Target Information

Target General Information

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Target ID

T42446 (Former ID: TTDS00022)

Target Name

Gamma-aminobutyric acid B receptor (GABBR)

Synonyms

Gamma-aminobutyric acid type B receptor; GPRC3; GABABR; GABA-BR; GABA-B-R; GABA-B receptor

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Gene Name

GABBR1; GABBR2

Target Type

Successful target

[1]

Disease

[+] 4 Target-related Diseases

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

Epilepsy/seizure [ICD-11: 8A61-8A6Z]

Multiple sclerosis [ICD-11: 8A40]

Narcolepsy [ICD-11: 7A20]

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.

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BioChemical Class

GPCR glutamate

UniProt ID

GABR1_HUMAN ; GABR2_HUMAN

Sequence

MLLLLLLAPLFLRPPGAGGAQTPNATSEGCQIIHPPWEGGIRYRGLTRDQVKAINFLPVD
YEIEYVCRGEREVVGPKVRKCLANGSWTDMDTPSRCVRICSKSYLTLENGKVFLTGGDLP
ALDGARVDFRCDPDFHLVGSSRSICSQGQWSTPKPHCQVNRTPHSERRAVYIGALFPMSG
GWPGGQACQPAVEMALEDVNSRRDILPDYELKLIHHDSKCDPGQATKYLYELLYNDPIKI
ILMPGCSSVSTLVAEAARMWNLIVLSYGSSSPALSNRQRFPTFFRTHPSATLHNPTRVKL
FEKWGWKKIATIQQTTEVFTSTLDDLEERVKEAGIEITFRQSFFSDPAVPVKNLKRQDAR
IIVGLFYETEARKVFCEVYKERLFGKKYVWFLIGWYADNWFKIYDPSINCTVDEMTEAVE
GHITTEIVMLNPANTRSISNMTSQEFVEKLTKRLKRHPEETGGFQEAPLAYDAIWALALA
LNKTSGGGGRSGVRLEDFNYNNQTITDQIYRAMNSSSFEGVSGHVVFDASGSRMAWTLIE
QLQGGSYKKIGYYDSTKDDLSWSKTDKWIGGSPPADQTLVIKTFRFLSQKLFISVSVLSS
LGIVLAVVCLSFNIYNSHVRYIQNSQPNLNNLTAVGCSLALAAVFPLGLDGYHIGRNQFP
FVCQARLWLLGLGFSLGYGSMFTKIWWVHTVFTKKEEKKEWRKTLEPWKLYATVGLLVGM
DVLTLAIWQIVDPLHRTIETFAKEEPKEDIDVSILPQLEHCSSRKMNTWLGIFYGYKGLL
LLLGIFLAYETKSVSTEKINDHRAVGMAIYNVAVLCLITAPVTMILSSQQDAAFAFASLA
IVFSSYITLVVLFVPKMRRLITRGEWQSEAQDTMKTGSSTNNNEEEKSRLLEKENRELEK
IIAEKEERVSELRHQLQSRQQLRSRRHPPTPPEPSGGLPRGPPEPPDRLSCDGSRVHLLY
K

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HIT2.0 ID

T09TS5

Drugs and Modes of Action

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Approved Drug(s)

[+] 4 Approved Drugs

Baclofen

Drug Info

Approved

Multiple sclerosis

[2], [3]

Gabapentin

Drug Info

Approved

Complex partial seizure

[4], [5]

Gamma Hydroxybutyric Acid

Drug Info

Approved

Narcolepsy

[6], [7]

Progabide

Drug Info

Approved

Depression

[8]

Clinical Trial Drug(s)

[+] 7 Clinical Trial Drugs

Arabaclofen

Drug Info

Phase 3

Fragile X syndrome

[9]

Arbaclofen placarbil

Drug Info

Phase 3

Fragile X syndrome

[10]

[3H](R)-(-)-baclofen

Drug Info

Phase 3

Multiple sclerosis

[11]

ASP8062

Drug Info

Phase 2

Fibromyalgia

[12]

GSK683699

Drug Info

Phase 2

Inflammatory bowel disease

[13]

SGS742

Drug Info

Phase 2

Schizophrenia

[14]

SSTarbaclofen

Drug Info

Phase 2

Fragile X syndrome

[15], [16]

Discontinued Drug(s)

[+] 5 Discontinued Drugs

SUN-09

Drug Info

Discontinued in Phase 3

Hypertonia

[17]

AZD3355

Drug Info

Discontinued in Phase 2

Gastroesophageal reflux disease

[18], [19]

AZD-9343

Drug Info

Discontinued in Phase 1

Gastroesophageal reflux disease

[20]

CGP-35348

Drug Info

Terminated

Epilepsy

[22], [23]

SCH 50911

Drug Info

Terminated

Absence seizure

[24], [25]

