Metabotropic glutamate receptor 2: Difference between revisions

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{{Infobox_gene}}
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'''Metabotropic glutamate receptor 2''' is a [[protein]] that in humans is encoded by the ''GRM2'' [[gene]].<ref name="pmid7620613">{{cite journal | vauthors = Flor PJ, Lindauer K, Püttner I, Rüegg D, Lukic S, Knöpfel T, Kuhn R | title = Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2 | journal = The European Journal of Neuroscience | volume = 7 | issue = 4 | pages = 622–9 | date = April 1995 | pmid = 7620613 | pmc =  | doi = 10.1111/j.1460-9568.1995.tb00666.x }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: GRM2 glutamate receptor, metabotropic 2| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2912| accessdate = }}</ref>
{{GNF_Protein_box
| image =
| image_source = 
| PDB =
| Name = Glutamate receptor, metabotropic 2, GluR2
| HGNCid = 4594
| Symbol = GRM2
| AltSymbols =; GLUR2; GPRC1B; MGLUR2; mGlu2
| OMIM = 604099
| ECnumber = 
| Homologene = 20229
| MGIid = 
| GeneAtlas_image1 = PBB_GE_GRM2_208465_at_tn.png
| Function = {{GNF_GO|id=GO:0004872 |text = receptor activity}} {{GNF_GO|id=GO:0008067 |text = metabotropic glutamate, GABA-B-like receptor activity}}
| Component = {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}}
| Process = {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007186 |text = G-protein coupled receptor protein signaling pathway}} {{GNF_GO|id=GO:0007194 |text = negative regulation of adenylate cyclase activity}} {{GNF_GO|id=GO:0007268 |text = synaptic transmission}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 2912
    | Hs_Ensembl = ENSG00000164082
    | Hs_RefseqProtein = NP_000830
    | Hs_RefseqmRNA = NM_000839
    | Hs_GenLoc_db =   
    | Hs_GenLoc_chr = 3
    | Hs_GenLoc_start = 51716118
    | Hs_GenLoc_end = 51727663
    | Hs_Uniprot = Q14416
    | Mm_EntrezGene = 
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = 
    | Mm_RefseqProtein = 
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Glutamate receptor, [[metabotropic receptor|metabotropic]] 2, GluR2''', also known as '''GRM2''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: GRM2 glutamate receptor, metabotropic 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2912| accessdate = }}</ref>


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== Function ==
{{PBB_Summary
[[L-glutamate]] is the major excitatory [[neurotransmitter]] in the central nervous system and activates both ionotropic and metabotropic [[glutamate receptor]]s. 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 receptor]]s, 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.<ref name="entrez"/>
| section_title =  
 
| summary_text = 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 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.<ref name="entrez">{{cite web | title = Entrez Gene: GRM2 glutamate receptor, metabotropic 2| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2912| accessdate = }}</ref>
=== Role in hallucinogenesis ===
}}
Many [[psychedelic drug|psychedelic]] drugs (e.g. [[LSD-25]]) produce their effects by binding to the [[GPCR oligomer|oligomerized complexes]] of the [[5HT2A]] and mGlu2 receptors.<ref>{{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 | pmid = 26758213 | doi = 10.1126/scisignal.aab0467 | year=2016}}</ref><ref>{{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 = Pflugers Archiv | date = January 2016 | pmid = 26780666 | doi = 10.1007/s00424-015-1780-7 | volume=468 | pages=775–93}}</ref> [[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 agonist]]s for either subunit potentiate the signaling through the partner subunit.


==Ligands==
==Ligands==
===Subtype-selective potentiators ===
The development of subtype-2-selective [[allosteric modulator|positive allosteric modulators]] (PAMs) experienced steady advance in recent years.<ref>{{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 }}</ref> mGluR2 potentiation is a new approach for the treatment of schizophrenia.<ref name="pmid19079073">{{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 }}</ref><ref name="MuguruzaMeana2016">{{cite journal|last1=Muguruza|first1=Carolina|last2=Meana|first2=J. Javier|last3=Callado|first3=Luis F.|title=Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs|journal=Frontiers in Pharmacology|volume=7|year=2016|issn=1663-9812|doi=10.3389/fphar.2016.00130}}</ref> On the other hand, antagonists and negative allosteric modulators of mGluR<sub>2/3</sub> have potential as [[antidepressant]] drugs.<ref name="pmid15781145">{{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 }}</ref><ref name="pmid18634781">{{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 }}</ref><ref name="pmid22114864">{{cite journal | vauthors = Dwyer JM, Lepack AE, Duman RS |author-link1=John Dwyer (medicine) | 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 }}</ref><ref name="pmid23098797">{{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 | issue = | pages = 48–52 | date = February 2013 | pmid = 23098797 | doi = 10.1016/j.bbr.2012.10.023 }}</ref>
Although a number of [[Metabotropic glutamate receptor#Classification|group-II]]-selective (GluR2/3) ligands are known, ligands displaying high selectivity, including subtype-selectivity over [[Metabotropic glutamate receptor 3|GluR3]], are currently rare (2008). Examples of subtype-selective ligands are the following [[Allosteric regulation#Allosteric activation and inhibition|allosteric potentiator]]s.<ref>{{cite journal |author=Rudd MT, McCauley JA |title=Positive allosteric modulators of the metabotropic glutamate receptor subtype 2 (mGluR2) |journal=Curr Top Med Chem |volume=5 |issue=9 |pages=869–84 |year=2005 |pmid=16178732 |doi= |url=http://openurl.ingenta.com/content/nlm?genre=article&issn=1568-0266&volume=5&issue=9&spage=869&aulast=Rudd}}</ref> GluR2 potentiation is a new approach for the treatment of schizophrenia.
 
