Target Information

Target General Infomation
Target ID
T08910
Former ID
TTDS00428
Target Name
Gamma-aminobutyric acid receptor subunit gamma-2
Gene Name
GABRG2
Synonyms
GABA(A) receptor subunit gamma-2; GABRG2
Target Type
Successful
Disease Alcohol use disorders [ICD9: 303; ICD10: F10.2]
Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Epileptic seizures [ICD9: 345.9, 780.3; ICD10: G40, P90, R56]
Inflammation [ICD10: E08-E13, E10.2, E11, E11.2, E13.2, I73.9, I80-I82, N00-N29, G89]
Muscle spasm [ICD10: M62.838]
Premenstrual syndrome [ICD10: N94.3]
Function
Component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the vertebrate brain. Functions also as histamine receptor and mediates cellular responsesto histamine. Functions as receptor for diazepines and various anesthetics, such as pentobarbital; these are bound at a separate allosteric effector binding site. Functions as ligand- gated chloride channel.
BioChemical Class
Ligand-gated ion channel
Target Validation
T08910
UniProt ID
P18507
Sequence
MSSPNIWSTGSSVYSTPVFSQKMTVWILLLLSLYPGFTSQKSDDDYEDYASNKTWVLTPK
VPEGDVTVILNNLLEGYDNKLRPDIGVKPTLIHTDMYVNSIGPVNAINMEYTIDIFFAQT
WYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRMLRIWNDGRVLY
TLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKRSSVEVGDTRSWRLYQF
SFVGLRNTTEVVKTTSGDYVVMSVYFDLSRRMGYFTIQTYIPCTLIVVLSWVSFWINKDA
VPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFSALVEYGTLHYFV
SNRKPSKDKDKKKKNPAPTIDIRPRSATIQMNNATHLQERDEEYGYECLDGKDCASFFCC
FEDCRTGAWRHGRIHIRIAKMDSYARIFFPTAFCLFNLVYWVSYLYL
Drugs and Mode of Action
Drug(s) THIOCOLCHICOSIDE Drug Info Approved Muscle spasm [1]
ZK-93423 Drug Info Phase 3 Epileptic seizures [2], [3]
ALLOPREGNANOLONE Drug Info Phase 2 Discovery agent [4], [5]
ELTANOLONE Drug Info Discontinued in Phase 3 Premenstrual syndrome [6]
U-78875 Drug Info Discontinued in Phase 1 Anxiety disorder [7]
CGS-17867A Drug Info Terminated Alcohol use disorders [8]
CGS-9896 Drug Info Terminated Discovery agent [9]
Inhibitor (2E,4S)-4-ammoniopent-2-enoate Drug Info [10]
(4R)-4-ammoniopentanoate Drug Info [10]
(4S)-4-ammoniopentanoate Drug Info [10]
(9-Benzyl-9H-purin-6-yl)-cyclopropyl-amine Drug Info [11]
(beta-CCE)9H-beta-Carboline-3-carboxylic acid Drug Info [12]
1,1-Dimethyl-5-oxa-spiro[2.4]heptan-4-one Drug Info [13]
1,3-Diphenyl-1H-chromeno[4,3-c]pyrazol-4-one Drug Info [14]
1-(4-chlorophenyl)-4-phenyl-1H-imidazole Drug Info [15]
1-Methyl-5-oxa-spiro[2.4]heptan-4-one Drug Info [13]
2-(1H-Indol-3-yl)-2-oxo-N-phenethyl-acetamide Drug Info [12]
2-(4-chlorophenyl)-5-phenyl-4-isoxazolin-3-one Drug Info [15]
2-(9-Benzyl-9H-purin-6-ylamino)-ethanol Drug Info [11]
2-Isoxazol-5-yl-3H-imidazo[4,5-c]quinoline Drug Info [16]
2-Oxa-spiro[4.4]nonan-1-one Drug Info [13]
2-Thiophen-2-yl-3H-imidazo[4,5-c]quinoline Drug Info [16]
3,3-Diethyl-dihydro-furan-2-one Drug Info [13]
3,3-Diisopropyl-dihydro-furan-2-one Drug Info [13]
3-(benzyloxy)-9H-pyrido[3,4-b]indole Drug Info [17]
3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole Drug Info [17]
3-(isopentyloxy)-9H-pyrido[3,4-b]indole Drug Info [17]
