GABOXADOL

Details

Stereochemistry	ACHIRAL
Molecular Formula	C6H8N2O2
Molecular Weight	140.1399
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

OC1=NOC2=C1CCNC2

InChI

InChIKey=ZXRVKCBLGJOCEE-UHFFFAOYSA-N

InChI=1S/C6H8N2O2/c9-6-4-1-2-7-3-5(4)10-8-6/h7H,1-3H2,(H,8,9)

HIDE SMILES / InChI

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/28993837 | https://harpers.org/archive/2013/08/gaboxadol/5/ | https://www.ncbi.nlm.nih.gov/pubmed/15451401 | http://www.ovidrx.com/our-pipeline/

Gaboxadol (or THIP) is a direct GABA mimetic ligand at delta-containing receptors. Gaboxadol went into human clinical trials to test if the drug promoted sleep. It was generally well tolerated. Gaboxadol enhances delta power in NREM sleep in humans. Gaboxadol failed in Phase III for sleep studies. The side effects of Gaboxadol have been described as mild and similar in quality to those of other GABA-mimetics. Gaboxadol is in development with Ovid Therapeutics as a treatment for Angelman syndrome, fragile X syndrome and epilepsy.

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
GABA-A receptor; anion channel 202 Target ID: CHEMBL2093872 Sources: http://adisinsight.springer.com/drugs/800014543 \| https://www.ncbi.nlm.nih.gov/pubmed/28993837 \| http://www.ovidrx.com/our-pipeline/	Agonist 2678

Conditions

Condition	Modality	Highest Phase	Product
Insomnia 108 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22057018 https://www.ncbi.nlm.nih.gov/pubmed/22003345	Primary	Phase III 656	Unknown Approved Use Unknown
Major depressive disorder 173 Sources: https://www.ncbi.nlm.nih.gov/pubmed/22008735	Primary	Phase II 1132	Unknown Approved Use Unknown
Angelman syndrome 4 Sources: http://www.ovidrx.com/our-pipeline/	Primary	Phase II 1132	Unknown Approved Use Unknown

C_max

Value	Dose	Co-administered	Analyte	Population
123 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
147 ng/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

AUC

Value	Dose	Co-administered	Analyte	Population
408 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
440 ng × h/mL EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

T_1/2

Value	Dose	Co-administered	Analyte	Population
2.1 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: MALE food status: UNKNOWN
1.5 h EXPERIMENT https://pubmed.ncbi.nlm.nih.gov/19094161	10 mg single, oral dose: 10 mg route of administration: Oral experiment type: SINGLE co-administered:		GABOXADOL plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE food status: UNKNOWN

Doses

Dose	Population	Adverse events
10 mg single, oral (unknown) Studied dose Dose: 10 mg Route: oral Route: single Dose: 10 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19094161	healthy n = 14 Health Status: healthy Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/19094161	Disc. AE: vomiting, Vasovagal reaction... AEs leading to discontinuation/dose reduction: vomiting (1 pt) Vasovagal reaction (1 pt) Sources: https://pubmed.ncbi.nlm.nih.gov/19094161
15 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19346160	unhealthy n = 153 Health Status: unhealthy Condition: primary insomnia Sex: M+F Food Status: UNKNOWN Population Size: 153 Sources: https://pubmed.ncbi.nlm.nih.gov/19346160	Disc. AE: Dizziness, headache... AEs leading to discontinuation/dose reduction: Dizziness (9.2%) headache (9.2%) Sources: https://pubmed.ncbi.nlm.nih.gov/19346160