*BINA:<ref>{{cite journal |author=Galici R, Jones CK, Hemstapat K, ''et al'' |title=Biphenyl-indanone A, a positive allosteric modulator of the metabotropic glutamate receptor subtype 2, has antipsychotic- and anxiolytic-like effects in mice |journal=J. Pharmacol. Exp. Ther. |volume=318 |issue=1 |pages=173–85 |year=2006 |pmid=16608916 |doi=10.1124/jpet.106.102046 |url=}}</ref><ref>{{cite journal |author=Bonnefous C, Vernier JM, Hutchinson JH, ''et al'' |title=Biphenyl-indanones: allosteric potentiators of the metabotropic glutamate subtype 2 receptor |journal=Bioorg. Med. Chem. Lett. |volume=15 |issue=19 |pages=4354–8 |year=2005 |pmid=16046122 |doi=10.1016/j.bmcl.2005.06.062 |url=}}</ref> potent potentiator; modest direct agonist; robust in-vivo activity [→''formula'']
===Agonists===
*LY487379:<ref>{{cite journal |author=Johnson MP, Baez M, Jagdmann GE, ''et al'' |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=J. Med. Chem. |volume=46 |issue=15 |pages=3189–92 |year=2003 |pmid=12852748 |doi=10.1021/jm034015u |url=}}</ref><ref>{{cite journal |author=Johnson MP, Barda D, Britton TC, ''et al'' |title=Metabotropic glutamate 2 receptor potentiators: receptor modulation, frequency-dependent synaptic activity, and efficacy in preclinical anxiety and psychosis model(s) |journal=Psychopharmacology (Berl.) |volume=179 |issue=1 |pages=271–83 |year=2005 |pmid=15717213 |doi=10.1007/s00213-004-2099-9 |url=}}</ref><ref>{{cite journal |author=Schaffhauser H, Rowe BA, Morales S, ''et al'' |title=Pharmacological characterization and identification of amino acids involved in the positive modulation of metabotropic glutamate receptor subtype 2 |journal=Mol. Pharmacol. |volume=64 |issue=4 |pages=798–810 |year=2003 |pmid=14500736 |doi=10.1124/mol.64.4.798 |url=}}</ref> devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides<ref>{{cite journal |author=Barda DA, Wang ZQ, Britton TC, ''et al'' |title=SAR study of a subtype selective allosteric potentiator of metabotropic glutamate 2 receptor, N-(4-phenoxyphenyl)-N-(3-pyridinylmethyl)ethanesulfonamide |journal=Bioorg. Med. Chem. Lett. |volume=14 |issue=12 |pages=3099–102 |year=2004 |pmid=15149652 |doi=10.1016/j.bmcl.2004.04.017 |url=}}</ref><ref>{{cite journal |author=Pinkerton AB, Vernier JM, Schaffhauser H, ''et al'' |title=Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor |journal=J. Med. Chem. |volume=47 |issue=18 |pages=4595–9 |year=2004 |pmid=15317469 |doi=10.1021/jm040088h |url=}}</ref> the first subtype-2-selective potentiator published (2003).
* Compound 1d (see reference)<ref name="pmid26814576">{{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=J. Med. Chem. |volume=59 |issue=3 |pages=914–24 |year=2016 |pmid=26814576 |doi=10.1021/acs.jmedchem.5b01333 |url=}}</ref>
 