3-amino-3-demethoxythiocolchicine Drug Info [18]
3-butoxy-9H-pyrido[3,4-b]indole Drug Info [17]
3-butoxycarbonyl-4-quinolone Drug Info [19]
3-butoxycarbonyl-6-ethyl-4-quinolone Drug Info [19]
3-butylaminocarbonyl-6-ethyl-4-quinolone Drug Info [19]
3-carboxy-6-ethyl-4-quinolone Drug Info [19]
3-cyclopentoxycarbonyl-6-ethyl-4-quinolone Drug Info [19]
3-demethoxy-3-D-lyxopyranosylaminothiocolchicine Drug Info [18]
3-demethoxy-3-D-mannopyranosylaminothiocolchicine Drug Info [18]
3-demethoxy-3-D-xylopyranosylaminothiocolchicine Drug Info [18]
3-demethoxy-3-L-fucopyranosylaminothiocolchicine Drug Info [18]
3-demethoxy-3D-glucopyranosylaminothiocolchicine Drug Info [18]
3-Ethoxy-9H-beta-carboline Drug Info [20]
3-ethoxy-9H-pyrido[3,4-b]indole Drug Info [17]
3-ethoxycarbonyl-4-quinolone Drug Info [19]
3-ethoxycarbonyl-6-ethyl-2-methyl-4-quinolone Drug Info [19]
3-ethoxycarbonyl-6-propyl-4-quinolone Drug Info [19]
3-Ethyl-3-isopropyl-dihydro-furan-2-one Drug Info [13]
3-Ethyl-3-methyl-dihydro-furan-2-one Drug Info [13]
3-isobutoxy-9H-pyrido[3,4-b]indole Drug Info [17]
3-Isopropyl-3-methyl-dihydro-furan-2-one Drug Info [13]
3-Isothiocyanato-9H-beta-carboline Drug Info [21]
3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one Drug Info [14]
3-Methyl-2-phenyl-2H-chromeno[4,3-c]pyrazol-4-one Drug Info [14]
3-Methyl-9H-beta-carboline Drug Info [22]
3-propoxy-9H-pyrido[3,4-b]indole Drug Info [17]
3-tert-Butyl-3-ethyl-dihydro-furan-2-one Drug Info [13]
4-(2-aminoethyl)-1,2,5-oxadiazol-3-ol Drug Info [23]
4-(4-chlorophenyl)-1-pyrid-2-yl-pyrazole Drug Info [15]
4-(biphenyl-3-yl)-5-(piperidin-4-yl)isoxazol-3-ol Drug Info [24]
4-benzyl-5-(4-piperidyl)isothiazol-3-ol Drug Info [25]
4-Benzyl-5-piperidin-4-yl-isoxazol-3-ol Drug Info [26]
4-Methyl-5-(4-piperidyl)isothiazol-3-ol Drug Info [25]
4-Naphthalen-1-yl-5-piperidin-4-yl-isoxazol-3-ol Drug Info [26]
4-Naphthalen-2-yl-5-piperidin-4-yl-isoxazol-3-ol Drug Info [26]
4-Phenyl-5-piperidin-4-yl-isoxazol-3-ol Drug Info [26]
5-(4-piperidyl)-4-propylisothiazol-3-ol Drug Info [25]
5-(piperidin-4-yl)isothiazol-3-ol Drug Info [25]
5-(piperidin-4-yl)isoxazol-3-ol Drug Info [26]
5-[(1R)-1-ammonioethyl]isoxazol-3-olate Drug Info [10]
5-[(1S)-1-ammonioethyl]isoxazol-3-olate Drug Info [10]
6,6-Dimethyl-2-oxa-spiro[4.4]nonan-1-one Drug Info [13]
6,9-Dimethyl-2-oxa-spiro[4.4]nonan-1-one Drug Info [13]
6-benzyl-3-ethoxycarbonyl-4-quinolone Drug Info [19]
6-benzyl-3-propoxycarbonyl-4-quinolone Drug Info [19]
6-benzyl-3-propylaminocarbonyl-4-quinolone Drug Info [19]
6-bromo-3-ethoxycarbonyl-2-methyl-4-quinolone Drug Info [19]
6-bromo-3-ethoxycarbonyl-4-quinolone Drug Info [19]
6-ethyl-3-(2-ethylbutoxycarbonyl)-4-quinolone Drug Info [19]
6-ethyl-3-(2-methylbutoxycarbonyl)-4-quinolone Drug Info [19]
6-ethyl-3-(3-methylbutoxycarbonyl)-4-quinolone Drug Info [19]
6-ethyl-3-(3-pentoxycarbonyl)-4-quinolone Drug Info [19]
6-ethyl-3-i-propoxycarbonyl-4-quinolone Drug Info [19]
6-ethyl-3-pentoxycarbonyl-4-quinolone Drug Info [19]
6-ethyl-3-propoxycarbonyl-4-quinolone Drug Info [19]
