Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTVPQTF)

• DTT Name: Glutamate receptor AMPA 1 (GRIA1)
• Synonyms: Glutamate receptor ionotropic, AMPA 1; Glutamate receptor 1; GluR-K1; GluR-A; GluR-1; GluA1; GLUR1; GLUH1; AMPA-selective glutamate receptor 1
• Gene Name: GRIA1
• DTT Type: Successful target; [1]
• BioChemical Class: Glutamate-gated ion channel
• UniProt ID: GRIA1_HUMAN
• TTD ID: T33584
• Sequence:
  MQHIFAFFCTGFLGAVVGANFPNNIQIGGLFPNQQSQEHAAFRFALSQLTEPPKLLPQID
  IVNISDSFEMTYRFCSQFSKGVYAIFGFYERRTVNMLTSFCGALHVCFITPSFPVDTSNQ
  FVLQLRPELQDALISIIDHYKWQKFVYIYDADRGLSVLQKVLDTAAEKNWQVTAVNILTT
  TEEGYRMLFQDLEKKKERLVVVDCESERLNAILGQIIKLEKNGIGYHYILANLGFMDIDL
  NKFKESGANVTGFQLVNYTDTIPAKIMQQWKNSDARDHTRVDWKRPKYTSALTYDGVKVM
  AEAFQSLRRQRIDISRRGNAGDCLANPAVPWGQGIDIQRALQQVRFEGLTGNVQFNEKGR
  RTNYTLHVIEMKHDGIRKIGYWNEDDKFVPAATDAQAGGDNSSVQNRTYIVTTILEDPYV
  MLKKNANQFEGNDRYEGYCVELAAEIAKHVGYSYRLEIVSDGKYGARDPDTKAWNGMVGE
  LVYGRADVAVAPLTITLVREEVIDFSKPFMSLGISIMIKKPQKSKPGVFSFLDPLAYEIW
  MCIVFAYIGVSVVLFLVSRFSPYEWHSEEFEEGRDQTTSDQSNEFGIFNSLWFSLGAFMQ
  QGCDISPRSLSGRIVGGVWWFFTLIIISSYTANLAAFLTVERMVSPIESAEDLAKQTEIA
  YGTLEAGSTKEFFRRSKIAVFEKMWTYMKSAEPSVFVRTTEEGMIRVRKSKGKYAYLLES
  TMNEYIEQRKPCDTMKVGGNLDSKGYGIATPKGSALRNPVNLAVLKLNEQGLLDKLKNKW
  WYDKGECGSGGGDSKDKTSALSLSNVAGVFYILIGGLGLAMLVALIEFCYKSRSESKRMK
  GFCLIPQQSINEAIRTSTLPRNSGAGASSGGSGENGRVVSHDFPKSMQSIPCMSHSSGMP
  LGATGL
• Function: L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate. Ionotropic glutamate receptor.
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Circadian entrainment (hsa04713)
  Long-term potentiation (hsa04720)
  Retrograde endocannabinoid signaling (hsa04723)
  Glutamatergic synapse (hsa04724)
  Dopaminergic synapse (hsa04728)
  Long-term depression (hsa04730)
  Amyotrophic lateral sclerosis (ALS) (hsa05014)
  Amphetamine addiction (hsa05031)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  Trafficking of AMPA receptors (R-HSA-399719)
  Trafficking of GluR2-containing AMPA receptors (R-HSA-416993)
  Unblocking of NMDA receptor, glutamate binding and activation (R-HSA-438066)
  Cargo concentration in the ER (R-HSA-5694530)
  COPII (Coat Protein 2) Mediated Vesicle Transport (R-HSA-204005)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
E-2007	DMJDYNQ	Diabetic neuropathy	8C0Z	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
NBQX	DMPHZI5	Neurological disorder	6B60	Phase 1	[2]

6 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
YM-90K	DMWRT4L	Convulsion	8A68.Z	Discontinued in Phase 2	[3]
Farampator	DM76GRQ	Major depressive disorder	6A70.3	Discontinued in Phase 1	[4]
GYKI-52466	DM3YG5P	Alzheimer disease	8A20	Terminated	[5]
GYKI-53655	DMC0JN8	N. A.	N. A.	Terminated	[6]
SORETOLIDE	DMTDLHG	Convulsion	8A68.Z	Terminated	[7]
Zonampanel	DM70HZD	N. A.	N. A.	Terminated	[3]

