Target Information
| Target General Information | Top | |||||
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| Target ID |
T51452
(Former ID: TTDR01177)
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| Target Name |
GABA(A) receptor alpha-2 (GABRA2)
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| Synonyms |
GABRA2; GABA-A receptor alpha 2; GABA(A)Gamma-aminobutyric-acid receptor alpha-2 subunit precursor receptor
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| Gene Name |
GABRA2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Intentional self-harm [ICD-11: PC91] | |||||
| 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.
Click to Show/Hide
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| BioChemical Class |
Neurotransmitter receptor
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| UniProt ID | ||||||
| Sequence |
MKTKLNIYNMQFLLFVFLVWDPARLVLANIQEDEAKNNITIFTRILDRLLDGYDNRLRPG
LGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQKWKDERLKFKGPMNILRLNNLMASK IWTPDTFFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSC PLKFGSYAYTTSEVTYIWTYNASDSVQVAPDGSRLNQYDLLGQSIGKETIKSSTGEYTVM TAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKSVVNDKKKEKASV MIQNNAYAVAVANYAPNLSKDPVLSTISKSATTPEPNKKPENKPAEAKKTFNSVSKIDRM SRIVFPVLFGTFNLVYWATYLNREPVLGVSP Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T29GRI | |||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Flumazenil | Drug Info | Approved | Benzodiazepine overdose | [2], [3] | |
| Clinical Trial Drug(s) | [+] 1 Clinical Trial Drugs | + | ||||
| 1 | GSK683699 | Drug Info | Phase 2 | Inflammatory bowel disease | [4] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | PF-4480682 | Drug Info | Discontinued in Phase 2 | Neuropathic pain | [5] | |
| 2 | CGS-17867A | Drug Info | Terminated | Alcohol dependence | [6] | |
| Mode of Action | [+] 5 Modes of Action | + | ||||
| Modulator (allosteric modulator) | [+] 8 Modulator (allosteric modulator) drugs | + | ||||
| 1 | Flumazenil | Drug Info | [1] | |||
| 2 | alpha3IA | Drug Info | [1] | |||
| 3 | alpha5IA | Drug Info | [1] | |||
| 4 | DMCM | Drug Info | [1] | |||
| 5 | tetrahydrodeoxycorticosterone | Drug Info | [1] | |||
| 6 | TP003 | Drug Info | [1] | |||
| 7 | [18F]fluoroethylflumazenil | Drug Info | [1] | |||
| 8 | [3H]CGS8216 | Drug Info | [1] | |||
| Inhibitor | [+] 26 Inhibitor drugs | + | ||||
| 1 | GSK683699 | Drug Info | [7] | |||
| 2 | CGS-17867A | Drug Info | [9] | |||
| 3 | (2E,4S)-4-ammoniopent-2-enoate | Drug Info | [10] | |||
| 4 | (4R)-4-ammoniopentanoate | Drug Info | [10] | |||
| 5 | (4S)-4-ammoniopentanoate | Drug Info | [10] | |||
| 6 | 3-(3-Methyl-butoxy)-9H-beta-carboline | Drug Info | [11] | |||
| 7 | 3-(benzyloxy)-9H-pyrido[3,4-b]indole | Drug Info | [11] | |||
| 8 | 3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole | Drug Info | [11] | |||
| 9 | 3-Butoxy-9H-beta-carboline | Drug Info | [11] | |||
| 10 | 3-Ethoxy-9H-beta-carboline | Drug Info | [11], [12] | |||
| 11 | 3-Isobutoxy-9H-beta-carboline | Drug Info | [11] | |||
| 12 | 3-Propoxy-9H-beta-carboline | Drug Info | [11] | |||
| 13 | 5-[(1R)-1-ammonioethyl]isoxazol-3-olate | Drug Info | [10] | |||
| 14 | 5-[(1S)-1-ammonioethyl]isoxazol-3-olate | Drug Info | [10] | |||
| 15 | 9H-beta-Carboline-3-carboxylic acid ethyl ester | Drug Info | [11] | |||
| 16 | AMENTOFLAVONE | Drug Info | [13] | |||
| 17 | Barbituric acid derivative | Drug Info | [14] | |||
| 18 | Beta-Carboline-3-carboxylic acid t-butyl ester | Drug Info | [11] | |||
| 19 | CI-218872 | Drug Info | [11] | |||
| 20 | Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate | Drug Info | [11] | |||
| 21 | L-655708 | Drug Info | [15] | |||
| 22 | Ro-15-3505 | Drug Info | [18] | |||
| 23 | Ro-4938581 | Drug Info | [19] | |||
| 24 | RY-066 | Drug Info | [20] | |||
| 25 | Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate | Drug Info | [11] | |||