Preclinical Drug(s)

[+] 1 Preclinical Drugs

ADX-71943

Drug Info

Preclinical

Gastroesophageal reflux disease

[21]

Mode of Action

[+] 5 Modes of Action

Modulator

[+] 15 Modulator drugs

Baclofen

Drug Info

[26], [27]

Gamma Hydroxybutyric Acid

Drug Info

[29]

Arbaclofen placarbil

Drug Info

[33]

ASP8062

Drug Info

[12]

SGS742

Drug Info

[14]

SSTarbaclofen

Drug Info

[36]

SUN-09

Drug Info

[37]

AZD3355

Drug Info

[38]

AZD-9343

Drug Info

[39]

ADX-71943

Drug Info

[40]

CGP-35348

Drug Info

[41], [42]

AVE-1876

Drug Info

[50]

BHF-177

Drug Info

[27]

CGP-29030A

Drug Info

[55], [56]

GABA-B receptor PAM

Drug Info

[27]

Antagonist

[+] 14 Antagonist drugs

Gabapentin

Drug Info

[28]

SCH 50911

Drug Info

[43]

2-hydroxy-saclofen

Drug Info

[47]

CGP 46381

Drug Info

[51]

CGP 54626A

Drug Info

[52], [53]

CGP 55845

Drug Info

[51]

CGP 56999A

Drug Info

[47]

CGP 62349

Drug Info

[54], [53]

CGP 64213

Drug Info

[47]

CGP 71872

Drug Info

[47]

Phaclofen

Drug Info

[59], [60]

saclofen

Drug Info

[47], [53]

[125I]CGP 64213

Drug Info

[62], [47]

[125I]CGP 71872

Drug Info

[47]

Agonist

[+] 7 Agonist drugs

Progabide

Drug Info

[1], [30], [31]

Arabaclofen

Drug Info

[32]

[3H](R)-(-)-baclofen

Drug Info

[34]

amino-propylphosphinic acid

Drug Info

[34], [47]

CGP 47656

Drug Info

[47], [44]

CGP-44532

Drug Info

[58], [57]

TG-3030

Drug Info

[27]

Inhibitor

[+] 23 Inhibitor drugs

GSK683699

Drug Info

[35]

((E)-3-Amino-propenyl)-methyl-phosphinic acid

Drug Info

[44]

((Z)-3-Amino-propenyl)-methyl-phosphinic acid

Drug Info

[44]

(3-Amino-1-ethyl-propyl)-methyl-phosphinic acid

Drug Info

[44]

(3-Amino-1-hydroxy-propyl)-methyl-phosphinic acid

Drug Info

[44]

(3-Amino-phenyl)-phosphonic acid diphenyl ester

Drug Info

[45]

(3-Amino-propyl)-hexyl-phosphinic acid

Drug Info

[46]

(3-Amino-propyl)-hydroxymethyl-phosphinic acid

Drug Info

[44]

(3-Amino-propyl)-phosphonic acid

Drug Info

[45]

(R)-5-Amino-3-(4-chloro-phenyl)-pentanoic acid

Drug Info

[26]

3-ammoniopropane-1-sulfinate

Drug Info

[48]

4-Amino-3-(2-chloro-phenyl)-butyric acid

Drug Info

[35]

4-Amino-3-(4-fluoro-phenyl)-butyric acid

Drug Info

[35]

4-Amino-3-(5-bromo-thiophen-2-yl)-butyric acid

Drug Info

[35]

4-Amino-3-(5-chloro-thiophen-2-yl)-butyric acid

Drug Info

[35]

4-Amino-3-(5-methyl-thiophen-2-yl)-butyric acid

Drug Info

[35]

4-Amino-3-benzofuran-2-yl-butyric acid

Drug Info

[49]

4-Amino-3-thiophen-2-yl-butyric acid

Drug Info

[35]

CGP-34938

Drug Info

[44]

CGP-35024

Drug Info

[57], [46]

CGP-35582

Drug Info

[44]

CGP-36216

Drug Info

[46]

[3H]CGP27492

Drug Info

[46]

Modulator (allosteric modulator)

[+] 1 Modulator (allosteric modulator) drugs

PMID25050158C14

Drug Info

[61]

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 Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-regulating microRNAs

Target-regulating microRNAs Info

Target Profiles in Patients

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Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 5 KEGG Pathways

cAMP signaling pathway

Neuroactive ligand-receptor interaction

GABAergic synapse

Estrogen signaling pathway

Morphine addiction

Reactome

[+] 4 Reactome Pathways

Activation of G protein gated Potassium channels

G alpha (i) signalling events

Class C/3 (Metabotropic glutamate/pheromone receptors)

Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits

WikiPathways

[+] 5 WikiPathways

GPCRs, Class C Metabotropic glutamate, pheromone

Neurotransmitter Receptor Binding And Downstream Transmission In The Postsynaptic Cell

Potassium Channels

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 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.