AEs

AE	Significance	Dose	Population
Vasovagal reaction	1 pt Disc. AE	10 mg single, oral (unknown) Studied dose Dose: 10 mg Route: oral Route: single Dose: 10 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19094161	healthy n = 14 Health Status: healthy Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/19094161
vomiting	1 pt Disc. AE	10 mg single, oral (unknown) Studied dose Dose: 10 mg Route: oral Route: single Dose: 10 mg Sources: https://pubmed.ncbi.nlm.nih.gov/19094161	healthy n = 14 Health Status: healthy Sex: M+F Food Status: UNKNOWN Population Size: 14 Sources: https://pubmed.ncbi.nlm.nih.gov/19094161
Dizziness	9.2% Disc. AE	15 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19346160	unhealthy n = 153 Health Status: unhealthy Condition: primary insomnia Sex: M+F Food Status: UNKNOWN Population Size: 153 Sources: https://pubmed.ncbi.nlm.nih.gov/19346160
headache	9.2% Disc. AE	15 mg 1 times / day multiple, oral (unknown) Studied dose Dose: 15 mg, 1 times / day Route: oral Route: multiple Dose: 15 mg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19346160	unhealthy n = 153 Health Status: unhealthy Condition: primary insomnia Sex: M+F Food Status: UNKNOWN Population Size: 153 Sources: https://pubmed.ncbi.nlm.nih.gov/19346160

Sourcing

Vendor/Aggregator	ID	URL
1PlusChem LLC	1P003R6A	https://www.1pchem.com/search?query=1P003R6A
1PlusChem LLC	1P006TKI	https://www.1pchem.com/search?query=1P006TKI
A2B Chem	AB74386	http://a2bchem.com/prod/AB74386
AA Blocks	AA003QMU	http://aablocks.com/goods/Goods/detail?id=AA003QMU
AK Scientific	7955AL	https://aksci.com/item_detail.php?cat=7955AL
Alfa Chemistry	85118-33-8	http://www.alfa-chemistry.com/search.aspx?q=85118-33-8
ApexBio Technology	B6460	https://www.apexbt.com/catalogsearch/result/?q=B6460
AstaTech	P17040	http://astatechinc.com/CPSResult.php?CRNO=P17040
BOC Sciences	64603-91-4	http://www.bocsci.com/description.asp?cas=64603-91-4
Cayman Chemical	16355	http://www.caymanchem.com/app/template/Product.vm/catalog/16355
Chem Scene	CS-0002508	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-0002508
Chemspace	CSC000065342	https://chem-space.com/CSC000065342
Chemspace	CSC015310339	https://chem-space.com/CSC015310339
Enamine	BBV-38271272	http://www.enaminestore.com/catalog/BBV-38271272
Enamine	BBV-38393882	http://www.enaminestore.com/catalog/BBV-38393882
Enamine	EN300-152453	https://www.enaminestore.com/catalog/EN300-152453
Fluorochem	535017	http://www.fluorochem.co.uk/Products/Product?code=535017
KeyOrganics	AS-53745	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-53745
Lab Network	LN01296249	https://labnetwork.com/frontend-app/p/#!/moleculedetails/LN01296249
MedChem Express	HY-10233	https://www.medchemexpress.com/search.html?q=HY-10233&ft=&fa=&fp=
MolPort	MolPort-003-666-496	https://www.molport.com/shop/molecule-link/MolPort-003-666-496
MolPort	MolPort-006-141-665	https://www.molport.com/shop/molecule-link/MolPort-006-141-665
MuseChem	R042364	https://www.musechem.com/product/R042364.html
Princeton BioMolecular Research	PBMR221636	http://www.princetonbio.com/order_online?common_id=PBMR221636
ShangHai Biochempartner	BCP07031	http://www.biochempartner.com/search_BCP07031
ShangHai Biochempartner	BCP16610	http://www.biochempartner.com/search_BCP16610
Tocris	807	https://www.tocris.com/search.php?Type=QuickSearch&Value=0807
Toronto Research Chemicals	C432755	https://www.trc-canada.com/product-detail/?CatNum=C432755
Toronto Research Chemicals	KIT1240	https://www.trc-canada.com/product-detail/?CatNum=KIT1240
eMolecules	300000141	https://orderbb.emolecules.com/search/#?query=300000141
eMolecules	300575231	https://orderbb.emolecules.com/search/#?query=300575231
eMolecules	42682706	https://orderbb.emolecules.com/search/#?query=42682706
eMolecules	50577872	https://orderbb.emolecules.com/search/#?query=50577872
eMolecules	93433782	https://orderbb.emolecules.com/search/#?query=93433782
eNovation Chemicals	D767308	https://www.enovationchem.com/Products.asp?SEARCHTEXT=D767308&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-8440237252	https://mcule.com/MCULE-8440237252/