===PAMs===
[[Image:Dhanya 2010.svg|thumb|right|290px|Highly selective mGluR2 PAM (2010),<ref>{{cite journal | vauthors = Dhanya RP, Sidique S, Sheffler DJ, Nickols HH, Herath A, Yang L, Dahl R, Ardecky R, Semenova S, Markou A, Conn PJ, Cosford ND | title = 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 = Journal of Medicinal Chemistry | volume = 54 | issue = 1 | pages = 342–53 | date = January 2011 | pmid = 21155570 | pmc = 3071440 | doi = 10.1021/jm1012165 }}</ref> analog of BINA]]
* JNJ-46356479<ref name="pmid27579727">{{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=J. Med. Chem. |volume= 59|issue= |pages= 8495–507|year=2016 |pmid=27579727 |doi=10.1021/acs.jmedchem.6b00913 |url=}}</ref>
*[[JNJ-40411813]]<ref>[http://www.addextherapeutics.com/rd/pipeline/adx71149-for-schizophrenia/ addextherapeutics – ADX71149 for schizophrenia]</ref>
*GSK-1331258<ref name="pmid20005096">{{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 }}</ref>
*Imidazo[1,2-''a'']pyridines<ref name="pmid19932615">{{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 }}</ref>
*3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones<ref>EJ Brnardic 2010</ref>
*3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable<ref name="pmid18812259">{{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 }}</ref>
*[[Biphenylindanone A|BINA]]:<ref name="pmid16608916">{{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 }}</ref><ref name="pmid16046122">{{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 }}</ref> potent; modest ago-allosteric modulator; robust in-vivo activity.
*[[LY-487,379]]:<ref name="pmid12852748">{{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 }}</ref><ref name="pmid15717213">{{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 }}</ref><ref name="pmid14500736">{{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 }}</ref> devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides<ref name="pmid15149652">{{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 }}</ref><ref name="pmid15317469">{{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 }}</ref> the first subtype-2-selective potentiator published (2003).
 
===Antagonists===
* [[LY-341,495]]
* [[MGS-0039]]
* [[EGLU]]
 
===NAMs===
* 7,8-dichloro-4-[3-(2-methylpyridin-4-yl)phenyl]-1,3-dihydro-1,5-benzodiazepin-2-one and related compounds.<ref name="pmid22016641">{{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 }}</ref>
* MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one<ref name="pmid17416742">{{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 }}</ref>
* [[RO4491533]] - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one<ref name="pmid22091727">{{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 }}</ref>
 
==Protein–protein interactions==
The metabotropic glutamate receptor 2 is able to form a [[GPCR oligomer|heteromeric complex]] with its isoform [[mGluR4]]. This heteromer exhibits a pharmacological profile distinct from the parent receptor monomers.<ref name="pmid24381270">{{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 }}</ref>


==See also==
== See also ==
* [[Metabotropic glutamate receptor]]
* [[Metabotropic glutamate receptor]]


==References==
== References ==
{{reflist|2}}
{{reflist|35em}}


==Further reading==
== External links ==
{{refbegin | 2}}
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2270 | title = Metabotropic Glutamate Receptors: mGlu<sub>2</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
{{PBB_Further_reading
| citations =  
*{{cite journal  | author=Flor PJ, Lindauer K, Püttner I, ''et al.'' |title=Molecular cloning, functional expression and pharmacological characterization of the human metabotropic glutamate receptor type 2. |journal=Eur. J. Neurosci. |volume=7 |issue= 4 |pages= 622-9 |year= 1995 |pmid= 7620613 |doi=  }}
*{{cite journal  | author=Scherer SW, Duvoisin RM, Kuhn R, ''et al.'' |title=Localization of two metabotropic glutamate receptor genes, GRM3 and GRM8, to human chromosome 7q. |journal=Genomics |volume=31 |issue= 2 |pages= 230-3 |year= 1997 |pmid= 8824806 |doi= 10.1006/geno.1996.0036 }}
*{{cite journal  | author=Gomeza J, Mary S, Brabet I, ''et al.'' |title=Coupling of metabotropic glutamate receptors 2 and 4 to G alpha 15, G alpha 16, and chimeric G alpha q/i proteins: characterization of new antagonists. |journal=Mol. Pharmacol. |volume=50 |issue= 4 |pages= 923-30 |year= 1996 |pmid= 8863838 |doi=  }}
*{{cite journal  | author=Snow BE, Hall RA, Krumins AM, ''et al.'' |title=GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. |journal=J. Biol. Chem. |volume=273 |issue= 28 |pages= 17749-55 |year= 1998 |pmid= 9651375 |doi=  }}
*{{cite journal  | author=Malherbe P, Knoflach F, Broger C, ''et al.'' |title=Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor. |journal=Mol. Pharmacol. |volume=60 |issue= 5 |pages= 944-54 |year= 2001 |pmid= 11641422 |doi=  }}
*{{cite journal  | author=Martí SB, Cichon S, Propping P, Nöthen M |title=Human metabotropic glutamate receptor 2 gene (GRM2): chromosomal sublocalization (3p21.1-p21.2) and genomic organization. |journal=Am. J. Med. Genet. |volume=114 |issue= 1 |pages= 12-4 |year= 2002 |pmid= 11840499 |doi=  }}
*{{cite journal  | author=Krampfl K, Schlesinger F, Zörner A, ''et al.'' |title=Control of kinetic properties of GluR2 flop AMPA-type channels: impact of R/G nuclear editing. |journal=Eur. J. Neurosci. |volume=15 |issue= 1 |pages= 51-62 |year= 2002 |pmid= 11860506 |doi=  }}
*{{cite journal  | author=Dietrich D, Kral T, Clusmann H, ''et al.'' |title=Presynaptic group II metabotropic glutamate receptors reduce stimulated and spontaneous transmitter release in human dentate gyrus. |journal=Neuropharmacology |volume=42 |issue= 3 |pages= 297-305 |year= 2002 |pmid= 11897108 |doi=  }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
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}}
{{refend}}


