Target Information

Target General Infomation
Target ID
T22285
Former ID
TTDS00123
Target Name
Glutamate [NMDA] receptor subunit epsilon 1
Gene Name
GRIN2A
Synonyms
HNR2A; N-methyl D-aspartate receptor subtype 2A; NMDA receptor NR2A; NMDAR2A; NR2A; GRIN2A
Target Type
Successful
Disease Cerebrovascular ischaemia [ICD9: 434.91; ICD10: I61-I63]
Convulsions [ICD9: 780.3; ICD10: R56.0]
Dietary shortage [ICD9: 260-269; ICD10: E40-E46]
Neurological disease [ICD9: 338, 338.2, 410, 782.3,780; ICD10: I21, I22, R52, R52.1-R52.2, R60.9, G89]
Function
NMDA receptor subtype of glutamate-gated ion channels possesses high calcium permeability and voltage-dependent sensitivity to magnesium. Activation requires binding of agonist to both types of subunits.
BioChemical Class
Glutamate-gated ion channel
Target Validation
T22285
UniProt ID
Q12879
Sequence
MGRVGYWTLLVLPALLVWRGPAPSAAAEKGPPALNIAVMLGHSHDVTERELRTLWGPEQA
AGLPLDVNVVALLMNRTDPKSLITHVCDLMSGARIHGLVFGDDTDQEAVAQMLDFISSHT
FVPILGIHGGASMIMADKDPTSTFFQFGASIQQQATVMLKIMQDYDWHVFSLVTTIFPGY
REFISFVKTTVDNSFVGWDMQNVITLDTSFEDAKTQVQLKKIHSSVILLYCSKDEAVLIL
SEARSLGLTGYDFFWIVPSLVSGNTELIPKEFPSGLISVSYDDWDYSLEARVRDGIGILT
TAASSMLEKFSYIPEAKASCYGQMERPEVPMHTLHPFMVNVTWDGKDLSFTEEGYQVHPR
LVVIVLNKDREWEKVGKWENHTLSLRHAVWPRYKSFSDCEPDDNHLSIVTLEEAPFVIVE
DIDPLTETCVRNTVPCRKFVKINNSTNEGMNVKKCCKGFCIDILKKLSRTVKFTYDLYLV
TNGKHGKKVNNVWNGMIGEVVYQRAVMAVGSLTINEERSEVVDFSVPFVETGISVMVSRS
NGTVSPSAFLEPFSASVWVMMFVMLLIVSAIAVFVFEYFSPVGYNRNLAKGKAPHGPSFT
IGKAIWLLWGLVFNNSVPVQNPKGTTSKIMVSVWAFFAVIFLASYTANLAAFMIQEEFVD
QVTGLSDKKFQRPHDYSPPFRFGTVPNGSTERNIRNNYPYMHQYMTKFNQKGVEDALVSL
KTGKLDAFIYDAAVLNYKAGRDEGCKLVTIGSGYIFATTGYGIALQKGSPWKRQIDLALL
QFVGDGEMEELETLWLTGICHNEKNEVMSSQLDIDNMAGVFYMLAAAMALSLITFIWEHL
FYWKLRFCFTGVCSDRPGLLFSISRGIYSCIHGVHIEEKKKSPDFNLTGSQSNMLKLLRS
AKNISSMSNMNSSRMDSPKRAADFIQRGSLIMDMVSDKGNLMYSDNRSFQGKESIFGDNM
NELQTFVANRQKDNLNNYVFQGQHPLTLNESNPNTVEVAVSTESKANSRPRQLWKKSVDS
IRQDSLSQNPVSQRDEATAENRTHSLKSPRYLPEEMAHSDISETSNRATCHREPDNSKNH
KTKDNFKRSVASKYPKDCSEVERTYLKTKSSSPRDKIYTIDGEKEPGFHLDPPQFVENVT
LPENVDFPDPYQDPSENFRKGDSTLPMNRNPLHNEEGLSNNDQYKLYSKHFTLKDKGSPH
SETSERYRQNSTHCRSCLSNMPTYSGHFTMRSPFKCDACLRMGNLYDIDEDQMLQETGNP
ATGEQVYQQDWAQNNALQLQKNKLRISRQHSYDNIVDKPRELDLSRPSRSISLKDRERLL
EGNFYGSLFSVPSSKLSGKKSSLFPQGLEDSKRSKSLLPDHTSDNPFLHSHRDDQRLVIG
RCPSDPYKHSLPSQAVNDSYLRSSLRSTASYCSRDSRGHNDVYISEHVMPYAANKNNMYS
TPRVLNSCSNRRVYKKMPSIESDV
Drugs and Mode of Action
Drug(s) Glycine Drug Info Approved Dietary shortage [538479], [542289]
NBQX Drug Info Phase 1 Neurological disease [467600]
YM-90K Drug Info Discontinued in Phase 2 Convulsions [545107]
DIZOCILPINE Drug Info Terminated Cerebrovascular ischaemia [539532], [544717]
L-687414 Drug Info Terminated Discovery agent [544996]
L-695902 Drug Info Terminated Discovery agent [545371]
L-698532 Drug Info Terminated Neurological disease [546154]