PubMed

Title	Date	PubMed
Antagonism by NOS inhibition of the behavioral effects of benzodiazepine and GABAA receptor agonists in the mouse elevated plus-maze.	2004 Aug	15136793
GABA receptor modulation of 5-HT neuronal firing: characterization and effect of moderate in vivo variations in glucocorticoid levels.	2004 Dec	15337305
Charged residues at the 2' position of human GABAC rho 1 receptors invert ion selectivity and influence open state probability.	2004 Dec 24	15485818
Gaboxadol. Lundbeck/Merck.	2004 Jul	15298075
Effects of a low dose of ethanol in an animal model of premenstrual anxiety.	2004 May	15353172
Compounds exhibiting selective efficacy for different beta subunits of human recombinant gamma-aminobutyric acid A receptors.	2004 Nov	15210837
Over-expression of the fyn-kinase gene reduces hypnotic sensitivity to ethanol in mice.	2004 Nov 30	15531078
GABA pharmacology--what prospects for the future?	2004 Oct 15	15451396
Altered pharmacology of synaptic and extrasynaptic GABAA receptors on CA1 hippocampal neurons is consistent with subunit changes in a model of alcohol withdrawal and dependence.	2004 Sep	15126642
Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys.	2005 Apr	15765255
Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects.	2005 Apr	15602499
Calcium-stimulated adenylyl cyclases are critical modulators of neuronal ethanol sensitivity.	2005 Apr 20	15843614
Ischemic tolerance induction in organotypic hippocampal slices: role for the GABA(A) receptor?	2005 Aug 12-19	15908115
An extrasynaptic GABAA receptor mediates tonic inhibition in thalamic VB neurons.	2005 Dec	16162835
Internalized GABA-receptor subunits are transferred to an intracellular pool associated with the postsynaptic density.	2005 Jan	15673433
Gateways to clinical trials.	2005 Jun	16082422
Pharmacological characterisation of place escape/avoidance behaviour in the rat chronic constriction injury model of neuropathic pain.	2006 Apr	16479373
Sleep circuitry and the hypnotic mechanism of GABAA drugs.	2006 Apr 15	17557503
THIP, a hypnotic and antinociceptive drug, enhances an extrasynaptic GABAA receptor-mediated conductance in mouse neocortex.	2006 Aug	16221925
Treating insomnia: Current and investigational pharmacological approaches.	2006 Dec	16876255
Involvement of GABAergic modulation of antinociception induced by morphine microinjected into the ventrolateral orbital cortex.	2006 Feb 16	16448630
Potent 4-arylalkyl-substituted 3-isothiazolol GABA(A) competitive/noncompetitive antagonists: synthesis and pharmacology.	2006 Feb 23	16480274
Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors.	2006 Feb 8	16467523
Impact of epsilon and theta subunits on pharmacological properties of alpha3beta1 GABAA receptors expressed in Xenopus oocytes.	2006 Jan 13	16412217
delta-Subunit containing GABAA receptor knockout mice are less sensitive to the actions of 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol.	2006 Jul 17	16777089
Steroid withdrawal in the mouse results in anxiogenic effects of 3alpha,5beta-THP: a possible model of premenstrual dysphoric disorder.	2006 Jun	16193334
Gateways to clinical trials.	2006 Oct	17136234
Deletion of the GABA(A) receptor alpha1 subunit increases tonic GABA(A) receptor current: a role for GABA uptake transporters.	2006 Sep 6	16957088
Flumazenil selectively prevents the increase in alpha(4)-subunit gene expression and an associated change in GABA(A) receptor function induced by ethanol withdrawal.	2007 Aug	17403139
The progesterone metabolite allopregnanolone potentiates GABA(A) receptor-mediated inhibition of 5-HT neuronal activity.	2007 Jan 15	16574382
Gateways to clinical trials.	2007 Jan-Feb	17344945
New perspectives for the treatment of disorders of sleep and arousal.	2007 Jul	17652996
Lack of generalisation between the GABAA receptor agonist, gaboxadol, and allosteric modulators of the benzodiazepine binding site in the rat drug discrimination procedure.	2007 Jul	17361395
Dual GABAA receptor-mediated inhibition in rat presympathetic paraventricular nucleus neurons.	2007 Jul 15	17495040
[New hypnotics: perspectives from sleep physiology].	2007 Jul-Aug	18265473
The importance of genetic background on pain behaviours and pharmacological sensitivity in the rat spared serve injury model of peripheral neuropathic pain.	2007 Jun 14	17383631
Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia.	2007 Mar	17425224
The EEG effects of THIP (Gaboxadol) on sleep and waking are mediated by the GABA(A)delta-subunit-containing receptors.	2007 Mar	17408425
GABAA receptors in the thalamus: alpha4 subunit expression and alcohol sensitivity.	2007 May	17521848
Plasma and CNS concentrations of Gaboxadol in rats following subcutaneous administration.	2007 May 7	17362924
Identification of a domain in the delta subunit (S238-V264) of the alpha4beta3delta GABAA receptor that confers high agonist sensitivity.	2007 Nov	17711419
GABAergic modulation of binge-like ethanol intake in C57BL/6J mice.	2007 Nov	17698181
Development and validation of a selective and sensitive bioanalytical procedure for the quantitative determination of gaboxadol in human plasma employing mixed mode solid phase extraction and hydrophilic interaction liquid chromatography with tandem mass spectroscopic detection.	2007 Oct 15	17851145
Postnatal development and kinetics of [3H]gaboxadol binding in rat brain: in vitro homogenate binding and quantitative autoradiography.	2007 Sep 19	17692833
Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over-expressing hippocampal extrasynaptic alpha6beta GABA(A) receptors.	2008 Apr	18021290
The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells.	2008 Feb 15	18079158
Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells.	2008 Jan	18070250
The role of GABA(A) receptors in the control of transient lower oesophageal sphincter relaxations in the dog.	2008 Mar	18204479
Discriminative stimulus effects of tiagabine and related GABAergic drugs in rats.	2008 May	18264695
Efficacy of the selective extrasynaptic GABA A agonist, gaboxadol, in a model of transient insomnia: a randomized, controlled clinical trial.	2008 May	17765013

