of BINA
  • JNJ-46356479[17]
  • JNJ-40411813[18]
  • GSK-1331258[19]
  • Imidazo[1,2-a]pyridines[20]
  • 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones[21]
  • 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable[22]
  • BINA:[23][24] potent; modest ago-allosteric modulator; robust in-vivo activity.
  • LY-487,379:[25][26][27] devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides[28][29] the first subtype-2-selective potentiator published (2003).

Antagonists

NAMs

  • 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.[30]
  • MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one[31]
  • RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one[32]

Role in hallucinogenesis

Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors.[33][34] Lisuride acts preferentially or exclusively on the non-heteromerized 5HT2A receptors, which are not capable of inducing psychedelic effects. Due to this, lisuride is capable of reducing the hallucinogenic effects of these drugs through competitive agonistic activity (producing the effect of a silent-agonist in the presence of these drugs).

Strong agonists for either subunit of the 5HT2A-mGlu2R heterocomplex suppress signaling through the partner subunit and inverse agonists for either subunit potentiate the signaling through the partner subunit.

See also

References

  1. ↑ Flor PJ, Lindauer K, Püttner I, Rüegg D, Lukic S, Knöpfel T, Kuhn R (April 1995). "Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2". The European Journal of Neuroscience. 7 (4): 622–9. doi:10.1111/j.1460-9568.1995.tb00666.x. PMID 7620613.
  2. ↑ 2.0 2.1 "Entrez Gene: GRM2 glutamate receptor, metabotropic 2".
  3. ↑ Kammermeier PJ, Davis MI, Ikeda SR (January 2003). "Specificity of metabotropic glutamate receptor 2 coupling to G proteins". Molecular Pharmacology. 63 (1): 183–91. doi:10.1124/mol.63.1.183. PMID 12488551.
  4. ↑ "Tissue expression of GRM2 - Summary - The Human Protein Atlas". www.proteinatlas.org. Retrieved 2017-12-28.
  5. ↑ Jin LE, Wang M, Yang ST, Yang Y, Galvin VC, Lightbourne TC, Ottenheimer D, Zhong Q, Stein J, Raja A, Paspalas CD, Arnsten AF (November 2017). "mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions". Molecular Psychiatry. 22 (11): 1511. doi:10.1038/mp.2017.206. PMC 5298940. PMID 29068001.
  6. ↑ Yin S, Noetzel MJ, Johnson KA, Zamorano R, Jalan-Sakrikar N, Gregory KJ, Conn PJ, Niswender CM (January 2014). "Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS". The Journal of Neuroscience. 34 (1): 79–94. doi:10.1523/JNEUROSCI.1129-13.2014. PMC 3866496. PMID 24381270.
  7. ↑ Fraley ME (September 2009). "Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia". Expert Opinion on Therapeutic Patents. 19 (9): 1259–75. doi:10.1517/13543770903045009. PMID 19552508.
  8. ↑ 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.
  9. ↑ Muguruza C, Meana JJ, Callado LF (2016). "Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs". Frontiers in Pharmacology. 7: 130. doi:10.3389/fphar.2016.00130. PMC 4873505. PMID 27242534.
  10. ↑ 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". Neuroscience Letters. 378 (3): 131–4. doi:10.1016/j.neulet.2004.12.021. PMID 15781145.
  11. ↑ 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". European Journal of Pharmacology. 592 (1–3): 96–102. doi:10.1016/j.ejphar.2008.06.089. PMID 18634781.
  12. ↑ Dwyer JM, Lepack AE, Duman RS (May 2012). "mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade". The International Journal of Neuropsychopharmacology. 15 (4): 429–34. doi:10.1017/S1461145711001702. PMC 3580765. PMID 22114864.
  13. ↑ 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". Behavioural Brain Research. 238: 48–52. doi:10.1016/j.bbr.2012.10.023. PMID 23098797.
  14. ↑ Fukumoto K, Iijima M, Funakoshi T, Chaki S (May 2018). "5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice". Neuropharmacology. 137: 96–103. doi:10.1016/j.neuropharm.2018.05.001. PMID 29738849.
  15. ↑ 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 (February 2016). "New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III". Journal of Medicinal Chemistry. 59 (3): 914–24. doi:10.1021/acs.jmedchem.5b01333. PMID 26814576.
  16. ↑ Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND (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.
  17. ↑ 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 (September 2016). "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)". Journal of Medicinal Chemistry. 59 (18): 8495–507. doi:10.1021/acs.jmedchem.6b00913. PMID 27579727.
  18. ↑ addextherapeutics – ADX71149 for schizophrenia
  19. ↑ 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". Bioorganic & Medicinal Chemistry Letters. 20 (2): 759–62. doi:10.1016/j.bmcl.2009.11.032. PMID 20005096.
  20. ↑ 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". Bioorganic & Medicinal Chemistry Letters. 20 (1): 175–9. doi:10.1016/j.bmcl.2009.11.008. PMID 19932615.
  21. ↑ 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 (May 2010). "3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts". Bioorganic & Medicinal Chemistry Letters. 20 (10): 3129–33. doi:10.1016/j.bmcl.2010.03.089. PMID 20409708.
  22. ↑ 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". Bioorganic & Medicinal Chemistry Letters. 18 (20): 5493–6. doi:10.1016/j.bmcl.2008.09.026. PMID 18812259.
  23. ↑ 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". The Journal of Pharmacology and Experimental Therapeutics. 318 (1): 173–85. doi:10.1124/jpet.106.102046. PMID 16608916.
  24. ↑ 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". Bioorganic & Medicinal Chemistry Letters. 15 (19): 4354–8. doi:10.1016/j.bmcl.2005.06.062. PMID 16046122.
  25. ↑ 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.
  26. ↑ 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. 179 (1): 271–83. doi:10.1007/s00213-004-2099-9. PMID 15717213.
  27. ↑ 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". Molecular Pharmacology. 64 (4): 798–810. doi:10.1124/mol.64.4.798. PMID 14500736.
  28. ↑ 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". Bioorganic & Medicinal Chemistry Letters. 14 (12): 3099–102. doi:10.1016/j.bmcl.2004.04.017. PMID 15149652.
  29. ↑ 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.
  30. ↑ 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". International Journal of Molecular Sciences. 12 (9): 5999–6023. doi:10.3390/ijms12095999. PMC 3189765. PMID 22016641.
  31. ↑ 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". The Journal of Pharmacology and Experimental Therapeutics. 322 (1): 254–64. doi:10.1124/jpet.106.117093. PMID 17416742.
  32. ↑ 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". Journal of Neurogenetics. 25 (4): 152–66. doi:10.3109/01677063.2011.627485. PMID 22091727.
  33. ↑ 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 (January 2016). "Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia". Science Signaling. 9 (410): ra5. doi:10.1126/scisignal.aab0467. PMC 4819166. PMID 26758213.
  34. ↑ Baki L, Fribourg M, Younkin J, Eltit JM, Moreno JL, Park G, Vysotskaya Z, Narahari A, Sealfon SC, Gonzalez-Maeso J, Logothetis DE (May 2016). "Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells". Pflügers Archiv. 468 (5): 775–93. doi:10.1007/s00424-015-1780-7. PMID 26780666.

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