Target Information

Target General Information

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Target ID

T08910 (Former ID: TTDS00428)

Target Name

GABA(A) receptor gamma-2 (GABRG2)

Synonyms

Gamma-aminobutyric acid receptor subunit gamma-2; GABA(A) receptor subunit gamma-2

Gene Name

GABRG2

Target Type

Successful target

[1]

Disease

[+] 3 Target-related Diseases

Depression [ICD-11: 6A70-6A7Z]

Mental/behavioural/neurodevelopmental disorder [ICD-11: 6E20-6E8Z]

Tonus and reflex abnormality [ICD-11: MB47]

Function

Plays an important role in the formation of functional inhibitory GABAergic synapses in addition to mediating synaptic inhibition as a GABA-gated ion channel. The gamma2 subunit is necessary but not sufficient for a rapid formation of active synaptic contacts and the synaptogenic effect of this subunit is influenced by the type of alpha and beta subunits present in the receptor pentamer. The alpha1/beta2/gamma2 receptor and the alpha1/beta3/gamma2 receptor exhibit synaptogenic activity. The alpha2/beta2/gamma2 receptor exhibits synatogenic activity whereas the alpha2/beta3/gamma2 receptor shows very little or no synaptogenic activity. Functions also as histamine receptor and mediates cellular responses to histamine. Ligand-gated chloride channel which is a component of the heteropentameric receptor for GABA, the major inhibitory neurotransmitter in the brain.

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BioChemical Class

Neurotransmitter receptor

UniProt ID

GBRG2_HUMAN

Sequence

MSSPNIWSTGSSVYSTPVFSQKMTVWILLLLSLYPGFTSQKSDDDYEDYASNKTWVLTPK
VPEGDVTVILNNLLEGYDNKLRPDIGVKPTLIHTDMYVNSIGPVNAINMEYTIDIFFAQT
WYDRRLKFNSTIKVLRLNSNMVGKIWIPDTFFRNSKKADAHWITTPNRMLRIWNDGRVLY
TLRLTIDAECQLQLHNFPMDEHSCPLEFSSYGYPREEIVYQWKRSSVEVGDTRSWRLYQF
SFVGLRNTTEVVKTTSGDYVVMSVYFDLSRRMGYFTIQTYIPCTLIVVLSWVSFWINKDA
VPARTSLGITTVLTMTTLSTIARKSLPKVSYVTAMDLFVSVCFIFVFSALVEYGTLHYFV
SNRKPSKDKDKKKKNPAPTIDIRPRSATIQMNNATHLQERDEEYGYECLDGKDCASFFCC
FEDCRTGAWRHGRIHIRIAKMDSYARIFFPTAFCLFNLVYWVSYLYL

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3D Structure

Click to Show 3D Structure of This Target

PDB

Drugs and Modes of Action

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Approved Drug(s)

[+] 2 Approved Drugs

Allopregnanolone

Drug Info

Approved

Postpartum depression

[2], [3]

THIOCOLCHICOSIDE

Drug Info

Approved

Muscle spasm

[4]

Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

ZK-93423

Drug Info

Phase 3

Epileptic seizures

[5], [6]

GSK683699

Drug Info

Phase 2

Inflammatory bowel disease

[7]

Discontinued Drug(s)

[+] 3 Discontinued Drugs

ELTANOLONE

Drug Info

Discontinued in Phase 3

Premenstrual syndrome

[8]

U-78875

Drug Info

Discontinued in Phase 1

Anxiety disorder

[9]

CGS-17867A

Drug Info

Terminated

Alcohol dependence

[10]

Mode of Action

[+] 2 Modes of Action

Inhibitor

[+] 116 Inhibitor drugs

Allopregnanolone

Drug Info

[11]

THIOCOLCHICOSIDE

Drug Info

[1]

ZK-93423

Drug Info

[12]

GSK683699

Drug Info

[1]

ELTANOLONE

Drug Info

[11]

U-78875

Drug Info

[13]

CGS-17867A

Drug Info

[14]

CGS-9896

Drug Info

[15]