6-ethyl-3-propylaminocarbonyl-4-quinolone Drug Info [19]
6-Methyl-2-oxa-spiro[4.4]nonan-1-one Drug Info [13]
6-Nitro-2-(3-nitro-phenyl)-chromen-4-one Drug Info [27]
6-Nitro-2-(4-nitro-phenyl)-chromen-4-one Drug Info [27]
9H-beta-Carboline-3-carboxylic acid butyl ester Drug Info [28]
9H-beta-Carboline-3-carboxylic acid ethyl ester Drug Info [28]
9H-beta-Carboline-3-carboxylic acid propyl ester Drug Info [28]
ALLOPREGNANOLONE Drug Info [29]
AMENTOFLAVONE Drug Info [30]
Beta-Carboline-3-carboxylic acid t-butyl ester Drug Info [17]
BETA-CCM Drug Info [28]
CGS-13767 Drug Info [31]
CGS-17867A Drug Info [32]
CGS-8216 Drug Info [31]
CGS-9895 Drug Info [33]
CGS-9896 Drug Info [15]
CI-218872 Drug Info [22]
ELTANOLONE Drug Info [29]
Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [17]
Ethyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [17]
GABAZINE Drug Info [25]
GAMMA-AMINO-BUTANOIC ACID Drug Info [18]
GNF-PF-3645 Drug Info [19]
GNF-PF-4421 Drug Info [19]
L-655708 Drug Info [34]
N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide Drug Info [35]
N-Benzyl-2-(1H-indol-3-yl)-2-oxo-acetamide Drug Info [35]
N-benzyl-2-(5-nitro-1H-indol-3-yl)-2-oxoacetamide Drug Info [35]
N-butyl-2-(1H-indol-3-yl)-2-oxoacetamide Drug Info [35]
N-butyl-2-(5-nitro-1H-indol-3-yl)-2-oxoacetamide Drug Info [35]
N-Indan-1-yl-2-(1H-indol-3-yl)-2-oxo-acetamide Drug Info [36]
Ridine-5-carboxylic acid ethyl ester Drug Info [37]
RO-145974 Drug Info [38]
RO-145975 Drug Info [38]
RO-147437 Drug Info [38]
Ro-151310 Drug Info [38]
Ro-154513 Drug Info [39]
RO-194603 Drug Info [38]
Ro-4938581 Drug Info [40]
RY-066 Drug Info [41]
Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate Drug Info [17]
THIOCOLCHICOSIDE Drug Info [18]
U-78875 Drug Info [42]
U-89267 Drug Info [39]
ZK-93423 Drug Info [43]
Blocker (channel blocker) TBPS Drug Info [44]
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 1Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
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REF 3Abecarnil enhances GABA-induced currents in acutely isolated cerebellar Purkinje cells. Neuropharmacology. 1995 Feb;34(2):157-63.
REF 4(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: 4108).
REF 5ClinicalTrials.gov (NCT01673828) Allopregnanolone for the Treatment of Traumatic Brain Injury. U.S. National Institutes of Health.
REF 6Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005875)
REF 7Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001194)
REF 8Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000696)
REF 9Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000585)
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REF 11J Med Chem. 1989 May;32(5):1020-4.Benzodiazepine receptor binding activity of 6,9-disubstituted purines.
REF 12J Med Chem. 1992 Jun 12;35(12):2214-20.Benzodiazepine receptor affinity and interaction of some N-(indol-3-ylglyoxylyl)amine derivatives.
REF 13J Med Chem. 1994 Jan 21;37(2):275-86.Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant alpha,alpha-disubstituted gamma-butyrolactones.
