Target Information

Target General Information

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Target ID

T51452 (Former ID: TTDR01177)

Target Name

GABA(A) receptor alpha-2 (GABRA2)

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

Target Type

Successful target

[1]

Disease

[+] 1 Target-related Diseases

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.

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BioChemical Class

Neurotransmitter receptor

UniProt ID

GBRA2_HUMAN

Sequence

MKTKLNIYNMQFLLFVFLVWDPARLVLANIQEDEAKNNITIFTRILDRLLDGYDNRLRPG
LGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQKWKDERLKFKGPMNILRLNNLMASK
IWTPDTFFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSC
PLKFGSYAYTTSEVTYIWTYNASDSVQVAPDGSRLNQYDLLGQSIGKETIKSSTGEYTVM
TAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA
RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKSVVNDKKKEKASV
MIQNNAYAVAVANYAPNLSKDPVLSTISKSATTPEPNKKPENKPAEAKKTFNSVSKIDRM
SRIVFPVLFGTFNLVYWATYLNREPVLGVSP

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3D Structure

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AlphaFold

HIT2.0 ID

T29GRI

Drugs and Modes of Action

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Approved Drug(s)

[+] 1 Approved Drugs

Flumazenil

Drug Info

Approved

Benzodiazepine overdose

[2], [3]

Clinical Trial Drug(s)

[+] 1 Clinical Trial Drugs

GSK683699

Drug Info

Phase 2

Inflammatory bowel disease

[4]

Discontinued Drug(s)

[+] 2 Discontinued Drugs

PF-4480682

Drug Info

Discontinued in Phase 2

Neuropathic pain

[5]

CGS-17867A

Drug Info

Terminated

Alcohol dependence

[6]

Mode of Action

[+] 5 Modes of Action

Modulator (allosteric modulator)

[+] 8 Modulator (allosteric modulator) drugs

Flumazenil

Drug Info

[1]

alpha3IA

Drug Info

[1]

alpha5IA

Drug Info

[1]

DMCM

Drug Info

[1]

tetrahydrodeoxycorticosterone

Drug Info

[1]

TP003

Drug Info

[1]

[18F]fluoroethylflumazenil

Drug Info

[1]

[3H]CGS8216

Drug Info

[1]

Inhibitor

[+] 26 Inhibitor drugs

GSK683699

Drug Info

[7]

CGS-17867A

Drug Info

[9]

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

Drug Info

[10]

(4R)-4-ammoniopentanoate

Drug Info

[10]

(4S)-4-ammoniopentanoate

Drug Info

[10]

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

Drug Info

[11]

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

Drug Info

[11]

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

Drug Info

[11]

3-Butoxy-9H-beta-carboline

Drug Info

[11]

3-Ethoxy-9H-beta-carboline

Drug Info

[11], [12]

3-Isobutoxy-9H-beta-carboline

Drug Info

[11]

3-Propoxy-9H-beta-carboline

Drug Info

[11]

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

Drug Info

[10]

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

Drug Info

[10]

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

Drug Info

[11]

AMENTOFLAVONE

Drug Info

[13]

Barbituric acid derivative

Drug Info

[14]

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

Drug Info

[11]

CI-218872

Drug Info

[11]

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

Drug Info

[11]

L-655708

Drug Info

[15]

Ro-15-3505

Drug Info

[18]

Ro-4938581

Drug Info

[19]

RY-066

Drug Info

[20]

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

Drug Info

[11]

[3H]Ro154513

Drug Info

[21]

Modulator

[+] 3 Modulator drugs

PF-4480682

Drug Info

[8]

MK-0343

Drug Info

[16]

MRK016

Drug Info

[17]

Agonist

[+] 2 Agonist drugs

isonipecotic acid

Drug Info

[1]

piperidine-4-sulphonic acid

Drug Info

[1]

Blocker (channel blocker)

[+] 2 Blocker (channel blocker) drugs

TBPS

Drug Info

[1]

[35S]TBPS

Drug Info

[1]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Retrograde endocannabinoid signaling	hsa04723	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
GABAergic synapse	hsa04727	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Taste transduction	hsa04742	Affiliated Target
Class: Organismal Systems => Sensory system	Pathway Hierarchy

Degree	1	Degree centrality	1.07E-04	Betweenness centrality	0.00E+00
Closeness centrality	1.72E-01	Radiality	1.27E+01	Clustering coefficient	0.00E+00
Neighborhood connectivity	1.00E+01	Topological coefficient	1.00E+00	Eccentricity	13
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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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 Affiliated Biological Pathways

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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

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Target Validation

Target Validation Info

References

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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

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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