VANOXERINE

Investigational

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H32F2N2O
Molecular Weight	450.5643
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

c1ccc(cc1)CCCN2CCN(CC2)CCOC(c3ccc(cc3)F)c4ccc(cc4)F

InChI

InChIKey=NAUWTFJOPJWYOT-UHFFFAOYSA-N

InChI=1S/C28H32F2N2O/c29-26-12-8-24(9-13-26)28(25-10-14-27(30)15-11-25)33-22-21-32-19-17-31(18-20-32)16-4-7-23-5-2-1-3-6-23/h1-3,5-6,8-15,28H,4,7,16-22H2

HIDE SMILES / InChI

Molecular Formula	C28H32F2N2O
Molecular Weight	450.5643
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11249581 | https://www.ncbi.nlm.nih.gov/pubmed/19817928 | https://www.ncbi.nlm.nih.gov/pubmed/26616666

Vanoxerine, also known as GBR-12909, is a piperazine derivative exhibiting potent selective inhibition of sodium-dependent dopamine reuptake transporters. Vanoxerine has been in clinical trials for Parkinsonism, depression and cocaine addiction but lacked efficacy. Vanoxerine has also been observed as a potent blocker of the following channels: cardiac hERG/IKr potassium channel, Calcium channel, voltage-dependent, L type, alpha 1C subunit (also known as Cav1.2) and voltage-gated sodium channel Nav 1.5. Vanoxerine was studied as a potential treatment for atrial fibrillation. However, phase III clinical trials for this condition were terminated because of cardiac safety concerns. Research also indicates that vanoxerine may have additional mechanisms of action including antagonist action at nicotinic acetylcholine receptors (nAChRs).

CNS Activity

Originator

Approval Year

Targets

Primary Target	Pharmacology	Potency
Potassium voltage-gated channel subfamily H member 2 1 Target ID: Q12809\|\|\|Q9BUT7 Gene ID: 3757.0 Gene Symbol: KCNH2 Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666	Blocker 231	9.3 nM [IC50]
Voltage-dependent L-type calcium channel subunit alpha-1C 1 Target ID: Q13936\|\|\|Q13922\|\|\|Q13930\|\|\|Q4VMI9 Gene ID: 775.0 Gene Symbol: CACNA1C Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666	Blocker 231	16.2 nM [IC50]
Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584	Antagonist 1131	2.32 µM [IC50]
Dopamine transporter 92 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078	Inhibitor 3315	0.7 nM [Ki]
Sodium channel protein type 5 subunit alpha 7 Target ID: Q14524\|\|\|E9PFW7 Gene ID: 6331.0 Gene Symbol: SCN5A Target Organism: Homo sapiens (Human) Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666	Blocker 231	34.6 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Atrial fibrillation 51 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817929	Primary	Phase III 257	Unknown Approved Use Unknown
Cocaine addiction 8 Sources: https://clinicaltrials.gov/ct2/show/NCT00218049	Primary	Phase I 135	Unknown Approved Use Unknown
Depression 92 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2530094	Primary	Not Provided 208	Unknown Approved Use Unknown
Parkinson's disease 83 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817928	Primary	Not Provided 208	Unknown Approved Use Unknown

Doses

Dose	Population	Adverse events
400 mg single, oral (unknown) Studied dose Dose: 400 mg Route: oral Route: single Dose: 400 mg Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283	unhealthy n = 26 Health Status: unhealthy Condition: atrial fibrillation Sex: M+F Food Status: UNKNOWN Population Size: 26 Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283	Disc. AE: Polymorphic ventricular tachycardia, torsades de pointe... AEs leading to discontinuation/dose reduction: Polymorphic ventricular tachycardia (serious, 11.54%) torsades de pointe (serious, 3.85%) Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283