{{NLM content}}
{{NLM content}}
{{G protein-coupled receptors}}
{{G protein-coupled receptors|g3}}
[[Category:G protein coupled receptors]]
{{Metabotropic glutamate receptor modulators}}
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[[Category:Metabotropic glutamate receptors]]

Revision as of 01:06, 27 October 2017

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

Function

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]

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.[3][4] 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.

Ligands

The development of subtype-2-selective positive allosteric modulators (PAMs) experienced steady advance in recent years.[5] mGluR2 potentiation is a new approach for the treatment of schizophrenia.[6][7] On the other hand, antagonists and negative allosteric modulators of mGluR2/3 have potential as antidepressant drugs.[8][9][10][11]

Agonists

  • Compound 1d (see reference)[12]

PAMs

File:Dhanya 2010.svg
Highly selective mGluR2 PAM (2010),[13] analog of BINA
  • JNJ-46356479[14]
  • JNJ-40411813[15]
  • GSK-1331258[16]
  • Imidazo[1,2-a]pyridines[17]
  • 3-Aryl-5-phenoxymethyl-1,3-oxazolidin-2-ones[18]
  • 3-(Imidazolyl methyl)-3-aza-bicyclo[3.1.0]hexan-6-yl)methyl ethers: potent, orally stable[19]
  • BINA:[20][21] potent; modest ago-allosteric modulator; robust in-vivo activity.
  • LY-487,379:[22][23][24] devoid of orthosteric activity; along with related 3-pyridylmethylsulfonamides[25][26] 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.[27]
  • MNI-137 - 8-bromo-4-(2-cyanopyridin-4-yl)-1H-benzo[b][1,4]diazepin-2(3H)-one[28]
  • RO4491533 - 4-[3-(2,6-dimethylpyridin-4-yl)phenyl]-7-methyl-8-trifluoromethyl-1,3-dihydrobenzo[b][1,4]diazepin-2-one[29]

Protein–protein interactions

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.[30]

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. ↑ 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 (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. PMID 26758213.
  4. ↑ Baki L, Fribourg M, Younkin J, Eltit JM, Moreno JL, Park G, Vysotskaya Z, Narahari A, Sealfon SC, Gonzalez-Maeso J, Logothetis DE (January 2016). "Cross-signaling in metabotropic glutamate 2 and serotonin 2A receptor heteromers in mammalian cells". Pflugers Archiv. 468: 775–93. doi:10.1007/s00424-015-1780-7. PMID 26780666.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Muguruza, Carolina; Meana, J. Javier; Callado, Luis F. (2016). "Group II Metabotropic Glutamate Receptors as Targets for Novel Antipsychotic Drugs". Frontiers in Pharmacology. 7. doi:10.3389/fphar.2016.00130. ISSN 1663-9812.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ 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.
  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 (2016). "New 4-Functionalized Glutamate Analogues Are Selective Agonists at Metabotropic Glutamate Receptor Subtype 2 or Selective Agonists at Metabotropic Glutamate Receptor Group III". J. Med. Chem. 59 (3): 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 (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.
  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 (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)". J. Med. Chem. 59: 8495–507. doi:10.1021/acs.jmedchem.6b00913. PMID 27579727.
  15. ↑ addextherapeutics – ADX71149 for schizophrenia
  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 (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.
  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 (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.
  18. ↑ EJ Brnardic 2010
  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 (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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ 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.
  23. ↑ 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.
  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 (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.
  25. ↑ 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  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 (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.
  30. ↑ 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.

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