L-701324 Drug Info Terminated Cerebrovascular ischaemia [467575], [525504], [534277]
MDL-105519 Drug Info Terminated Discovery agent [546254]
RPR-104632 Drug Info Terminated Discovery agent [545739]
SPERMINE Drug Info Terminated Discovery agent [542107], [546483]
Agonist (+)-HA966 Drug Info [543837]
(RS)-(tetrazol-5-yl)glycine Drug Info [543837]
D-aspartic acid Drug Info [543837]
homoquinolinic acid Drug Info [543837]
L-aspartic acid Drug Info [543837]
NMDA Drug Info [543837]
[3H]glycine Drug Info [543837]
Inhibitor (D)-Ala-Pro-Glu Drug Info [527903]
(R)-2-Amino-5-phosphono-pentanoic acid Drug Info [527496]
(R)-2-Amino-7-phosphono-heptanoic acid Drug Info [527496]
2-Methylamino-succinic acid(NMDA) Drug Info [531531]
3-Benzoyl-7-chloro-4-hydroxy-1H-quinolin-2-one Drug Info [551249]
3-Hydroxy-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
3-Hydroxy-6-methyl-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
3-Hydroxy-7-nitro-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
3-Hydroxy-8-methyl-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
3-phenyl-4-hydroxyquinolin-2(1H)-one Drug Info [527994]
4,5,7-Trichloro-3-hydroxy-1H-quinolin-2-one Drug Info [551312]
4,6-Dichloro-1H-indole-2-carboxylic acid Drug Info [531421]
4-Bromo-3-hydroxy-1H-quinolin-2-one Drug Info [551312]
4-Bromo-5,7-dichloro-3-hydroxy-1H-quinolin-2-one Drug Info [551312]
4-Chloro-3-hydroxy-1H-quinolin-2-one Drug Info [551312]
4-hydroxy-5-phenylthieno[2,3-b]pyridin-6(7H)-one Drug Info [527994]
4-Phosphonomethyl-piperidine-2-carboxylic acid Drug Info [533067]
4-[2-(4-Phenyl-butylamino)-ethyl]-phenol Drug Info [534696]
4-[2-(5-Phenyl-pentylamino)-ethyl]-phenol Drug Info [534696]
4-[2-(6-Phenyl-hexylamino)-ethyl]-phenol Drug Info [534696]
4-[3-(4-Phenyl-butylamino)-propyl]-phenol Drug Info [534696]
4-[3-(5-Phenyl-pentylamino)-propyl]-phenol Drug Info [534696]
5,7-Dichloro-3-hydroxy-1H-quinazoline-2,4-dione Drug Info [527036]
5,7-Dichloro-4-hydroxy-3-phenyl-1H-quinolin-2-one Drug Info [551249]
5,7-Dinitro-1,4-dihydro-quinoxaline-2,3-dione Drug Info [551249]
6,7-Dichloro-3-hydroxy-1H-quinazoline-2,4-dione Drug Info [527036]
6-Chloro-1,4-dihydro-quinoxaline-2,3-dione Drug Info [534504]
6-Nitro-1,4-dihydro-quinoxaline-2,3-dione Drug Info [534504]
7-chloro-3-hydroxyquinazoline-2,4-dione Drug Info [528453]
7-Chloro-3-nitro-3,4-dihydro-1H-quinolin-2-one Drug Info [551249]
8-Bromo-3-hydroxy-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
8-Chloro-3-hydroxy-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
8-Ethyl-3-hydroxy-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
8-Fluoro-3-hydroxy-1H-benzo[b]azepine-2,5-dione Drug Info [534270]
Ala-Pro-Glu Drug Info [527903]
AP-7 Drug Info [526787]
Benzyl 4-aminobutyl(3-aminopropyl)carbamate Drug Info [528098]
Conantokin-R Drug Info [529118]
DITOLYLGUANIDINE Drug Info [534685]