| 26 | [3H]Ro154513 | Drug Info | [21] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | PF-4480682 | Drug Info | [8] | |||
| 2 | MK-0343 | Drug Info | [16] | |||
| 3 | MRK016 | Drug Info | [17] | |||
| Agonist | [+] 2 Agonist drugs | + | ||||
| 1 | isonipecotic acid | Drug Info | [1] | |||
| 2 | piperidine-4-sulphonic acid | Drug Info | [1] | |||
| Blocker (channel blocker) | [+] 2 Blocker (channel blocker) drugs | + | ||||
| 1 | TBPS | Drug Info | [1] | |||
| 2 | [35S]TBPS | Drug Info | [1] | |||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
| 1 | Neuroactive ligand-receptor interaction | |||||
| 2 | Retrograde endocannabinoid signaling | |||||
| 3 | GABAergic synapse | |||||
| 4 | Morphine addiction | |||||
| 5 | Nicotine addiction | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Ligand-gated ion channel transport | |||||
| 2 | GABA A receptor activation | |||||
| WikiPathways | [+] 2 WikiPathways | + | ||||
| 1 | Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell | |||||
| 2 | Iron uptake and transport | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | 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: 405). | |||||
| REF 2 | 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. (Ligand id: 4192). | |||||
| REF 3 | ClinicalTrials.gov (NCT00997087) A Randomized, Double-Blind, Placebo-Controlled Trial of Flumazenil for the Treatment of Obsessive Compulsive Disorder. U.S. National Institutes of Health. | |||||
| REF 4 | Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59. | |||||
| REF 5 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800025530) | |||||
| REF 6 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000696) | |||||
| REF 7 | New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide. J Med Chem. 1980 Jun;23(6):702-4. | |||||
| REF 8 | WO patent application no. 2014,1515,17, Methods of improving microvascular integrity. | |||||
| REF 9 | 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine binding site ligands on the GABAA receptor. Bioorg Med Chem Lett. 2004 Jul 5;14(13):3441-4. | |||||
| REF 10 | gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects. J Med Chem. 1981 Dec;24(12):1377-83. | |||||
| REF 11 | Design, synthesis, and subtype selectivity of 3,6-disubstituted -carbolines at Bz/GABA(A)ergic receptors. SAR and studies directed toward agents f... Bioorg Med Chem. 2010 Nov 1;18(21):7548-64. | |||||
| REF 12 | Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) a... J Med Chem. 1998 Jul 2;41(14):2537-52. | |||||
| REF 13 | Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4. | |||||
| REF 14 | Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57. | |||||
| REF 15 | 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor li... J Med Chem. 2004 Mar 25;47(7):1807-22. | |||||
| REF 16 | Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABA(A) alpha2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers.J Psychopharmacol.2008 Jan;22(1):24-32. | |||||
| REF 17 | A randomized clinical trial of MK-0777 for the treatment of cognitive impairments in people with schizophrenia.Biol Psychiatry.2011 Mar 1;69(5):442-9. | |||||
| REF 18 | The GABA(A) receptor as a target for photochromic molecules. Bioorg Med Chem. 2010 Nov 15;18(22):7731-8. | |||||
| REF 19 | The discovery and unique pharmacological profile of RO4938581 and RO4882224 as potent and selective GABAA alpha5 inverse agonists for the treatment... Bioorg Med Chem Lett. 2009 Oct 15;19(20):5940-4. | |||||
| REF 20 | Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines a... J Med Chem. 1998 Oct 8;41(21):4130-42. | |||||
| REF 21 | Synthesis and pharmacological properties of novel 8-substituted imidazobenzodiazepines: high-affinity, selective probes for alpha 5-containing GABA... J Med Chem. 1996 Apr 26;39(9):1928-34. | |||||
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