Metabotropic glutamate receptor 2

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.

In humans, mGluR2 is only expressed in the brain, and not in any other tissue.{{Cite web|url=http://www.proteinatlas.org/ENSG00000164082-GRM2/tissue|title=Tissue expression of GRM2 - Summary - The Human Protein Atlas|website=www.proteinatlas.org|access-date=2017-12-28}} 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.{{cite journal | vauthors = Jin LE, Wang M, Yang ST, Yang Y, Galvin VC, Lightbourne TC, Ottenheimer D, Zhong Q, Stein J, Raja A, Paspalas CD, Arnsten AF | title = mGluR2/3 mechanisms in primate dorsolateral prefrontal cortex: evidence for both presynaptic and postsynaptic actions | journal = Molecular Psychiatry | volume = 22 | issue = 11 | pages = 1615–1625 | date = November 2017 | pmid = 27502475 | doi = 10.1038/mp.2016.129 | pmc = 5298940 }}

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.

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.{{cite journal | vauthors = Yin S, Noetzel MJ, Johnson KA, Zamorano R, Jalan-Sakrikar N, Gregory KJ, Conn PJ, Niswender CM | title = Selective actions of novel allosteric modulators reveal functional heteromers of metabotropic glutamate receptors in the CNS | journal = The Journal of Neuroscience | volume = 34 | issue = 1 | pages = 79–94 | date = January 2014 | pmid = 24381270 | pmc = 3866496 | doi = 10.1523/JNEUROSCI.1129-13.2014 }} Another example is with serotonin receptor 2A (5HT2A); see below.

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.{{cite journal | vauthors = Fraley ME | title = Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia | journal = Expert Opinion on Therapeutic Patents | volume = 19 | issue = 9 | pages = 1259–75 | date = September 2009 | pmid = 19552508 | doi = 10.1517/13543770903045009 | s2cid = 23242384 }} mGluR2 potentiation is a new approach for the treatment of schizophrenia.{{cite journal | vauthors = Conn PJ, Jones CK | title = Promise of mGluR2/3 activators in psychiatry | journal = Neuropsychopharmacology | volume = 34 | issue = 1 | pages = 248–9 | date = January 2009 | pmid = 19079073 | pmc = 2907744 | doi = 10.1038/npp.2008.156 }}{{cite journal | vauthors = Muguruza C, Meana JJ, Callado LF | title = Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs | journal = Frontiers in Pharmacology | volume = 7 | pages = 130 | year = 2016 | pmid = 27242534 | doi = 10.3389/fphar.2016.00130 | pmc=4873505| doi-access = free }} On the other hand, antagonists and negative allosteric modulators of mGluR_2/3 have potential as antidepressant drugs.{{cite journal | vauthors = Kawashima N, Karasawa J, Shimazaki T, Chaki S, Okuyama S, Yasuhara A, Nakazato A | title = Neuropharmacological profiles of antagonists of group II metabotropic glutamate receptors | journal = Neuroscience Letters | volume = 378 | issue = 3 | pages = 131–4 | date = April 2005 | pmid = 15781145 | doi = 10.1016/j.neulet.2004.12.021 | s2cid = 26509964 }}{{cite journal | vauthors = Bespalov AY, van Gaalen MM, Sukhotina IA, Wicke K, Mezler M, Schoemaker H, Gross G | title = Behavioral characterization of the mGlu group II/III receptor antagonist, LY-341495, in animal models of anxiety and depression | journal = European Journal of Pharmacology | volume = 592 | issue = 1–3 | pages = 96–102 | date = September 2008 | pmid = 18634781 | doi = 10.1016/j.ejphar.2008.06.089 }}{{cite journal | vauthors = Dwyer JM, Lepack AE, Duman RS | title = mTOR activation is required for the antidepressant effects of mGluR₂/₃ blockade | journal = The International Journal of Neuropsychopharmacology | volume = 15 | issue = 4 | pages = 429–34 | date = May 2012 | pmid = 22114864 | pmc = 3580765 | doi = 10.1017/S1461145711001702 | author-link1 = John Dwyer (medicine) }}{{cite journal | vauthors = Koike H, Fukumoto K, Iijima M, Chaki S | title = Role of BDNF/TrkB signaling in antidepressant-like effects of a group II metabotropic glutamate receptor antagonist in animal models of depression | journal = Behavioural Brain Research | volume = 238 | pages = 48–52 | date = February 2013 | pmid = 23098797 | doi = 10.1016/j.bbr.2012.10.023 | s2cid = 19518629 }}{{cite journal |vauthors=Fukumoto K, Iijima M, Funakoshi T, Chaki S |title=5-HT1A receptor stimulation in the medial prefrontal cortex mediates the antidepressant effects of mGlu2/3 receptor antagonist in mice |journal=Neuropharmacology |volume=137 |pages=96–103 |date=May 2018 |pmid=29738849 |doi=10.1016/j.neuropharm.2018.05.001 |s2cid=13689614 }}