AEs

AE	Significance	Dose	Population
Polymorphic ventricular tachycardia	serious, 11.54% Disc. AE	400 mg single, oral (unknown) Studied dose Dose: 400 mg Route: oral Route: single Dose: 400 mg Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283	unhealthy n = 26 Health Status: unhealthy Condition: atrial fibrillation Sex: M+F Food Status: UNKNOWN Population Size: 26 Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283
torsades de pointe	serious, 3.85% Disc. AE	400 mg single, oral (unknown) Studied dose Dose: 400 mg Route: oral Route: single Dose: 400 mg Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283	unhealthy n = 26 Health Status: unhealthy Condition: atrial fibrillation Sex: M+F Food Status: UNKNOWN Population Size: 26 Sources: https://clinicaltrials.gov/ct2/show/results/NCT02454283

Sourcing

Vendor/Aggregator	ID	URL
001 Chemical	DY106842	https://www.001chemical.com/chem/search?q=DY106842
1PlusChem LLC	1P006HBF	https://www.1pchem.com/search?query=1P006HBF
A2B Chem	AD01579	http://a2bchem.com/prod/AD01579
AK Scientific	4145AH	https://aksci.com/item_detail.php?cat=4145AH
AbovChem LLC	HY-13217A	http://www.abovchem.com/pc/en/product_list.aspx?wd=HY-13217A
Ambeed	A268853	http://www.ambeed.com/search/Search.html?keyword=A268853
Angene	AGN-PC-0JLEKB	http://www.angenechemical.com/productshow/AGN-PC-0JLEKB.html
ApexBio Technology	B3248	https://www.apexbt.com/catalogsearch/result/?q=B3248
ApexBio Technology	B3249	https://www.apexbt.com/catalogsearch/result/?q=B3249
AstaTech	C10391	http://astatechinc.com/CPSResult.php?CRNO=C10391
BLD Pharm	BD156353	http://www.bldpharm.com/search/Search.html?keyword=BD156353
BLD Pharm	BD316951	http://www.bldpharm.com/search/Search.html?keyword=BD316951
BOC Sciences	67469-69-6	http://www.bocsci.com/description.asp?cas=67469-69-6
BOC Sciences	67469-78-7	http://www.bocsci.com/description.asp?cas=67469-78-7
BioSynth	J-502921	https://www.biosynth.com/en/products/life-science/other-biochemicals/products/J-502921
Cayman Chemical	15622	http://www.caymanchem.com/app/template/Product.vm/catalog/15622
Chem Scene	CS-2713	http://www.chemscene.com/goproductList/searchProductList?productObj=CS-2713
ChemShuttle	106833	https://www.chemshuttle.com/catalogsearch/result/?q=106833
Combi-Blocks	QH-6623	http://www.combi-blocks.com/cgi-bin/find.cgi?QH-6623
Hairui	HR117738	http://www.hairuichem.com/en/product/search.do?q=HR117738
KeyOrganics	AS-62613	http://www.keyorganicsinc.com/bionet/catalogsearch/result?q=AS-62613
Matrix Scientific	132201	http://www.matrixscientific.com/132201.html
MedChem Express	HY-13217	https://www.medchemexpress.com/search.html?q=HY-13217&ft=&fa=&fp=
MolPort	MolPort-003-983-576	https://www.molport.com/shop/molecule-link/MolPort-003-983-576
MolPort	MolPort-046-416-952	https://www.molport.com/shop/molecule-link/MolPort-046-416-952
Molcore	MC106842	http://www.molcore.com/CatMC106842.html
Molnova	M15575	https://www.molnova.com/en/serch-list.html?keywords=M15575
Molnova	M15576	https://www.molnova.com/en/serch-list.html?keywords=M15576
MuseChem	I004536	https://www.musechem.com/product/I004536.html
PI Chemicals	PI-45614	http://www.pipharm.com/catalog_products/PI-45614.html
ShangHai Biochempartner	BCP000300	http://www.biochempartner.com/search_BCP000300
ShangHai Biochempartner	BCP02306	http://www.biochempartner.com/search_BCP02306
TargetMol	T7153	https://www.targetmol.com/search?keyword=T7153
Tocris	421	https://www.tocris.com/search.php?Type=QuickSearch&Value=0421
eMolecules	1933654	https://orderbb.emolecules.com/search/#?query=1933654
eMolecules	299983474	https://orderbb.emolecules.com/search/#?query=299983474
eMolecules	50283008	https://orderbb.emolecules.com/search/#?query=50283008
eMolecules	536707	https://orderbb.emolecules.com/search/#?query=536707
eNovation Chemicals	K31304	https://www.enovationchem.com/Products.asp?SEARCHTEXT=K31304&searchbtn.x=0&searchbtn.y=0
mcule	MCULE-2896065228	https://mcule.com/MCULE-2896065228/
mcule	MCULE-9401171768	https://mcule.com/MCULE-9401171768/