Patents

Sample Use Guides

In Vivo Use Guide

5 or 10 mg once daily before bedtime for 8 weeks

Route of Administration: Oral

In Vitro Use Guide

In recombinant experiments it was found that δ subunit coexpression leads to receptors activated by nanomolar THIP concentrations (EC(50) of 30-50 nM for α4β3δ and α6β3δ), a sensitivity almost 1,000-fold higher than receptors formed by α4/6 and β3 subunits. In contrast, γ2 subunit expression significantly reduces THIP sensitivity.

Name

Type

Language

GABOXADOL

Official Name

English

LU-02-030

Code

English

gaboxadol [INN]

Common Name

English

GABOXADOL [USAN]

Common Name

English

GABOXADOL [MI]

Common Name

English

ISOXAZOLO(5,4-C)PYRIDIN-3(2H)-ONE, 4,5,6,7-TETRAHYDRO-

Systematic Name

English

Gaboxadol [WHO-DD]

Common Name

English

4,5,6,7-TETRAHYDROISOXAZOLO(5,4-C)PYRIDIN-3-OL

Systematic Name

English

NSC-759585

Code

English

4,5,6,7-Tetrahydroisoxazolo[5,4-c]pyridin-3(2H)-one

Systematic Name

English

LU-02030

Code

English

MK-0928

Code

English

LU 02-030

Code

English

Classification Tree Code System Code

FDA ORPHAN DRUG

605517