(2E,4S)-4-ammoniopent-2-enoate

Drug Info

[16]

(4R)-4-ammoniopentanoate

Drug Info

[16]

(4S)-4-ammoniopentanoate

Drug Info

[16]

(9-Benzyl-9H-purin-6-yl)-cyclopropyl-amine

Drug Info

[17]

(beta-CCE)9H-beta-Carboline-3-carboxylic acid

Drug Info

[18]

1,1-Dimethyl-5-oxa-spiro[2.4]heptan-4-one

Drug Info

[19]

1,3-Diphenyl-1H-chromeno[4,3-c]pyrazol-4-one

Drug Info

[20]

1-(4-chlorophenyl)-4-phenyl-1H-imidazole

Drug Info

[15]

1-Methyl-5-oxa-spiro[2.4]heptan-4-one

Drug Info

[19]

2-(1H-Indol-3-yl)-2-oxo-N-phenethyl-acetamide

Drug Info

[18]

2-(4-chlorophenyl)-5-phenyl-4-isoxazolin-3-one

Drug Info

[15]

2-(9-Benzyl-9H-purin-6-ylamino)-ethanol

Drug Info

[17]

2-Isoxazol-5-yl-3H-imidazo[4,5-c]quinoline

Drug Info

[21]

2-Oxa-spiro[4.4]nonan-1-one

Drug Info

[19]

2-Thiophen-2-yl-3H-imidazo[4,5-c]quinoline

Drug Info

[21]

3,3-Diethyl-dihydro-furan-2-one

Drug Info

[19]

3,3-Diisopropyl-dihydro-furan-2-one

Drug Info

[19]

3-(3-Methyl-butoxy)-9H-beta-carboline

Drug Info

[22]

3-(benzyloxy)-9H-pyrido[3,4-b]indole

Drug Info

[22]

3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole

Drug Info

[22]

3-amino-3-demethoxythiocolchicine

Drug Info

[1]

3-Butoxy-9H-beta-carboline

Drug Info

[22]

3-butoxycarbonyl-4-quinolone

Drug Info

[23]

3-butoxycarbonyl-6-ethyl-4-quinolone

Drug Info

[23]

3-butylaminocarbonyl-6-ethyl-4-quinolone

Drug Info

[23]

3-carboxy-6-ethyl-4-quinolone

Drug Info

[23]

3-cyclopentoxycarbonyl-6-ethyl-4-quinolone

Drug Info

[23]

3-demethoxy-3-D-lyxopyranosylaminothiocolchicine

Drug Info

[1]

3-demethoxy-3-D-mannopyranosylaminothiocolchicine

Drug Info

[1]

3-demethoxy-3-D-xylopyranosylaminothiocolchicine

Drug Info

[1]

3-demethoxy-3-L-fucopyranosylaminothiocolchicine

Drug Info

[1]

3-demethoxy-3D-glucopyranosylaminothiocolchicine

Drug Info

[1]

3-Ethoxy-9H-beta-carboline

Drug Info

[22], [24]

3-ethoxycarbonyl-4-quinolone

Drug Info

[23]

3-ethoxycarbonyl-6-ethyl-2-methyl-4-quinolone

Drug Info

[23]

3-ethoxycarbonyl-6-propyl-4-quinolone

Drug Info

[23]

3-Ethyl-3-isopropyl-dihydro-furan-2-one

Drug Info

[19]

3-Ethyl-3-methyl-dihydro-furan-2-one

Drug Info

[19]

3-Isobutoxy-9H-beta-carboline

Drug Info

[22]

3-Isopropyl-3-methyl-dihydro-furan-2-one

Drug Info

[19]

3-Isothiocyanato-9H-beta-carboline

Drug Info

[25]

3-Methyl-1-phenyl-1H-chromeno[4,3-c]pyrazol-4-one

Drug Info

[20]

3-Methyl-2-phenyl-2H-chromeno[4,3-c]pyrazol-4-one

Drug Info

[20]

3-Methyl-9H-beta-carboline

Drug Info

[26]

