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; GABBR2
• DTT Type: Successful target; [1]
• Related Disease:
  Depression [ICD-11: 6A70-6A7Z]
  Epilepsy/seizure [ICD-11: 8A61-8A6Z]
  Multiple sclerosis [ICD-11: 8A40]
  Narcolepsy [ICD-11: 7A20]
• 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], [3]
Gabapentin	DM6T924	Complex partial seizure	8A68.0	Approved	[4]
Gamma hydroxybutyric acid	DMGBKVD	Narcolepsy	7A20	Approved	[5]
Progabide	DM671NG	Depression	6A70-6A7Z	Approved	[1], [6], [7]

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	[8]
Arbaclofen placarbil	DMO628K	Fragile X syndrome	LD55	Phase 3	[9]
[3H](R)-(-)-baclofen	DMLRHM5	Multiple sclerosis	8A40	Phase 3	[10]
ASP8062	DMR1MIV	Fibromyalgia	MG30.01	Phase 2	[11]
GSK683699	DMTW79H	Inflammatory bowel disease	DD72	Phase 2	[12]
SGS742	DM5XYFH	Schizophrenia	6A20	Phase 2	[13]
SSTarbaclofen	DMRGTZ2	Autism spectrum disorder	6A02	Phase 2	[14]

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	[15]
AZD3355	DMT5ZK3	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 2	[16]
AZD-9343	DM1ZVO3	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 1	[17]
CGP-35348	DMZM70X	Epilepsy	8A60-8A68	Terminated	[19], [20]
SCH 50911	DMW9H4A	Absence seizure	8A68.2	Terminated	[21]

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	[18]

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	[22]
((Z)-3-Amino-propenyl)-methyl-phosphinic acid	DM6H0FW	Discovery agent	N.A.	Investigative	[22]
(3-Amino-1-ethyl-propyl)-methyl-phosphinic acid	DMPHCX7	Discovery agent	N.A.	Investigative	[22]
(3-Amino-1-hydroxy-propyl)-methyl-phosphinic acid	DM7HF4I	Discovery agent	N.A.	Investigative	[22]
(3-Amino-phenyl)-phosphonic acid diphenyl ester	DMDGFS0	Discovery agent	N.A.	Investigative	[23]
(3-Amino-propyl)-hexyl-phosphinic acid	DMBJYTD	Discovery agent	N.A.	Investigative	[24]
(3-Amino-propyl)-hydroxymethyl-phosphinic acid	DMGFIJV	Discovery agent	N.A.	Investigative	[22]
(3-Amino-propyl)-phosphonic acid	DMK3JZS	Discovery agent	N.A.	Investigative	[23]
(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	[25]
3-ammoniopropane-1-sulfinate	DM5SQVC	Discovery agent	N.A.	Investigative	[26]
4-Amino-3-(2-chloro-phenyl)-butyric acid	DMIX81A	Discovery agent	N.A.	Investigative	[12]
4-Amino-3-(4-fluoro-phenyl)-butyric acid	DMVKPF1	Discovery agent	N.A.	Investigative	[12]
4-Amino-3-(5-bromo-thiophen-2-yl)-butyric acid	DMTO8NV	Discovery agent	N.A.	Investigative	[12]
4-Amino-3-(5-chloro-thiophen-2-yl)-butyric acid	DM415DB	Discovery agent	N.A.	Investigative	[12]
4-Amino-3-(5-methyl-thiophen-2-yl)-butyric acid	DMEDRAX	Discovery agent	N.A.	Investigative	[12]
4-Amino-3-benzofuran-2-yl-butyric acid	DM1IHCV	Discovery agent	N.A.	Investigative	[27]
4-Amino-3-thiophen-2-yl-butyric acid	DMZJS2E	Discovery agent	N.A.	Investigative	[12]
amino-propylphosphinic acid	DMT5HOA	Discovery agent	N.A.	Investigative	[10], [25]
AVE-1876	DMC0PY5	Discovery agent	N.A.	Investigative	[28]
BHF-177	DMP21ST	Anxiety disorder	6B00-6B0Z	Investigative	[3]
CGP 46381	DMXV6RD	Discovery agent	N.A.	Investigative	[29]
CGP 47656	DME39UQ	Discovery agent	N.A.	Investigative	[25], [22]
CGP 54626A	DMEHYVS	Discovery agent	N.A.	Investigative	[30], [31]
CGP 55845	DMNMG0I	Discovery agent	N.A.	Investigative	[29]
CGP 56999A	DMR708D	Discovery agent	N.A.	Investigative	[25]
CGP 62349	DMYXE39	Discovery agent	N.A.	Investigative	[32], [31]
CGP 64213	DMR8U1M	Discovery agent	N.A.	Investigative	[25]
CGP 71872	DMJWED7	Discovery agent	N.A.	Investigative	[25]
CGP-29030A	DMS61KA	Pain	MG30-MG3Z	Investigative	[33], [34]
CGP-34938	DM84TSH	Discovery agent	N.A.	Investigative	[22]
CGP-35024	DMHKETG	Discovery agent	N.A.	Investigative	[35], [24]
CGP-35582	DM3J6HM	Discovery agent	N.A.	Investigative	[22]
CGP-36216	DM9U8TO	Discovery agent	N.A.	Investigative	[24]
CGP-44532	DMKF0GH	Drug abuse	6C4G.1Z	Investigative	[36], [35]
GABA-B receptor PAM	DMOF7JL	Anxiety disorder	6B00-6B0Z	Investigative	[3]
Phaclofen	DMALRCH	Discovery agent	N.A.	Investigative	[37], [38]
PMID25050158C14	DMRFQ1W	Discovery agent	N.A.	Investigative	[39]
saclofen	DM3TO27	Discovery agent	N.A.	Investigative	[25], [31]
TG-3030	DM8RSDE	Nicotine dependence	6C4A.2	Investigative	[3]
[125I]CGP 64213	DMIAO4V	Discovery agent	N.A.	Investigative	[40], [25]
[125I]CGP 71872	DMQVW4E	Discovery agent	N.A.	Investigative	[25]
[3H]CGP27492	DMQTBRM	Discovery agent	N.A.	Investigative	[24]