• Compound 1d (see reference){{cite journal | vauthors = 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 | title = New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III | journal = Journal of Medicinal Chemistry | volume = 59 | issue = 3 | pages = 914–24 | date = February 2016 | pmid = 26814576 | doi = 10.1021/acs.jmedchem.5b01333 }}{{Cite journal|vauthors=Monn JA, Henry SS, Massey SM, Clawson DK, Chen Q, Diseroad BA, Bhardwaj RM, Shane A, Frances L, Wang J, Russell M, Heinz BA, Wang XS|date=2018|title=Synthesis and Pharmacological Characterization of C4β-Amide-Substituted 2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylates. Identification of (1S,2S,4S,5R,6S)-2-Amino-4-[(3-methoxybenzoyl)amino]bicyclo[3.1.0]hexane-2,6-dicarboxylic Acid (LY2794193), a Highly Potent and Selective mGlu3 Receptor Agonist|journal=Journal of Medicinal Chemistry|volume=61|issue=6|pages=2303–2328|doi=10.1021/acs.jmedchem.7b01481|pmid=29350927}}
• LY-2812223

Image:Dhanya 2010.svg

• JNJ-46356479{{cite journal | vauthors = 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 | title = 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 = Journal of Medicinal Chemistry | volume = 59 | issue = 18 | pages = 8495–507 | date = September 2016 | pmid = 27579727 | doi = 10.1021/acs.jmedchem.6b00913 }}
• JNJ-40411813{{Cite web |url=http://www.addextherapeutics.com/rd/pipeline/adx71149-for-schizophrenia/ |title=addextherapeutics – ADX71149 for schizophrenia |access-date=2013-01-06 |archive-url=https://web.archive.org/web/20171216151251/http://www.addextherapeutics.com/rd/pipeline/adx71149-for-schizophrenia/ |archive-date=2017-12-16 |url-status=dead }}
• GSK-1331258{{cite journal | vauthors = 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 | title = The identification of structurally novel, selective, orally bioavailable positive modulators of mGluR2 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 2 | pages = 759–62 | date = January 2010 | pmid = 20005096 | doi = 10.1016/j.bmcl.2009.11.032 }}
• Imidazo[1,2-a]pyridines{{cite journal | vauthors = 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 | title = Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 1 | pages = 175–9 | date = January 2010 | pmid = 19932615 | doi = 10.1016/j.bmcl.2009.11.008 }}
• 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones{{cite journal | vauthors = 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 | title = 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones as positive allosteric modulators of mGluR2 for the treatment of schizophrenia: Hit-to-lead efforts | journal = Bioorganic & Medicinal Chemistry Letters | volume = 20 | issue = 10 | pages = 3129–33 | date = May 2010 | pmid = 20409708 | doi = 10.1016/j.bmcl.2010.03.089 }}
• 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable{{cite journal | vauthors = 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 | title = 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: a novel series of mGluR2 positive allosteric modulators | journal = Bioorganic & Medicinal Chemistry Letters | volume = 18 | issue = 20 | pages = 5493–6 | date = October 2008 | pmid = 18812259 | doi = 10.1016/j.bmcl.2008.09.026 }}
• BINA:{{cite journal | vauthors = Galici R, Jones CK, Hemstapat K, Nong Y, Echemendia NG, Williams LC, de Paulis T, Conn PJ | title = Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 318 | issue = 1 | pages = 173–85 | date = July 2006 | pmid = 16608916 | doi = 10.1124/jpet.106.102046 | s2cid = 14653620 }}{{cite journal | vauthors = Bonnefous C, Vernier JM, Hutchinson JH, Gardner MF, Cramer M, James JK, Rowe BA, Daggett LP, Schaffhauser H, Kamenecka TM | title = Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor | journal = Bioorganic & Medicinal Chemistry Letters | volume = 15 | issue = 19 | pages = 4354–8 | date = October 2005 | pmid = 16046122 | doi = 10.1016/j.bmcl.2005.06.062 }} potent; modest ago-allosteric modulator; robust in-vivo activity.
• LY-487,379:{{cite journal | vauthors = Johnson MP, Baez M, Jagdmann GE, Britton TC, Large TH, Callagaro DO, Tizzano JP, Monn JA, Schoepp DD | title = 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 = Journal of Medicinal Chemistry | volume = 46 | issue = 15 | pages = 3189–92 | date = July 2003 | pmid = 12852748 | doi = 10.1021/jm034015u }}{{cite journal | vauthors = Johnson MP, Barda D, Britton TC, Emkey R, Hornback WJ, Jagdmann GE, McKinzie DL, Nisenbaum ES, Tizzano JP, Schoepp DD | title = Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s) | journal = Psychopharmacology | volume = 179 | issue = 1 | pages = 271–83 | date = April 2005 | pmid = 15717213 | doi = 10.1007/s00213-004-2099-9 | s2cid = 2699540 }}{{cite journal | vauthors = 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 | title = Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2 | journal = Molecular Pharmacology | volume = 64 | issue = 4 | pages = 798–810 | date = October 2003 | pmid = 14500736 | doi = 10.1124/mol.64.4.798 | s2cid = 15919973 }} devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides{{cite journal | vauthors = Barda DA, Wang ZQ, Britton TC, Henry SS, Jagdmann GE, Coleman DS, Johnson MP, Andis SL, Schoepp DD | title = SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide | journal = Bioorganic & Medicinal Chemistry Letters | volume = 14 | issue = 12 | pages = 3099–102 | date = June 2004 | pmid = 15149652 | doi = 10.1016/j.bmcl.2004.04.017 }}{{cite journal | vauthors = Pinkerton AB, Vernier JM, Schaffhauser H, Rowe BA, Campbell UC, Rodriguez DE, Lorrain DS, Baccei CS, Daggett LP, Bristow LJ | title = Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor | journal = Journal of Medicinal Chemistry | volume = 47 | issue = 18 | pages = 4595–9 | date = August 2004 | pmid = 15317469 | doi = 10.1021/jm040088h }} the first subtype-2-selective potentiator published (2003).