3-Propoxy-9H-beta-carboline

Drug Info

[22]

3-tert-Butyl-3-ethyl-dihydro-furan-2-one

Drug Info

[19]

4-(2-aminoethyl)-1,2,5-oxadiazol-3-ol

Drug Info

[27]

4-(4-chlorophenyl)-1-pyrid-2-yl-pyrazole

Drug Info

[15]

4-(biphenyl-3-yl)-5-(piperidin-4-yl)isoxazol-3-ol

Drug Info

[28]

4-benzyl-5-(4-piperidyl)isothiazol-3-ol

Drug Info

[29]

4-Benzyl-5-piperidin-4-yl-isoxazol-3-ol

Drug Info

[30]

4-Methyl-5-(4-piperidyl)isothiazol-3-ol

Drug Info

[29]

4-Naphthalen-1-yl-5-piperidin-4-yl-isoxazol-3-ol

Drug Info

[30]

4-Naphthalen-2-yl-5-piperidin-4-yl-isoxazol-3-ol

Drug Info

[30]

4-Phenyl-5-piperidin-4-yl-isoxazol-3-ol

Drug Info

[30]

5-(4-piperidyl)-4-propylisothiazol-3-ol

Drug Info

[29]

5-(piperidin-4-yl)isothiazol-3-ol

Drug Info

[29]

5-(piperidin-4-yl)isoxazol-3-ol

Drug Info

[30]

5-[(1R)-1-ammonioethyl]isoxazol-3-olate

Drug Info

[16]

5-[(1S)-1-ammonioethyl]isoxazol-3-olate

Drug Info

[16]

6,6-Dimethyl-2-oxa-spiro[4.4]nonan-1-one

Drug Info

[19]

6,9-Dimethyl-2-oxa-spiro[4.4]nonan-1-one

Drug Info

[19]

6-benzyl-3-ethoxycarbonyl-4-quinolone

Drug Info

[23]

6-benzyl-3-propoxycarbonyl-4-quinolone

Drug Info

[23]

6-benzyl-3-propylaminocarbonyl-4-quinolone

Drug Info

[23]

6-bromo-3-ethoxycarbonyl-2-methyl-4-quinolone

Drug Info

[23]

6-bromo-3-ethoxycarbonyl-4-quinolone

Drug Info

[23]

6-ethyl-3-(2-ethylbutoxycarbonyl)-4-quinolone

Drug Info

[23]

6-ethyl-3-(2-methylbutoxycarbonyl)-4-quinolone

Drug Info

[23]

6-ethyl-3-(3-methylbutoxycarbonyl)-4-quinolone

Drug Info

[23]

6-ethyl-3-(3-pentoxycarbonyl)-4-quinolone

Drug Info

[23]

6-ethyl-3-i-propoxycarbonyl-4-quinolone

Drug Info

[23]

6-ethyl-3-pentoxycarbonyl-4-quinolone

Drug Info

[23]

6-ethyl-3-propoxycarbonyl-4-quinolone

Drug Info

[23]

6-ethyl-3-propylaminocarbonyl-4-quinolone

Drug Info

[23]

6-Methyl-2-oxa-spiro[4.4]nonan-1-one

Drug Info

[19]

6-Nitro-2-(3-nitro-phenyl)-chromen-4-one

Drug Info

[31]

6-Nitro-2-(4-nitro-phenyl)-chromen-4-one

Drug Info

[31]

9H-beta-Carboline-3-carboxylic acid ethyl ester

Drug Info

[22], [32]

9H-beta-Carboline-3-carboxylic acid propyl ester

Drug Info

[32]

AMENTOFLAVONE

Drug Info

[33]

Beta-Carboline-3-carboxylic acid t-butyl ester

Drug Info

[22]

BETA-CCM

Drug Info

[32]

CGS-13767

Drug Info

[34]

CGS-9895

Drug Info

[35]

CI-218872

Drug Info

[26]

Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate

Drug Info

[22]

GNF-PF-3645

Drug Info

[23]

GNF-PF-4421

Drug Info

[23]

