Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT0MYE2)

• DTT Name: Glutamate receptor ionotropic kainate 1 (GRIK1)
• Synonyms: Glutamate receptor 5; GluR5 kainate receptor; GluR5; GluR-5; GRIK1; Excitatory amino acid receptor 3; EAA3
• Gene Name: GRIK1
• DTT Type: Successful target; [1]
• Related Disease:
  Epilepsy/seizure [ICD-11: 8A61-8A6Z]
  Substance abuse [ICD-11: 6C40]
• BioChemical Class: Glutamate-gated ion channel
• UniProt ID: GRIK1_HUMAN
• TTD ID: T73495
• Sequence:
  MEHGTLLAQPGLWTRDTSWALLYFLCYILPQTAPQVLRIGGIFETVENEPVNVEELAFKF
  AVTSINRNRTLMPNTTLTYDIQRINLFDSFEASRRACDQLALGVAALFGPSHSSSVSAVQ
  SICNALEVPHIQTRWKHPSVDNKDLFYINLYPDYAAISRAILDLVLYYNWKTVTVVYEDS
  TGLIRLQELIKAPSRYNIKIKIRQLPSGNKDAKPLLKEMKKGKEFYVIFDCSHETAAEIL
  KQILFMGMMTEYYHYFFTTLDLFALDLELYRYSGVNMTGFRLLNIDNPHVSSIIEKWSME
  RLQAPPRPETGLLDGMMTTEAALMYDAVYMVAIASHRASQLTVSSLQCHRHKPWRLGPRF
  MNLIKEARWDGLTGHITFNKTNGLRKDFDLDIISLKEEGTEKAAGEVSKHLYKVWKKIGI
  WNSNSGLNMTDSNKDKSSNITDSLANRTLIVTTILEEPYVMYRKSDKPLYGNDRFEGYCL
  DLLKELSNILGFIYDVKLVPDGKYGAQNDKGEWNGMVKELIDHRADLAVAPLTITYVREK
  VIDFSKPFMTLGISILYRKPNGTNPGVFSFLNPLSPDIWMYVLLACLGVSCVLFVIARFT
  PYEWYNPHPCNPDSDVVENNFTLLNSFWFGVGALMQQGSELMPKALSTRIVGGIWWFFTL
  IIISSYTANLAAFLTVERMESPIDSADDLAKQTKIEYGAVRDGSTMTFFKKSKISTYEKM
  WAFMSSRQQTALVRNSDEGIQRVLTTDYALLMESTSIEYVTQRNCNLTQIGGLIDSKGYG
  VGTPIGSPYRDKITIAILQLQEEGKLHMMKEKWWRGNGCPEEDNKEASALGVENIGGIFI
  VLAAGLVLSVFVAIGEFIYKSRKNNDIEQAFCFFYGLQCKQTHPTNSTSGTTLSTDLECG
  KLIREERGIRKQSSVHTV
• Function: Ionotropic glutamate receptor. 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 tothe 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. May be involved in the transmission of light information from the retina to the hypothalamus.
• Reactome Pathway:
  Activation of Ca-permeable Kainate Receptor (R-HSA-451308)
  Activation of Na-permeable kainate receptors (R-HSA-451307)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Topiramate	DM82Z30	Alcohol dependence	6C40.2	Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY293558	DM4N6EK	Pain	MG30-MG3Z	Phase 2	[2]
NS 1209	DM9EFH0	Epilepsy	8A60-8A68	Phase 2	[3]
NBQX	DMPHZI5	Neurological disorder	6B60	Phase 1	[4]

1 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	[4]