• LY-341,495
• MGS-0039
• EGLU

• 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.{{cite journal | vauthors = Zhang MQ, Zhang XL, Li Y, Fan WJ, Wang YH, Hao M, Zhang SW, Ai CZ | title = Investigation on quantitative structure activity relationships and pharmacophore modeling of a series of mGluR2 antagonists | journal = International Journal of Molecular Sciences | volume = 12 | issue = 9 | pages = 5999–6023 | year = 2011 | pmid = 22016641 | pmc = 3189765 | doi = 10.3390/ijms12095999 | doi-access = free }}
• MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one{{cite journal | vauthors = Hemstapat K, Da Costa H, Nong Y, Brady AE, Luo Q, Niswender CM, Tamagnan GD, Conn PJ | title = A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 322 | issue = 1 | pages = 254–64 | date = July 2007 | pmid = 17416742 | doi = 10.1124/jpet.106.117093 | s2cid = 3820477 }}
• RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one{{cite journal | vauthors = 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 | title = Characterization of an mGluR2/3 negative allosteric modulator in rodent models of depression | journal = Journal of Neurogenetics | volume = 25 | issue = 4 | pages = 152–66 | date = December 2011 | pmid = 22091727 | doi = 10.3109/01677063.2011.627485 | s2cid = 207440972 }}

Many psychedelic drugs (e.g. LSD-25) produce their effects by binding to the oligomerized complexes of the 5HT2A and mGlu2 receptors.{{cite journal | vauthors = 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 | title = Allosteric signaling through an mGlu2 and 5-HT2A heteromeric receptor complex and its potential contribution to schizophrenia | journal = Science Signaling | volume = 9 | issue = 410 | pages = ra5 | date = January 2016 | pmid = 26758213 | doi = 10.1126/scisignal.aab0467 | pmc = 4819166 }}{{cite journal | vauthors = Baki L, Fribourg M, Younkin J, Eltit JM, Moreno JL, Park G, Vysotskaya Z, Narahari A, Sealfon SC, Gonzalez-Maeso J, Logothetis DE | title = Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells | journal = Pflügers Archiv | volume = 468 | issue = 5 | pages = 775–93 | date = May 2016 | pmid = 26780666 | pmc = 4842341 | doi = 10.1007/s00424-015-1780-7 }} 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 antagonistic activity (producing the effect of a silent antagonist 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.

mGluR2 has been found to be a novel receptor for rabies virus.{{cite journal | vauthors = Wang J, Wang Z, Liu R, Shuai L, Wang X, Luo J, Wang C, Chen W, Wang X, Ge J, He X, Wen Z, Bu Z | display-authors = 6 | title = Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus | journal = PLOS Pathogens | volume = 14 | issue = 7 | pages = e1007189 | date = July 2018 | pmid = 30028877 | pmc = 6070288 | doi = 10.1371/journal.ppat.1007189 | doi-access = free }} The virus has a glycoprotein on its surface which interacts with the receptor. Rabies virus can bind to mGLuR2 directly and the virus-receptor complex is internalized into the cell together. The complex is then transported into early and late endosomes. Rabies virus enters the cells by clathrin-independent endocytosis which could suggest that mGLuR2 also uses this pathway. It is still to be clarified whether the Rabies virus glycoprotein can act as a PAM or NAM and in such a way affect the function of the receptor.

• Metabotropic glutamate receptor

{{Reflist|35em}}

• {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2270 | title = Metabotropic Glutamate Receptors: mGlu₂ | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-05 | archive-date = 2012-03-19 | archive-url = https://web.archive.org/web/20120319221350/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2270 | url-status = dead }}

{{NLM content}}

{{G protein-coupled receptors|g3}}

{{Metabotropic glutamate receptor modulators}}

Category:Metabotropic glutamate receptors