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 [525248]
Inhibitor (2E,4S)-4-ammoniopent-2-enoate Drug Info [533514]
(4R)-4-ammoniopentanoate Drug Info [533514]
(4S)-4-ammoniopentanoate Drug Info [533514]
3-(benzyloxy)-9H-pyrido[3,4-b]indole Drug Info [531188]
3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole Drug Info [531188]
3-(isopentyloxy)-9H-pyrido[3,4-b]indole Drug Info [531188]
3-butoxy-9H-pyrido[3,4-b]indole Drug Info [531188]
3-ethoxy-9H-pyrido[3,4-b]indole Drug Info [531188]
3-isobutoxy-9H-pyrido[3,4-b]indole Drug Info [531188]
3-propoxy-9H-pyrido[3,4-b]indole Drug Info [531188]
5-[(1R)-1-ammonioethyl]isoxazol-3-olate Drug Info [533514]
5-[(1S)-1-ammonioethyl]isoxazol-3-olate Drug Info [533514]
AMENTOFLAVONE Drug Info [526653]
Barbituric acid derivative Drug Info [551407]
Beta-Carboline-3-carboxylic acid t-butyl ester Drug Info [531188]
CI-218872 Drug Info [531188]
Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [531188]
Ethyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [531188]
GAMMA-AMINO-BUTANOIC ACID Drug Info [533580]
L-655708 Drug Info [527005]
Ro-151310 Drug Info [531044]
Ro-154513 Drug Info [534122]
Ro-4938581 Drug Info [530391]
Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [531188]
Modulator (allosteric modulator) alpha3IA Drug Info [543811]
alpha5IA Drug Info [543811]
DMCM Drug Info [543811]
RY024 Drug Info [543811]
tetrahydrodeoxycorticosterone Drug Info [543811]
TP003 Drug Info [543811]
[11C]flumazenil Drug Info [543811]
[18F]fluoroethylflumazenil Drug Info [543811]
[3H]CGS8216 Drug Info [543811]
[3H]L655708 Drug Info [543811]
Agonist HT-2678 Drug Info [543811]
isonipecotic acid Drug Info [543811]
piperidine-4-sulphonic acid Drug Info [543811]
RG-1662 Drug Info [551418]
[3H]muscimol Drug Info [543811]
Blocker (channel blocker) TBPS Drug Info [543811]
[35S]TBPS Drug Info [543811]
Modulator [3H]RY80 Drug Info [534498]
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 525248ClinicalTrials.gov (NCT02484703) A Study of RG1662 in Down Syndrome Among Children 6 to 11 Years of Age.
Ref 526653Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4.Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors.
Ref 527005J 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 530391Bioorg 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 531044Bioorg Med Chem. 2010 Nov 15;18(22):7731-8. Epub 2010 Jun 1.The GABA(A) receptor as a target for photochromic molecules.
Ref 531188Bioorg 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 533514J Med Chem. 1981 Dec;24(12):1377-83.gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects.
Ref 533580J Med Chem. 1980 Jun;23(6):702-4.New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide.
Ref 534122J 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 534498[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.
Ref 543811(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 551407Whiting 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 551418RG1662, 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.

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