Details of the Drug Therapeutic Target (DTT)

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

• DTT Name: Gamma-aminobutyric acid B receptor (GABBR)
• Synonyms: Gamma-aminobutyric acid type B receptor; GPRC3; GABABR; GABA-BR; GABA-B-R; GABA-B receptor
• Gene Name: GABBR1
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR glutamate
• UniProt ID: GABR1_HUMAN ; GABR2_HUMAN
• TTD ID: T42446
• Sequence:
  MLLLLLLAPLFLRPPGAGGAQTPNATSEGCQIIHPPWEGGIRYRGLTRDQVKAINFLPVD
  YEIEYVCRGEREVVGPKVRKCLANGSWTDMDTPSRCVRICSKSYLTLENGKVFLTGGDLP
  ALDGARVDFRCDPDFHLVGSSRSICSQGQWSTPKPHCQVNRTPHSERRAVYIGALFPMSG
  GWPGGQACQPAVEMALEDVNSRRDILPDYELKLIHHDSKCDPGQATKYLYELLYNDPIKI
  ILMPGCSSVSTLVAEAARMWNLIVLSYGSSSPALSNRQRFPTFFRTHPSATLHNPTRVKL
  FEKWGWKKIATIQQTTEVFTSTLDDLEERVKEAGIEITFRQSFFSDPAVPVKNLKRQDAR
  IIVGLFYETEARKVFCEVYKERLFGKKYVWFLIGWYADNWFKIYDPSINCTVDEMTEAVE
  GHITTEIVMLNPANTRSISNMTSQEFVEKLTKRLKRHPEETGGFQEAPLAYDAIWALALA
  LNKTSGGGGRSGVRLEDFNYNNQTITDQIYRAMNSSSFEGVSGHVVFDASGSRMAWTLIE
  QLQGGSYKKIGYYDSTKDDLSWSKTDKWIGGSPPADQTLVIKTFRFLSQKLFISVSVLSS
  LGIVLAVVCLSFNIYNSHVRYIQNSQPNLNNLTAVGCSLALAAVFPLGLDGYHIGRNQFP
  FVCQARLWLLGLGFSLGYGSMFTKIWWVHTVFTKKEEKKEWRKTLEPWKLYATVGLLVGM
  DVLTLAIWQIVDPLHRTIETFAKEEPKEDIDVSILPQLEHCSSRKMNTWLGIFYGYKGLL
  LLLGIFLAYETKSVSTEKINDHRAVGMAIYNVAVLCLITAPVTMILSSQQDAAFAFASLA
  IVFSSYITLVVLFVPKMRRLITRGEWQSEAQDTMKTGSSTNNNEEEKSRLLEKENRELEK
  IIAEKEERVSELRHQLQSRQQLRSRRHPPTPPEPSGGLPRGPPEPPDRLSCDGSRVHLLY
  K
• Function: Within the heterodimeric GABA receptor, only GABBR1 seems to bind agonists, while GABBR2 mediates coupling to G proteins. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling inhibits adenylate cyclase, stimulates phospholipase A2, activates potassium channels, inactivates voltage-dependent calcium-channels and modulates inositol phospholipid hydrolysis. Plays a critical role in the fine-tuning of inhibitory synaptic transmission. Pre-synaptic GABA receptor inhibits neurotransmitter release by down-regulating high-voltage activated calcium channels, whereas postsynaptic GABA receptor decreases neuronal excitability by activating a prominent inwardly rectifying potassium (Kir) conductance that underlies the late inhibitory postsynaptic potentials. Not only implicated in synaptic inhibition but also in hippocampal long-term potentiation, slow wave sleep, muscle relaxation and antinociception. Component of a heterodimeric G-protein coupled receptor for GABA, formed by GABBR1 and GABBR2.
• KEGG Pathway:
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  GABAergic synapse (hsa04727)
  Estrogen signaling pathway (hsa04915)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DTT

4 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Baclofen	DM0QV1J	Multiple sclerosis	8A40	Approved	[2]
Gabapentin	DM6T924	Complex partial seizure	8A68.0	Approved	[3]
Gamma Hydroxybutyric Acid	DMGBKVD	Narcolepsy	7A20	Approved	[4]
Progabide	DM671NG	Depression	6A70-6A7Z	Approved	[1]

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Arabaclofen	DMZB9RI	Fragile X syndrome	LD55	Phase 3	[5]
Arbaclofen placarbil	DMO628K	Fragile X syndrome	LD55	Phase 3	[6]
[3H](R)-(-)-baclofen	DMLRHM5	Multiple sclerosis	8A40	Phase 3	[7]
ASP8062	DMR1MIV	Fibromyalgia	MG30.01	Phase 2	[8]
GSK683699	DMTW79H	Inflammatory bowel disease	DD72	Phase 2	[9]
SGS742	DM5XYFH	Schizophrenia	6A20	Phase 2	[10]
SSTarbaclofen	DMRGTZ2	Autism spectrum disorder	6A02	Phase 2	[11]

5 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
SUN-09	DMMG47P	Hypertonia	KB08.1	Discontinued in Phase 3	[12]
AZD3355	DMT5ZK3	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 2	[13]
AZD-9343	DM1ZVO3	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 1	[14]
CGP-35348	DMZM70X	Epilepsy	8A60-8A68	Terminated	[16]
SCH 50911	DMW9H4A	Absence seizure	8A68.2	Terminated	[17]