L-655708

Drug Info

[36]

N-(p-methylbenzyl)-5-nitroindol-3-ylglyoxylamide

Drug Info

[37]

100

N-Benzyl-2-(1H-indol-3-yl)-2-oxo-acetamide

Drug Info

[37]

101

N-benzyl-2-(5-nitro-1H-indol-3-yl)-2-oxoacetamide

Drug Info

[37]

102

N-butyl-2-(1H-indol-3-yl)-2-oxoacetamide

Drug Info

[37]

103

N-butyl-2-(5-nitro-1H-indol-3-yl)-2-oxoacetamide

Drug Info

[37]

104

N-Indan-1-yl-2-(1H-indol-3-yl)-2-oxo-acetamide

Drug Info

[38]

105

Ridine-5-carboxylic acid ethyl ester

Drug Info

[39]

106

RO-145974

Drug Info

[40]

107

RO-145975

Drug Info

[40]

108

RO-147437

Drug Info

[40]

109

Ro-15-3505

Drug Info

[40]

110

RO-194603

Drug Info

[40]

111

Ro-4938581

Drug Info

[41]

112

RY-066

Drug Info

[42]

113

Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate

Drug Info

[22]

114

U-89267

Drug Info

[44]

115

[3H]CGS8216

Drug Info

[34]

116

[3H]Ro154513

Drug Info

[44]

Blocker (channel blocker)

[+] 1 Blocker (channel blocker) drugs

TBPS

Drug Info

[43]

Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"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

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Co-Targets

Co-Targets Info

Target Regulators

Top

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

Top

KEGG Pathway

[+] 5 KEGG Pathways

Neuroactive ligand-receptor interaction

Retrograde endocannabinoid signaling

GABAergic synapse

Morphine addiction

Nicotine addiction

Reactome

[+] 2 Reactome Pathways

Ligand-gated ion channel transport

GABA A receptor activation

WikiPathways

[+] 2 WikiPathways

Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell

Iron uptake and transport

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

3-demethoxy-3-glycosylaminothiocolchicines: Synthesis of a new class of putative muscle relaxant compounds. J Med Chem. 2006 Sep 7;49(18):5571-7.

REF 2

Antibodies and venom peptides: new modalities for ion channels. Nat Rev Drug Discov. 2019 May;18(5):339-357.

REF 3

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 4

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 5

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: 4346).

REF 6

Abecarnil enhances GABA-induced currents in acutely isolated cerebellar Purkinje cells. Neuropharmacology. 1995 Feb;34(2):157-63.

REF 7

Emerging drugs to treat Crohn's disease. Expert Opin Emerg Drugs. 2007 Mar;12(1):49-59.

REF 8

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005875)

REF 9

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001194)

REF 10

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 11

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 (... J Med Chem. 2005 Apr 21;48(8):3051-9.

REF 12

Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carbolin... J Med Chem. 1990 Mar;33(3):1062-9.

REF 13

3-Phenyl-substituted imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha]quinoxaline ureas that have high affinity at the GABAA/benzodiazepin... J Med Chem. 1996 Sep 13;39(19):3820-36.

REF 14

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 15

Synthesis, pharmacology, and structure-activity relationships of novel imidazolones and pyrrolones as modulators of GABAA receptors. J Med Chem. 2006 Mar 23;49(6):1855-66.

REF 16

gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects. J Med Chem. 1981 Dec;24(12):1377-83.

REF 17

Benzodiazepine receptor binding activity of 6,9-disubstituted purines. J Med Chem. 1989 May;32(5):1020-4.

REF 18

Benzodiazepine receptor affinity and interaction of some N-(indol-3-ylglyoxylyl)amine derivatives. J Med Chem. 1992 Jun 12;35(12):2214-20.

REF 19

Alpha-spirocyclopentyl- and alpha-spirocyclopropyl-gamma-butyrolactones: conformationally constrained derivatives of anticonvulsant and convulsant ... J Med Chem. 1994 Jan 21;37(2):275-86.