DIZOCILPINE Drug Info [533655]
DNQX Drug Info [529309]
GLUTAMATE Drug Info [526787]
Gly-Amp-Glu Drug Info [527903]
Gly-b7Pro-Glu Drug Info [527903]
Gly-Hyp-Glu Drug Info [527903]
Gly-Pip-Glu Drug Info [527903]
H-Gly-D-dmP-Glu-OH Drug Info [528176]
H-Gly-dmP-Glu-OH Drug Info [528176]
H-Gly-PMe-Glu-OH Drug Info [528176]
L-687414 Drug Info [551249]
L-695902 Drug Info [551249]
L-698532 Drug Info [527994]
L-701324 Drug Info [527994]
MDL-105519 Drug Info [527438]
N,N'-Bis-(4-butoxy-phenyl)-guanidine Drug Info [534685]
N,N'-Bis-(4-butyl-phenyl)-guanidine Drug Info [534685]
N,N'-Bis-(4-ethyl-phenyl)-guanidine Drug Info [534685]
N,N'-Bis-(4-hexyl-phenyl)-guanidine Drug Info [534685]
N,N'-Bis-(4-isopropyl-phenyl)-guanidine Drug Info [534685]
N,N'-Bis-(4-sec-butyl-phenyl)-guanidine Drug Info [534685]
N-(2-methoxybenzyl)cinnamamidine Drug Info [527787]
NBQX Drug Info [526134]
Nle-Pro-Glu Drug Info [527903]
Phe-Pro-Glu Drug Info [527903]
PHENCYCLIDINE Drug Info [534286]
RPR-104632 Drug Info [525816]
RPR-118723 Drug Info [525816]
SPERMINE Drug Info [530824]
TRANSTORINE Drug Info [531421]
YM-90K Drug Info [525786]
Antagonist d-AP5 Drug Info [543837]
d-CCPene Drug Info [543837]
Glycine Drug Info [537546]
LY233053 Drug Info [543837]
MDL 100,453 Drug Info [534895]
NVP-AAM077 Drug Info [528006]
Tenocyclidine Drug Info [551400]
UBP141 Drug Info [527496]
[3H]CGP39653 Drug Info [543837]
[3H]CGP61594 Drug Info [543837]
[3H]CGS19755 Drug Info [543837]
[3H]CPP Drug Info [543837]
[3H]L689560 Drug Info [543837]
[3H]MDL105519 Drug Info [543837]
Blocker (channel blocker) N1-dansyl-spermine Drug Info [543837]
[3H]dizocilpine Drug Info [543837]
Modulator (allosteric modulator) TCN-201 Drug Info [531892]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Ras signaling pathway
Rap1 signaling pathway
Calcium signaling pathway
cAMP signaling pathway
Neuroactive ligand-receptor interaction
Circadian entrainment
Long-term potentiation
Glutamatergic synapse
Dopaminergic synapse
Alzheimer&#039
s disease
Amyotrophic lateral sclerosis (ALS)
Cocaine addiction
Amphetamine addiction
Nicotine addiction
Alcoholism
Systemic lupus erythematosus
PANTHER Pathway Huntington disease
Ionotropic glutamate receptor pathway
Metabotropic glutamate receptor group III pathway
Metabotropic glutamate receptor group I pathway
Muscarinic acetylcholine receptor 1 and 3 signaling pathway
Pathway Interaction Database Reelin signaling pathway
Reactome Unblocking of NMDA receptor, glutamate binding and activation
CREB phosphorylation through the activation of CaMKII
Ras activation uopn Ca2+ infux through NMDA receptor
RAF/MAP kinase cascade
WikiPathways Hypothetical Network for Drug Addiction
Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
Alzheimers Disease
References
Ref 467575(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4240).