REF 14J Med Chem. 1988 Jan;31(1):1-3.Synthesis, binding studies, and structure-activity relationships of 1-aryl-and 2-aryl[1]benzopyranopyrazol-4-ones, central benzodiazepine receptor ligands.
REF 15J Med Chem. 2006 Mar 23;49(6):1855-66.Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors.
REF 16J Med Chem. 1996 Jul 5;39(14):2844-51.Synthesis and structure--activity relationships of fused imidazopyridines: a new series of benzodiazepine receptor ligands.
REF 17Bioorg 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 18J Med Chem. 2006 Sep 7;49(18):5571-7.3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds.
REF 19J Med Chem. 2006 Apr 20;49(8):2526-33.4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors. synthesis, pharmacology, and pharmacophore modeling.
REF 20J Med Chem. 1998 Jul 2;41(14):2537-52.Synthesis and evaluation of analogues of the partial agonist 6-(propyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (6-PBC) and the full agonist 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (Zk 93423) at wild type and recombinant GABAA receptors.
REF 21J Med Chem. 1990 Sep;33(9):2343-57.Synthetic and computer-assisted analyses of the pharmacophore for the benzodiazepine receptor inverse agonist site.
REF 22J Med Chem. 1994 Dec 23;37(26):4576-80.Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor.
REF 23J Med Chem. 2006 Jul 13;49(14):4442-6.Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and pharmacological characterization of gamma-aminobutyric acid (GABA) related compounds.
REF 24J Med Chem. 2010 Apr 22;53(8):3417-21.Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid(A) receptor ligands: synthesis, pharmacology, and structure-activity relationships.
REF 25J Med Chem. 2006 Feb 23;49(4):1388-96.Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology.
REF 26J Med Chem. 2005 Jan 27;48(2):427-39.Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling.
REF 276,3'-Dinitroflavone, a novel high affinity ligand for the benzodiazepine receptor with potent anxiolytic properties, Bioorg. Med. Chem. Lett. 5(22):2717-2720 (1995).
REF 28J Med Chem. 1983 Apr;26(4):499-503.beta-Carbolines as benzodiazepine receptor ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of beta-carboline-3-carboxylic acid.
REF 29J Med Chem. 2005 Apr 21;48(8):3051-9.Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3alpha,5alpha)-and (3alpha,5beta)-3-hydroxypregnan-20-one.
REF 30Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4.Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors.
REF 31J Med Chem. 1991 Jan;34(1):281-90.Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones.
REF 32Bioorg Med Chem Lett. 2004 Jul 5;14(13):3441-4.2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine binding site ligands on the GABAA receptor.
REF 33J Med Chem. 1987 Oct;30(10):1737-42.1,3-Diarylpyrazolo[4,5-c]- and -[5,4-c]quinolin-4-ones. 4. Synthesis and specific inhibition of benzodiazepine receptor binding.
REF 34J 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 35J Med Chem. 2007 Apr 5;50(7):1627-34. Epub 2007 Mar 3.Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-selective ligands.
REF 36J Med Chem. 2001 Jul 5;44(14):2286-97.Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular modeling analysis of the structure-activity relationships.
REF 37J Med Chem. 1989 Dec;32(12):2561-73.Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents.
REF 38J Med Chem. 1993 Apr 16;36(8):1001-6.Synthesis and evaluation of imidazo[1,5-a][1,4]benzodiazepine esters with high affinities and selectivities at "diazepam-insensitive" benzodiazepine receptors.
REF 39J Med Chem. 1994 Mar 18;37(6):758-68.Antagonist, partial agonist, and full agonist imidazo[1,5-a]quinoxaline amides and carbamates acting through the GABAA/benzodiazepine receptor.
REF 40Bioorg 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 41J Med Chem. 1998 Oct 8;41(21):4130-42.Predictive models for GABAA/benzodiazepine receptor subtypes: studies of quantitative structure-activity relationships for imidazobenzodiazepines at five recombinant GABAA/benzodiazepine receptor subtypes [alphaxbeta3gamma2 (x = 1-3, 5, and 6)] via comparative molecular field analysis.
REF 42J Med Chem. 1996 Sep 13;39(19):3820-36.3-Phenyl-substituted imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas that have high affinity at the GABAA/benzodiazepine receptor complex.
REF 43J Med Chem. 1990 Mar;33(3):1062-9.Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester.
REF 44(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: 414).

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