Target Information

Target General Infomation
Target ID
T26368
Former ID
TTDR01042
Target Name
Gamma-aminobutyric-acid receptor alpha-5 subunit
Gene Name
GABRA5
Synonyms
GABA-A alpha-5; GABAA alpha 5; GABRA5
Target Type
Clinical Trial
Disease Alzheimer disease [ICD9: 331; ICD10: G30]
Cognitive disorders [ICD9: 290-294, 294.0, 780.09, 780.9, 780.93; ICD10: F01-F07, F04, F05, R41.3]
Function
GABA, the major inhibitory neurotransmitter in the vertebrate brain, mediates neuronal inhibition by binding to the GABA/benzodiazepine receptor and opening an integral chloride channel.
BioChemical Class
Ligand-gated ion channel
Target Validation
T26368
UniProt ID
P31644
Sequence
MDNGMFSGFIMIKNLLLFCISMNLSSHFGFSQMPTSSVKDETNDNITIFTRILDGLLDGY
DNRLRPGLGERITQVRTDIYVTSFGPVSDTEMEYTIDVFFRQSWKDERLRFKGPMQRLPL
NNLLASKIWTPDTFFHNGKKSIAHNMTTPNKLLRLEDDGTLLYTMRLTISAECPMQLEDF
PMDAHACPLKFGSYAYPNSEVVYVWTNGSTKSVVVAEDGSRLNQYHLMGQTVGTENISTS
TGEYTIMTAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTM
TTLSISARNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKKALEAA
KIKKKREVILNKSTNAFTTGKMSHPPNIPKEQTPAGTSNTTSVSVKPSEEKTSESKKTYN
SISKIDKMSRIVFPVLFGTFNLVYWATYLNREPVIKGAASPK
Drugs and Mode of Action
Drug(s) RG-1662 Drug Info Phase 2 Alzheimer disease [1]
Inhibitor (2E,4S)-4-ammoniopent-2-enoate Drug Info [2]
(4R)-4-ammoniopentanoate Drug Info [2]
(4S)-4-ammoniopentanoate Drug Info [2]
3-(benzyloxy)-9H-pyrido[3,4-b]indole Drug Info [3]
3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole Drug Info [3]
3-(isopentyloxy)-9H-pyrido[3,4-b]indole Drug Info [3]
3-butoxy-9H-pyrido[3,4-b]indole Drug Info [3]
3-ethoxy-9H-pyrido[3,4-b]indole Drug Info [3]
3-isobutoxy-9H-pyrido[3,4-b]indole Drug Info [3]
3-propoxy-9H-pyrido[3,4-b]indole Drug Info [3]
5-[(1R)-1-ammonioethyl]isoxazol-3-olate Drug Info [2]
5-[(1S)-1-ammonioethyl]isoxazol-3-olate Drug Info [2]
AMENTOFLAVONE Drug Info [4]
Barbituric acid derivative Drug Info [5]
Beta-Carboline-3-carboxylic acid t-butyl ester Drug Info [3]
CI-218872 Drug Info [3]
Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [3]
Ethyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [3]
GAMMA-AMINO-BUTANOIC ACID Drug Info [6]
L-655708 Drug Info [7]
Ro-151310 Drug Info [8]
Ro-154513 Drug Info [9]
Ro-4938581 Drug Info [10]
Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [3]
Modulator (allosteric modulator) alpha3IA Drug Info [11]
alpha5IA Drug Info [11]
DMCM Drug Info [11]
RY024 Drug Info [11]
tetrahydrodeoxycorticosterone Drug Info [11]
TP003 Drug Info [11]
[11C]flumazenil Drug Info [11]
[18F]fluoroethylflumazenil Drug Info [11]
[3H]CGS8216 Drug Info [11]
[3H]L655708 Drug Info [11]
Agonist HT-2678 Drug Info [11]
isonipecotic acid Drug Info [11]
piperidine-4-sulphonic acid Drug Info [11]
RG-1662 Drug Info [12]
[3H]muscimol Drug Info [11]
Blocker (channel blocker) TBPS Drug Info [11]
[35S]TBPS Drug Info [11]
Modulator [3H]RY80 Drug Info [13]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Retrograde endocannabinoid signaling
GABAergic synapse
Morphine addiction
Nicotine addiction
Reactome Ligand-gated ion channel transport
GABA A receptor activation
WikiPathways Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell
Iron uptake and transport
References
REF 1ClinicalTrials.gov (NCT02484703) A Study of RG1662 in Down Syndrome Among Children 6 to 11 Years of Age.
REF 2J Med Chem. 1981 Dec;24(12):1377-83.gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects.
REF 3Bioorg Med Chem. 2010 Nov 1;18(21):7548-64. Epub 2010 Sep 29.Design, synthesis, and subtype selectivity of 3,6-disubstituted |A-carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents for treatment of alcohol abuse.
REF 4Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4.Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors.
REF 5Whiting PJ: The <span class="caps">GABAA</span> receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
REF 6J Med Chem. 1980 Jun;23(6):702-4.New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide.
REF 7J Med Chem. 2004 Mar 25;47(7):1807-22.3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1.
REF 8Bioorg Med Chem. 2010 Nov 15;18(22):7731-8. Epub 2010 Jun 1.The GABA(A) receptor as a target for photochromic molecules.
REF 9J Med Chem. 1996 Apr 26;39(9):1928-34.Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for alpha 5-containing GABAA receptors.
REF 10Bioorg Med Chem Lett. 2009 Oct 15;19(20):5940-4. Epub 2009 Aug 15.The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment of cognitive dysfunction.
REF 11(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: 408).
REF 12RG1662, a Selective GABAA alpha5 Receptor Negative Allosteric Modulator, Increases Gamma Power in Young Adults with Down Syndrome. Neurology April 6, 2015 vol. 84 no. 14.
REF 13[3H]RY 80: A high-affinity, selective ligand for gamma-aminobutyric acidA receptors containing alpha-5 subunits. J Pharmacol Exp Ther. 1997 Nov;283(2):488-93.

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