15 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(S)-5-fluorowillardiine	DMCIZ7P	Discovery agent	N.A.	Investigative	[8]
(S)-AMPA	DMNJSTM	Discovery agent	N.A.	Investigative	[9]
(S)-WILLARDIINE	DMXQ47M	Discovery agent	N.A.	Investigative	[10]
7-chloro-3-hydroxyquinazoline-2,4-dione	DM3OMLU	Discovery agent	N.A.	Investigative	[2]
Argiotoxin-636	DMQ1DWU	Discovery agent	N.A.	Investigative	[11]
ATPO	DMXLS78	Discovery agent	N.A.	Investigative	[8]
DNQX	DMQXPA5	Discovery agent	N.A.	Investigative	[12]
joro toxin	DMYBJ4K	Discovery agent	N.A.	Investigative	[8]
N-(4-hydroxyphenylpropanyl)-spermine	DM4QR2C	Discovery agent	N.A.	Investigative	[11]
Philanthotoxin-343	DMP3MOC	Discovery agent	N.A.	Investigative	[11]
Piriqualone	DM7XTHD	Discovery agent	N.A.	Investigative	[13]
RPR-118723	DMLDWCB	Discovery agent	N.A.	Investigative	[14]
[3H]AMPA	DMLF7SG	N. A.	N. A.	Investigative	[8]
[3H]CNQX	DMIFKUX	Discovery agent	N.A.	Investigative	[8]
[3H]kainate	DMMK7XU	Discovery agent	N.A.	Investigative	[15]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Alzheimer's disease	8A00.0	Entorhinal cortex	1.46E-06	-0.63	-0.78
Schizophrenia	6A20	Pre-frontal cortex	5.12E-02	-0.4	-0.21
Schizophrenia	6A20	Superior temporal cortex	2.97E-01	-4.20E-03	-0.01

References

• [1] Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.
• [2] Structural investigation of the 7-chloro-3-hydroxy-1H-quinazoline-2,4-dione scaffold to obtain AMPA and kainate receptor selective antagonists. Syn... J Med Chem. 2006 Oct 5;49(20):6015-26.
• [3] Synthesis and AMPA receptor antagonistic activity of a novel 7-imidazolyl-6-trifluoromethyl quinoxalinecarboxylic acid with a substituted phenyl gr... Bioorg Med Chem Lett. 2004 Oct 18;14(20):5107-11.
• [4] The pipeline and future of drug development in schizophrenia. Mol Psychiatry. 2007 Oct;12(10):904-22.
• [5] New 7,8-ethylenedioxy-2,3-benzodiazepines as noncompetitive AMPA receptor antagonists. Bioorg Med Chem Lett. 2006 Jan 1;16(1):167-70.
• [6] Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor. J Med Chem. 1996 Jan 19;39(2):343-6.
• [7] Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist. Acta Neurol Scand Suppl. 2013;(197):19-24.
• [8] URL: 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: 444).
• [9] Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors. J Med Chem. 2005 Dec 1;48(24):7867-81.
• [10] Synthesis of willardiine and 6-azawillardiine analogs: pharmacological characterization on cloned homomeric human AMPA and kainate receptor subtypes. J Med Chem. 1997 Oct 24;40(22):3645-50.
• [11] Developing a complete pharmacology for AMPA receptors: a perspective on subtype-selective ligands. Bioorg Med Chem. 2010 Feb 15;18(4):1381-7.
• [12] Synthesis of chiral 1-(2'-amino-2'-carboxyethyl)-1,4-dihydro-6,7-quinoxaline-2,3-diones: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate recep... J Med Chem. 1996 Oct 25;39(22):4430-8.
• [13] Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antag... Bioorg Med Chem Lett. 2001 Jan 22;11(2):177-81.
• [14] 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. J Med Chem. 2000 Jun 15;43(12):2371-81.
• [15] 1H-cyclopentapyrimidine-2,4(1H,3H)-dione-related ionotropic glutamate receptors ligands. structure-activity relationships and identification of pot... J Med Chem. 2008 Oct 23;51(20):6614-8.