Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTBMV1G)

• DTT 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
• Gene Name: GABRA2
• DTT Type: Successful target; [1]
• BioChemical Class: Neurotransmitter receptor
• UniProt ID: GBRA2_HUMAN
• TTD ID: T51452
• Sequence:
  MKTKLNIYNMQFLLFVFLVWDPARLVLANIQEDEAKNNITIFTRILDRLLDGYDNRLRPG
  LGDSITEVFTNIYVTSFGPVSDTDMEYTIDVFFRQKWKDERLKFKGPMNILRLNNLMASK
  IWTPDTFFHNGKKSVAHNMTMPNKLLRIQDDGTLLYTMRLTVQAECPMHLEDFPMDAHSC
  PLKFGSYAYTTSEVTYIWTYNASDSVQVAPDGSRLNQYDLLGQSIGKETIKSSTGEYTVM
  TAHFHLKRKIGYFVIQTYLPCIMTVILSQVSFWLNRESVPARTVFGVTTVLTMTTLSISA
  RNSLPKVAYATAMDWFIAVCYAFVFSALIEFATVNYFTKRGWAWDGKSVVNDKKKEKASV
  MIQNNAYAVAVANYAPNLSKDPVLSTISKSATTPEPNKKPENKPAEAKKTFNSVSKIDRM
  SRIVFPVLFGTFNLVYWATYLNREPVLGVSP
• 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.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Retrograde endocannabinoid signaling (hsa04723)
  GABAergic synapse (hsa04727)
  Morphine addiction (hsa05032)
  Nicotine addiction (hsa05033)
• Reactome Pathway:
  GABA A receptor activation (R-HSA-977441)
  Ligand-gated ion channel transport (R-HSA-975298)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Flumazenil	DMPCG2L	Benzodiazepine overdose	PC91	Approved	[1]

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK683699	DMTW79H	Inflammatory bowel disease	DD72	Phase 2	[2]

2 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PF-4480682	DMWYJHC	Neuropathic pain	8E43.0	Discontinued in Phase 2	[3]
CGS-17867A	DMMZJY3	Alcohol dependence	6C40.2	Terminated	[4]

37 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2E,4S)-4-ammoniopent-2-enoate	DMA9RIS	Discovery agent	N.A.	Investigative	[5]
(4R)-4-ammoniopentanoate	DMZFTI4	Discovery agent	N.A.	Investigative	[5]
(4S)-4-ammoniopentanoate	DMBLAY1	Discovery agent	N.A.	Investigative	[5]
3-(3-Methyl-butoxy)-9H-beta-carboline	DMTNCXP	Discovery agent	N.A.	Investigative	[6]
3-(benzyloxy)-9H-pyrido[3,4-b]indole	DMDNEKR	Discovery agent	N.A.	Investigative	[6]
3-(hexa-1,3-dienyloxy)-9H-pyrido[3,4-b]indole	DMKHNTY	Discovery agent	N.A.	Investigative	[6]
3-Butoxy-9H-beta-carboline	DMQ8H74	Discovery agent	N.A.	Investigative	[6]
3-Ethoxy-9H-beta-carboline	DM6K7BI	Discovery agent	N.A.	Investigative	[7]
3-Isobutoxy-9H-beta-carboline	DM6X5TZ	Discovery agent	N.A.	Investigative	[6]
3-Propoxy-9H-beta-carboline	DMDEV64	Discovery agent	N.A.	Investigative	[6]
5-[(1R)-1-ammonioethyl]isoxazol-3-olate	DM23PL4	Discovery agent	N.A.	Investigative	[5]
5-[(1S)-1-ammonioethyl]isoxazol-3-olate	DMYAPLT	Discovery agent	N.A.	Investigative	[5]
9H-beta-Carboline-3-carboxylic acid ethyl ester	DMK459I	Discovery agent	N.A.	Investigative	[6]
alpha3IA	DM257WX	Discovery agent	N.A.	Investigative	[1]
alpha5IA	DMTU5QR	Discovery agent	N.A.	Investigative	[1]
AMENTOFLAVONE	DMLRNV2	Discovery agent	N.A.	Investigative	[8]
Barbituric acid derivative	DM2I19P	Discovery agent	N.A.	Investigative	[9]
Beta-Carboline-3-carboxylic acid t-butyl ester	DM9LT60	N. A.	N. A.	Investigative	[6]
CI-218872	DM0RH3S	Discovery agent	N.A.	Investigative	[6]
DMCM	DMK3WY4	Discovery agent	N.A.	Investigative	[1]
Ethyl 6-iodo-9H-pyrido[3,4-b]indole-3-carboxylate	DM5G91Z	Discovery agent	N.A.	Investigative	[6]
isonipecotic acid	DMO1ZHE	Discovery agent	N.A.	Investigative	[1]
L-655708	DM4CDIB	Discovery agent	N.A.	Investigative	[10]
MK-0343	DMTFRLO	Discovery agent	N.A.	Investigative	[11]
MRK016	DM7VQTO	Discovery agent	N.A.	Investigative	[12]
piperidine-4-sulphonic acid	DMMIZWE	Discovery agent	N.A.	Investigative	[1]
Ro-15-3505	DM4NW3U	Discovery agent	N.A.	Investigative	[13]
Ro-4938581	DMCB2N9	Discovery agent	N.A.	Investigative	[14]
RY-066	DMGUX16	Discovery agent	N.A.	Investigative	[15]
Sec-butyl 9H-pyrido[3,4-b]indole-3-carboxylate	DM9QSDC	Discovery agent	N.A.	Investigative	[6]
TBPS	DMFC3XP	Discovery agent	N.A.	Investigative	[1]
tetrahydrodeoxycorticosterone	DMF8M0W	Discovery agent	N.A.	Investigative	[1]
TP003	DMRHDGN	Discovery agent	N.A.	Investigative	[1]
[18F]fluoroethylflumazenil	DMPWART	Discovery agent	N.A.	Investigative	[1]
[35S]TBPS	DMSD51L	Discovery agent	N.A.	Investigative	[1]
[3H]CGS8216	DMLP68J	Inflammation	1A00-CA43.1	Investigative	[1]
[3H]Ro154513	DMMBWKL	Discovery agent	N.A.	Investigative	[16]

References

• [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).
• [2] New anticonvulsants: Schiff bases of gamma-aminobutyric acid and gamma-aminobutyramide. J Med Chem. 1980 Jun;23(6):702-4.
• [3] WO patent application no. 2014,1515,17, Methods of improving microvascular integrity.
• [4] 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.
• [5] gamma-Aminobutyric acid agonists, antagonists, and uptake inhibitors. Design and therapeutic aspects. J Med Chem. 1981 Dec;24(12):1377-83.
• [6] 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.
• [7] 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.
• [8] Semisynthetic preparation of amentoflavone: A negative modulator at GABA(A) receptors. Bioorg Med Chem Lett. 2003 Jul 21;13(14):2281-4.
• [9] Whiting PJ: The GABAA receptor gene family: new opportunities for drug development. Curr Opin Drug Discov Devel. 2003 Sep;6(5):648-57.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] The GABA(A) receptor as a target for photochromic molecules. Bioorg Med Chem. 2010 Nov 15;18(22):7731-8.
• [14] 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.
• [15] 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.
• [16] 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.