28 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,4R)-4-(3-Methoxy-3-oxopropyl)glutamic Acid	DMTQF2G	Discovery agent	N.A.	Investigative	[5]
(S)-4-AHCP	DMN9YXL	Discovery agent	N.A.	Investigative	[6]
(S)-5-iodowillardiine	DM1DNRP	Discovery agent	N.A.	Investigative	[6]
2,4-epi-neodysiherbaine	DMZRY0Q	Discovery agent	N.A.	Investigative	[6]
2-(3-(3-bromophenyl)ureido)-4-chlorobenzoic acid	DMRX4HM	Discovery agent	N.A.	Investigative	[7]
2-(3-bromobenzoylamino)-4-chlorobenzoic acid	DMX4DUR	Discovery agent	N.A.	Investigative	[7]
2-AMINO-3-(4-HYDROXY-1,2,5-OXADIAZOL-3-YL)PROPIONIC ACID (STRUCTURAL MIX)	DMQKGL3	Discovery agent	N.A.	Investigative	[8]
2S,4R-4-METHYLGLUTAMATE	DMNU1YR	Discovery agent	N.A.	Investigative	[5]
8-deoxy-neodysiherbaine	DM7YW3B	Discovery agent	N.A.	Investigative	[6]
ACET	DMB2463	Discovery agent	N.A.	Investigative	[6]
ATPA	DM2DAFS	Discovery agent	N.A.	Investigative	[6]
DIHYDROKAINATE	DM9NO6F	Discovery agent	N.A.	Investigative	[9]
DNQX	DMQXPA5	Discovery agent	N.A.	Investigative	[10]
domoic acid	DMYPVO0	Discovery agent	N.A.	Investigative	[6]
Domoric acid	DMOJF6D	Discovery agent	N.A.	Investigative	[5]
dysiherbaine	DM0EBAF	Discovery agent	N.A.	Investigative	[6]
LY339434	DM8S7AO	Discovery agent	N.A.	Investigative	[6]
LY382884	DMWKYFO	Discovery agent	N.A.	Investigative	[6]
LY466195	DM97NBO	Discovery agent	N.A.	Investigative	[6]
MSVIII-19	DM4KM91	Discovery agent	N.A.	Investigative	[6]
NS3763	DMVL5KS	Discovery agent	N.A.	Investigative	[6]
S-ATPO	DMJQVAG	Discovery agent	N.A.	Investigative	[11]
SYM2081	DM30WDL	Discovery agent	N.A.	Investigative	[6]
TQX-173	DMZA6X3	Discovery agent	N.A.	Investigative	[12]
UBP-302	DMSJLX0	Discovery agent	N.A.	Investigative	[13]
UBP310	DMVQL3J	Discovery agent	N.A.	Investigative	[6], [14]
[3H]kainate	DMMK7XU	Discovery agent	N.A.	Investigative	[6], [5]
[3H]quisqualate	DMDQBTX	Discovery agent	N.A.	Investigative	[5]

References

• [1] Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.
• [2] Pharmacogenetics of new analgesics. Br J Pharmacol. 2011 Jun;163(3):447-60.
• [3] The efficacy of the AMPA receptor antagonist NS1209 and lidocaine in nerve injury pain: a randomized, double-blind, placebo-controlled, three-way crossover study. Anesth Analg. 2009 Apr;108(4):1311-9.
• [4] 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... Bioorg Med Chem Lett. 2000 May 15;10(10):1133-7.
• [5] Chemo-enzymatic synthesis of a series of 2,4-syn-functionalized (S)-glutamate analogues: new insight into the structure-activity relation of ionotr... J Med Chem. 2008 Jul 24;51(14):4093-103.
• [6] 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: 450).
• [7] Bioisosteric modifications of 2-arylureidobenzoic acids: selective noncompetitive antagonists for the homomeric kainate receptor subtype GluR5. J Med Chem. 2004 Dec 30;47(27):6948-57.
• [8] 4-hydroxy-1,2,5-oxadiazol-3-yl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and molecular pharmacological charact... J Med Chem. 2010 May 27;53(10):4110-8.
• [9] Chemo-enzymatic synthesis of (2S,4R)-2-amino-4-(3-(2,2-diphenylethylamino)-3-oxopropyl)pentanedioic acid: a novel selective inhibitor of human exci... J Med Chem. 2008 Jul 24;51(14):4085-92.
• [10] 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.
• [11] 3-Substituted phenylalanines as selective AMPA- and kainate receptor ligands. Bioorg Med Chem. 2009 Sep 1;17(17):6390-401.
• [12] Synthesis, ionotropic glutamate receptor binding affinity, and structure-activity relationships of a new set of 4,5-dihydro-8-heteroaryl-4-oxo-1,2,... J Med Chem. 2001 Sep 13;44(19):3157-65.
• [13] 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.
• [14] Mapping the ligand binding sites of kainate receptors: molecular determinants of subunit-selective binding of the antagonist [3H]UBP310. Mol Pharmacol. 2010 Dec;78(6):1036-45.