1 Preclinical Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ADX-71943	DMEWFOL	Gastroesophageal reflux disease	DA22.Z	Preclinical	[15]

43 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
((E)-3-Amino-propenyl)-methyl-phosphinic acid	DMEJRVW	Discovery agent	N.A.	Investigative	[18]
((Z)-3-Amino-propenyl)-methyl-phosphinic acid	DM6H0FW	Discovery agent	N.A.	Investigative	[18]
(3-Amino-1-ethyl-propyl)-methyl-phosphinic acid	DMPHCX7	Discovery agent	N.A.	Investigative	[18]
(3-Amino-1-hydroxy-propyl)-methyl-phosphinic acid	DM7HF4I	Discovery agent	N.A.	Investigative	[18]
(3-Amino-phenyl)-phosphonic acid diphenyl ester	DMDGFS0	Discovery agent	N.A.	Investigative	[19]
(3-Amino-propyl)-hexyl-phosphinic acid	DMBJYTD	Discovery agent	N.A.	Investigative	[20]
(3-Amino-propyl)-hydroxymethyl-phosphinic acid	DMGFIJV	Discovery agent	N.A.	Investigative	[18]
(3-Amino-propyl)-phosphonic acid	DMK3JZS	Discovery agent	N.A.	Investigative	[19]
(R)-5-Amino-3-(4-chloro-phenyl)-pentanoic acid	DMW87OE	Discovery agent	N.A.	Investigative	[2]
2-hydroxy-saclofen	DMHO8KQ	Discovery agent	N.A.	Investigative	[21]
3-ammoniopropane-1-sulfinate	DM5SQVC	Discovery agent	N.A.	Investigative	[22]
4-Amino-3-(2-chloro-phenyl)-butyric acid	DMIX81A	Discovery agent	N.A.	Investigative	[9]
4-Amino-3-(4-fluoro-phenyl)-butyric acid	DMVKPF1	Discovery agent	N.A.	Investigative	[9]
4-Amino-3-(5-bromo-thiophen-2-yl)-butyric acid	DMTO8NV	Discovery agent	N.A.	Investigative	[9]
4-Amino-3-(5-chloro-thiophen-2-yl)-butyric acid	DM415DB	Discovery agent	N.A.	Investigative	[9]
4-Amino-3-(5-methyl-thiophen-2-yl)-butyric acid	DMEDRAX	Discovery agent	N.A.	Investigative	[9]
4-Amino-3-benzofuran-2-yl-butyric acid	DM1IHCV	Discovery agent	N.A.	Investigative	[23]
4-Amino-3-thiophen-2-yl-butyric acid	DMZJS2E	Discovery agent	N.A.	Investigative	[9]
amino-propylphosphinic acid	DMT5HOA	Discovery agent	N.A.	Investigative	[7]
AVE-1876	DMC0PY5	Discovery agent	N.A.	Investigative	[24]
BHF-177	DMP21ST	Anxiety disorder	6B00-6B0Z	Investigative	[25]
CGP 46381	DMXV6RD	Discovery agent	N.A.	Investigative	[26]
CGP 47656	DME39UQ	Discovery agent	N.A.	Investigative	[21]
CGP 54626A	DMEHYVS	Discovery agent	N.A.	Investigative	[27]
CGP 55845	DMNMG0I	Discovery agent	N.A.	Investigative	[26]
CGP 56999A	DMR708D	Discovery agent	N.A.	Investigative	[21]
CGP 62349	DMYXE39	Discovery agent	N.A.	Investigative	[28]
CGP 64213	DMR8U1M	Discovery agent	N.A.	Investigative	[21]
CGP 71872	DMJWED7	Discovery agent	N.A.	Investigative	[21]
CGP-29030A	DMS61KA	Pain	MG30-MG3Z	Investigative	[29]
CGP-34938	DM84TSH	Discovery agent	N.A.	Investigative	[18]
CGP-35024	DMHKETG	Discovery agent	N.A.	Investigative	[30]
CGP-35582	DM3J6HM	Discovery agent	N.A.	Investigative	[18]
CGP-36216	DM9U8TO	Discovery agent	N.A.	Investigative	[20]
CGP-44532	DMKF0GH	Drug abuse	6C4G.1Z	Investigative	[31]
GABA-B receptor PAM	DMOF7JL	Anxiety disorder	6B00-6B0Z	Investigative	[25]
Phaclofen	DMALRCH	Discovery agent	N.A.	Investigative	[32]
PMID25050158C14	DMRFQ1W	Discovery agent	N.A.	Investigative	[33]
saclofen	DM3TO27	Discovery agent	N.A.	Investigative	[21]
TG-3030	DM8RSDE	Nicotine dependence	6C4A.2	Investigative	[25]
[125I]CGP 64213	DMIAO4V	Discovery agent	N.A.	Investigative	[34]
[125I]CGP 71872	DMQVW4E	Discovery agent	N.A.	Investigative	[21]
[3H]CGP27492	DMQTBRM	Discovery agent	N.A.	Investigative	[20]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Major depressive disorder	6A20	Pre-frontal cortex	8.22E-01	-0.09	-0.29

References

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