REF 2

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: 1084).

REF 3

Development of medications for alcohol use disorders: recent advances and ongoing challenges. Expert Opin Emerg Drugs. 2005 May;10(2):323-43.

REF 4

REF 5

Use of second-generation antiepileptic drugs in the pediatric population. Paediatr Drugs. 2008;10(4):217-54.

REF 6

REF 7

Sodium oxybate: a review of its use in the management of narcolepsy. CNS Drugs. 2007;21(4):337-54.

REF 8

Natural products as sources of new drugs over the last 25 years. J Nat Prod. 2007 Mar;70(3):461-77.

REF 9

ClinicalTrials.gov (NCT01555333) An Open Label Extension Study in Subjects With Fragile X Syndrome (209FX303). U.S. National Institutes of Health.

REF 10

ClinicalTrials.gov (NCT01325220) Efficacy and Safety Study of STX209 (Arbaclofen) for the Treatment of Social Withdrawal in Children With Fragile X Syndrome. U.S. National Institutes of Health.

REF 11

ClinicalTrials.gov (NCT02869425) To Assess Effects of Arbaclofen ER Tablets Compared With Placebo on Sperm Parameters in Male Subjects With MS. U.S. National Institutes of Health.

REF 12

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

REF 13

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

REF 14

SGS742: the first GABA(B) receptor antagonist in clinical trials. Biochem Pharmacol. 2004 Oct 15;68(8):1479-87.

REF 15

ClinicalTrials.gov (NCT01288716) Study of Arbaclofen for the Treatment of Social Withdrawal in Subjects With Autism Spectrum Disorders. U.S. National Institutes of Health.

REF 16

Effects of STX209 (Arbaclofen) on Neurobehavioral Function in Children and Adults with Fragile X Syndrome: A Randomized, Controlled, Phase 2 Trial. Science Translational Medicine Vol 4, Issue 152 19 September 2012.

REF 17

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800038116)

REF 18

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800016139)

REF 20

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800018389)

REF 21

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800024111)

REF 22

REF 23

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002440)

REF 24

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800005684)

REF 26

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.

REF 27

REF 28

Gabapentin increases a tonic inhibitory conductance in hippocampal pyramidal neurons. Anesthesiology. 2006 Aug;105(2):325-33.

REF 29

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

REF 30

Pentobarbital-like discriminative stimulus effects of direct GABA agonists in rats. Psychopharmacology (Berl). 1993;110(3):295-301.

REF 31

Suppression by progabide of ethanol withdrawal syndrome in rats. Eur J Pharmacol. 1985 Mar 12;109(3):321-5.

REF 32

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.

REF 33

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.

REF 34

REF 35

3-Thienyl- and 3-furylaminobutyric acids. Synthesis and binding GABAB receptor studies. J Med Chem. 1991 Aug;34(8):2557-60.

REF 36

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.

REF 37

The effects of the GABA agonist, baclofen, on sleep and breathing. Eur Respir J. 1995 Feb;8(2):230-4.

REF 38

Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial.Gut.2013 Sep;62(9):1248-55.

REF 39

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.

REF 40

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.

REF 41

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.

REF 42

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.

REF 43

Activation of nigral dopamine neurons by the selective GABA(B)-receptor antagonist SCH 50911. J Neural Transm. 1999;106(5-6):383-94.

REF 44

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists. J Med Chem. 1995 Aug 18;38(17):3297-312.

REF 45

Phosphorus analogues of gamma-aminobutyric acid, a new class of anticonvulsants. J Med Chem. 1984 May;27(5):654-9.

REF 46

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).

REF 47

Expression cloning of GABA(B) receptors uncovers similarity to metabotropic glutamate receptors. Nature. 1997 Mar 20;386(6622):239-46.

REF 48

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).

REF 49

Synthesis and pharmacological evaluation of gamma-aminobutyric acid analogues. New ligand for GABAB sites. J Med Chem. 1987 Apr;30(4):743-6.

REF 50

Company report (Sanofi)

REF 51

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.

REF 52

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.

REF 53

Pharmacological characterisation of a cell line expressing GABA B1b and GABA B2 receptor subunits. Biochem Pharmacol. 2003 Apr 1;65(7):1103-13.

REF 54

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.

REF 55

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.

REF 56

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

REF 57

Inhibition of transient LES relaxations and reflux in ferrets by GABA receptor agonists. Am J Physiol. 1999 Oct;277(4 Pt 1):G867-74.

REF 58

Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.

REF 59

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.

REF 60

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.

REF 61

Discovery of a Negative Allosteric Modulator of GABAB Receptors. ACS Med Chem Lett. 2014 May 27;5(7):742-7.

REF 62

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.

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