REF 20

Synthesis, binding studies, and structure-activity relationships of 1-aryl-and 2-aryl[1]benzopyranopyrazol-4-ones, central benzodiazepine receptor ... J Med Chem. 1988 Jan;31(1):1-3.

REF 21

Synthesis and structure--activity relationships of fused imidazopyridines: a new series of benzodiazepine receptor ligands. J Med Chem. 1996 Jul 5;39(14):2844-51.

REF 22

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 23

4-quinolone derivatives: high-affinity ligands at the benzodiazepine site of brain GABA A receptors. synthesis, pharmacology, and pharmacophore mod... J Med Chem. 2006 Apr 20;49(8):2526-33.

REF 24

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 25

Synthetic and computer-assisted analyses of the pharmacophore for the benzodiazepine receptor inverse agonist site. J Med Chem. 1990 Sep;33(9):2343-57.

REF 26

Four amino acid exchanges convert a diazepam-insensitive, inverse agonist-preferring GABAA receptor into a diazepam-preferring GABAA receptor. J Med Chem. 1994 Dec 23;37(26):4576-80.

REF 27

Hydroxy-1,2,5-oxadiazolyl moiety as bioisoster of the carboxy function. Synthesis, ionization constants, and pharmacological characterization of ga... J Med Chem. 2006 Jul 13;49(14):4442-6.

REF 28

Novel 4-(piperidin-4-yl)-1-hydroxypyrazoles as gamma-aminobutyric acid(A) receptor ligands: synthesis, pharmacology, and structure-activity relatio... J Med Chem. 2010 Apr 22;53(8):3417-21.

REF 29

Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology. J Med Chem. 2006 Feb 23;49(4):1388-96.

REF 30

Potent 4-aryl- or 4-arylalkyl-substituted 3-isoxazolol GABA(A) antagonists: synthesis, pharmacology, and molecular modeling. J Med Chem. 2005 Jan 27;48(2):427-39.

REF 31

6,3'-Dinitroflavone, a novel high affinity ligand for the benzodiazepine receptor with potent anxiolytic properties, Bioorg. Med. Chem. Lett. 5(22):2717-2720 (1995).

REF 32

beta-Carbolines as benzodiazepine receptor ligands. 1. Synthesis and benzodiazepine receptor interaction of esters of beta-carboline-3-carboxylic a... J Med Chem. 1983 Apr;26(4):499-503.

REF 33

Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4.

REF 34

Synthesis and benzodiazepine binding activity of a series of novel [1,2,4]triazolo[1,5-c]quinazolin-5(6H)-ones. J Med Chem. 1991 Jan;34(1):281-90.

REF 35

1,3-Diarylpyrazolo[4,5-c]- and -[5,4-c]quinolin-4-ones. 4. Synthesis and specific inhibition of benzodiazepine receptor binding. J Med Chem. 1987 Oct;30(10):1737-42.

REF 36

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 37

Novel N-substituted indol-3-ylglyoxylamides probing the LDi and L1/L2 lipophilic regions of the benzodiazepine receptor site in search for subtype-... J Med Chem. 2007 Apr 5;50(7):1627-34.

REF 38

Novel N-(arylalkyl)indol-3-ylglyoxylylamides targeted as ligands of the benzodiazepine receptor: synthesis, biological evaluation, and molecular mo... J Med Chem. 2001 Jul 5;44(14):2286-97.

REF 39

Synthesis and structure-activity relationships of a series of anxioselective pyrazolopyridine ester and amide anxiolytic agents. J Med Chem. 1989 Dec;32(12):2561-73.

REF 40

Synthesis and evaluation of imidazo[1,5-a][1,4]benzodiazepine esters with high affinities and selectivities at "diazepam-insensitive" benzodiazepin... J Med Chem. 1993 Apr 16;36(8):1001-6.

REF 41

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 42

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 43

REF 44

Antagonist, partial agonist, and full agonist imidazo[1,5-a]quinoxaline amides and carbamates acting through the GABAA/benzodiazepine receptor. J Med Chem. 1994 Mar 18;37(6):758-68.

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