Ref 467600(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 4264).
Ref 525504L-701,324, a selective antagonist at the glycine site of the NMDA receptor, counteracts haloperidol-induced muscle rigidity in rats. Psychopharmacology (Berl). 1999 Apr;143(3):235-43.
Ref 534277Anticonvulsant and behavioral profile of L-701,324, a potent, orally active antagonist at the glycine modulatory site on the N-methyl-D-aspartate receptor complex. J Pharmacol Exp Ther. 1996 Nov;279(2):492-501.
Ref 538479FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (NDA) 016784.
Ref 539532(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 2403).
Ref 542107(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 710).
Ref 542289(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 727).
Ref 544717Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000713)
Ref 544996Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001829)
Ref 545107Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002155)
Ref 545371Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800003055)
Ref 545739Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004459)
Ref 546154Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800006620)
Ref 546254Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800007135)
Ref 546483Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800008464)
Ref 525786Bioorg Med Chem Lett. 2000 May 15;10(10):1133-7.4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with in vivo activity.
Ref 525816J Med Chem. 2000 Jun 15;43(12):2371-81.Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.
Ref 526134J Med Chem. 2001 Sep 13;44(19):3157-65.Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,4-triazolo[1,5-a]quinoxaline-2-carboxylates analogues of TQX-173.
Ref 526787J Med Chem. 1992 Dec 11;35(25):4720-6.Bioisosteric replacement of the alpha-amino carboxylic acid functionality in 2-amino-5-phosphonopentanoic acid yields unique 3,4-diamino-3-cyclobutene-1,2-dione containing NMDA antagonists.
Ref 527036Bioorg Med Chem Lett. 2004 May 3;14(9):2345-9.3-hydroxy-quinazoline-2,4-dione as a useful scaffold to obtain selective Gly/NMDA and AMPA receptor antagonists.
Ref 527438J Med Chem. 2005 Feb 24;48(4):995-1018.CoMFA, synthesis, and pharmacological evaluation of (E)-3-(2-carboxy-2-arylvinyl)-4,6-dichloro-1H-indole-2-carboxylic acids: 3-[2-(3-aminophenyl)-2-carboxyvinyl]-4,6-dichloro-1H-indole-2-carboxylic acid, a potent selective glycine-site NMDA receptor antagonist.
Ref 527496J Med Chem. 2005 Apr 7;48(7):2627-37.Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists.
Ref 527787Bioorg Med Chem Lett. 2005 Dec 15;15(24):5439-41. Epub 2005 Oct 5.Indole-2-carboxamidines as novel NR2B selective NMDA receptor antagonists.
Ref 527903Bioorg Med Chem Lett. 2006 Mar 1;16(5):1392-6.New Gly-Pro-Glu (GPE) analogues: expedite solid-phase synthesis and biological activity.
Ref 527994J Med Chem. 2006 Feb 9;49(3):864-71.Synthesis of thieno[2,3-b]pyridinones acting as cytoprotectants and as inhibitors of [3H]glycine binding to the N-methyl-D-aspartate (NMDA) receptor.
Ref 528006Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J Neurosci. 2006 Feb 1;26(5):1331-3.
Ref 528098Bioorg Med Chem Lett. 2006 Jun 1;16(11):2837-41. Epub 2006 Mar 24.Polyamines and the NMDA receptor: modifying intrinsic activities with aromatic substituents.
Ref 528176Bioorg Med Chem Lett. 2006 Jul 1;16(13):3396-400. Epub 2006 May 2.The neuroprotective activity of GPE tripeptide analogues does not correlate with glutamate receptor binding affinity.