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

• [1] Interactions between dopamine and GABA in the control of ambulatory activity and neophobia in the mouse. Pharmacol Biochem Behav. 1998 Jan;59(1):239-47.
• [2] Synthesis and pharmacology of the baclofen homologues 5-amino-4-(4-chlorophenyl)pentanoic acid and the R- and S-enantiomers of 5-amino-3-(4-chlorop... J Med Chem. 1999 Jun 3;42(11):2053-9.
• [3] 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: 241).
• [4] Gabapentin increases a tonic inhibitory conductance in hippocampal pyramidal neurons. Anesthesiology. 2006 Aug;105(2):325-33.
• [5] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [6] Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology (Berl). 1993;110(3):295-301.
• [7] Suppression by progabide of ethanol withdrawal syndrome in rats. Eur J Pharmacol. 1985 Mar 12;109(3):321-5.
• [8] Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl). 2013 Jul;228(1):75-84.
• [9] Arbaclofen placarbil, a novel R-baclofen prodrug: improved absorption, distribution, metabolism, and elimination properties compared with R-baclofen.J Pharmacol Exp Ther.2009 Sep;330(3):911-21.
• [10] 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: 242).
• [11] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [12] 3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies. J Med Chem. 1991 Aug;34(8):2557-60.
• [13] SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol. 2004 Oct 15;68(8):1479-87.
• [14] Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci Transl Med. 2012 Sep 19;4(152):152ra128.
• [15] The effects of the GABA agonist, baclofen, on sleep and breathing. Eur Respir J. 1995 Feb;8(2):230-4.
• [16] Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial.Gut.2013 Sep;62(9):1248-55.
• [17] The GABA(B) receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study. Aliment Pharmacol Ther. 2009 Nov 1;30(9):937-46.
• [18] Evaluation of peripheral versus central effects of GABA(B) receptor activation using a novel, positive allosteric modulator of the GABA(B) receptor ADX71943, a pharmacological tool compound with a fully peripheral activity profile. Br J Pharmacol. 2014 Nov;171(21):4941-54.
• [19] The selective GABAB antagonist CGP-35348 blocks spike-wave bursts in the cholesterol synthesis rat absence epilepsy model. Brain Res. 1996 Aug 12;729(2):147-50.
• [20] The GABAB-receptor antagonist, CGP 35348, antagonises gamma-hydroxybutyrate- and baclofen-induced alterations in locomotor activity and forebrain d... J Neural Transm (Vienna). 1996;103(11):1255-63.
• [21] Activation of nigral dopamine neurons by the selective GABA(B)-receptor antagonist SCH 50911. J Neural Transm. 1999;106(5-6):383-94.
• [22] Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists. J Med Chem. 1995 Aug 18;38(17):3297-312.
• [23] Phosphorus analogues of gamma-aminobutyric acid, a new class of anticonvulsants. J Med Chem. 1984 May;27(5):654-9.
• [24] Biological activity of 3-aminopropyl (methyl) phosphinic acid, a potent and selective GABAB agonist with CNS activity, Bioorg. Med. Chem. Lett. 3(4):515-518 (1993).
• [25] Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature. 1997 Mar 20;386(6622):239-46.
• [26] A study of 3-amino-N-hydroxypropanesulfonamide derivatives as potential GABAB agonists and their fragmentation to 3-aminopropanesulfinic acid, Bioorg. Med. Chem. Lett. 6(14):1709-1714 (1996).
• [27] Synthesis and pharmacological evaluation of gamma-aminobutyric acid analogues. New ligand for GABAB sites. J Med Chem. 1987 Apr;30(4):743-6.
• [28] Company report (Sanofi)
• [29] The human GABA(B1b) and GABA(B2) heterodimeric recombinant receptor shows low sensitivity to phaclofen and saclofen. Br J Pharmacol. 2000 Nov;131(6):1050-4.
• [30] GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature. 1998 Dec 17;396(6712):674-9.
• [31] Pharmacological characterisation of a cell line expressing GABA B1b and GABA B2 receptor subunits. Biochem Pharmacol. 2003 Apr 1;65(7):1103-13.
• [32] Characterisation and partial purification of the GABA(B) receptor from the rat cerebellum using the novel antagonist [3H]CGP 62349. Brain Res Mol Brain Res. 1999 Aug 25;71(2):279-89.
• [33] Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat. Drugs Exp Clin Res. 1992;18(11-12):447-59.
• [34] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [35] Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am J Physiol. 1999 Oct;277(4 Pt 1):G867-74.
• [36] Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
• [37] Astrocytes and interneurons in memory processing in the chick hippocampus: roles for G-coupled protein receptors, GABA(B) and mGluR1. Neurochem Res. 2009 Oct;34(10):1712-20.
• [38] The role of group II and III metabotropic glutamate receptors in modulation of miniature synaptic activity in frog spinal cord motoneurons. Tsitologiia. 2008;50(9):747-56.
• [39] Discovery of a Negative Allosteric Modulator of GABAB Receptors. ACS Med Chem Lett. 2014 May 27;5(7):742-7.
• [40] Ca(2+) requirement for high-affinity gamma-aminobutyric acid (GABA) binding at GABA(B) receptors: involvement of serine 269 of the GABA(B)R1 subunit. Mol Pharmacol. 2000 Mar;57(3):419-26.