Ref 528453J Med Chem. 2006 Oct 5;49(20):6015-26.Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Synthesis, pharmacological, and molecular modeling studies.
Ref 529118J Biol Chem. 2007 Dec 21;282(51):36905-13. Epub 2007 Oct 25.Novel conantokins from Conus parius venom are specific antagonists of N-methyl-D-aspartate receptors.
Ref 529309J Med Chem. 1991 Apr;34(4):1243-52.Kynurenic acid derivatives. Structure-activity relationships for excitatory amino acid antagonism and identification of potent and selective antagonists at the glycine site on the N-methyl-D-aspartate receptor.
Ref 530824J Med Chem. 2010 May 13;53(9):3611-7.Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.
Ref 531421J Med Chem. 1990 Nov;33(11):2944-6.3-(2-carboxyindol-3-yl)propionic acid derivatives: antagonists of the strychnine-insensitive glycine receptor associated with the N-methyl-D-aspartate receptor complex.
Ref 531531J Med Chem. 1990 Oct;33(10):2772-7.2,4-Dihydro-3H-1,2,4-triazol-3-ones as anticonvulsant agents.
Ref 531892Subunit-selective allosteric inhibition of glycine binding to NMDA receptors. J Neurosci. 2012 May 2;32(18):6197-208.
Ref 533067J Med Chem. 1989 Sep;32(9):2171-8.4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors, and anticonvulsant activity.
Ref 533655J Med Chem. 1995 Jun 23;38(13):2483-9.Synthesis and evaluation of 6,11-ethanohexahydrobenzo[b]quinolizidines: a new class of noncompetitive N-methyl-D-aspartate antagonists.
Ref 534270J Med Chem. 1996 Nov 8;39(23):4643-53.Analogs of 3-hydroxy-1H-1-benzazepine-2,5-dione: structure-activity relationship at N-methyl-D-aspartate receptor glycine sites.
Ref 534286J Med Chem. 1996 Nov 22;39(24):4844-52.Synthesis and biological activity of conformationally restricted analogs of milnacipran: (1S,2R)-1-phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, an efficient noncompetitive N-methyl-D-aspartic acid receptor antagonist.
Ref 534504J Med Chem. 1997 Oct 24;40(22):3679-86.5-(N-oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: novel, systemically active and broad spectrum antagonists for NMDA/glycine, AMPA, and kainate receptors.
Ref 534685J Med Chem. 1998 Aug 13;41(17):3298-302.Synthesis and pharmacological evaluation of N,N'-diarylguanidines as potent sodium channel blockers and anticonvulsant agents.
Ref 534696J Med Chem. 1998 Aug 27;41(18):3499-506.Structure-activity relationships for a series of bis(phenylalkyl)amines: potent subtype-selective inhibitors of N-methyl-D-aspartate receptors.
Ref 534895Differing effects of N-methyl-D-aspartate receptor subtype selective antagonists on dyskinesias in levodopa-treated 1-methyl-4-phenyl-tetrahydropyridine monkeys. J Pharmacol Exp Ther. 1999 Sep;290(3):1034-40.
Ref 537546Glycine transport inhibitors for the treatment of schizophrenia: Symptom and disease modification. Curr Opin Drug Discov Devel. 2009 Jul;12(4):468-78.
Ref 543837(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 456).
Ref 551249Amino acid bioisosteres: design of 2-quinolone derivatives as glycine-site N-methyl-D-aspartate receptor antagonists, Bioorg. Med. Chem. Lett. 3(2):299-304 (1993).
Ref 5513123-Hydroxy-quinolin-2-ones: Inhibitors of [3H]-glycine binding to the site associated with the NMDA receptor, Bioorg. Med. Chem. Lett. 6(5):499-504 (1996).
Ref 551400The binding of [3H]thienyl cyclohexylpiperidine ([3H]<span class="caps">TCP</span>) to the <span class="caps">NMDA</span>-phencyclidine receptor complex. Neuropharmacology. 1989 Jan;28(1):1-7.

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