PubMed

Title	Date	PubMed
Oxygenated analogues of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909) as potential extended-action cocaine-abuse therapeutic agents.	1999 Dec 2	10585212
A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats.	2000 Aug 4	10904129
Effect of GBR 12909 and fluoxetine on the acute and long term changes induced by MDMA ('ecstasy') on the 5-HT and dopamine concentrations in mouse brain.	2001	11077072
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.	2001 Apr	11371002
Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys.	2001 Apr	11349390
Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity.	2001 Apr 27	11311862
[3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel probes for the dopamine transporter.	2001 Dec 17	11720867
Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus.	2001 Jul	11377917
Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene.	2001 May 1	11312315
Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior.	2001 Nov	11702085
Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge.	2001 Nov 29	11704265
Synthesis and biological evaluation of tropane-like 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) analogues.	2001 Nov 8	11689080
Mechanisms of MPP(+) incorporation into cerebellar granule cells.	2001 Sep 15	11704348
Drug addiction. Part III. Pharmacotherapy of addiction.	2001 Sep-Oct	11990060
Locomotor activity induced by noncompetitive NMDA receptor antagonists versus dopamine transporter inhibitors: opposite strain differences in inbred long-sleep and short-sleep mice.	2002 Apr	11981117
Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites.	2002 Dec	12413863
New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.	2002 Dec 15	12444599
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.	2002 Jul	12062575
Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate.	2002 Jun	12023554
Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.	2002 Jun-Aug	12175869
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.	2002 May 17	11988230
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens.	2002 Oct	12208558
Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.	2003	12732244
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture.	2003 Aug	12871774
Synthesis and dopamine transporter affinity of chiral 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(2-hydroxypropyl)piperazines as potential cocaine abuse therapeutic agents.	2003 Feb 10	12565970
Interaction of cis-(6-benzhydrylpiperidin-3-yl)benzylamine analogues with monoamine transporters: structure-activity relationship study of structurally constrained 3,6-disubstituted piperidine analogues of (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidin-4-ylmethyl]amine.	2003 May 22	12747792
Behavioral effects of rimcazole analogues alone and in combination with cocaine.	2003 May 9	12742518
Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.	2003 Sep	12808005
Agents in development for the management of cocaine abuse.	2004	15233592
A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding.	2004	15120861
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.	2004 Aug 23	15306127
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.	2004 Feb	14756813
Mutation of Trp84 and Asp313 of the dopamine transporter reveals similar mode of binding interaction for GBR12909 and benztropine as opposed to cocaine.	2004 May	15140185
Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake.	2004 May	15086525
Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission.	2004 May	14724217
Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors.	2004 Nov	15240827
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.	2004 Oct	15226739
Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).	2004 Sep	15302679

Patents

Sample Use Guides

In Vivo Use Guide

oral single doses of 100, 200 and 300 mg GBR 12909 (VANOXERINE) | 50, 100 and 150 mg GBR 12909 and placebo once daily for 7 days

Route of Administration: Oral

In Vitro Use Guide

To compare Multiple Ion Channel Effects (MICE) effects, it was measured block of hERG, hCav 1.2 and hNav 1.5 channel currents using concentrations related to drug exposure levels: 0-10000 nM for vanoxerine. It was defined the concentration-responses (CRs) of vanoxerine for hERG (9 nM), hCav 1.2 (16 nM) and peak and late hNav 1.5 currents (35 nM and 85 nM, correspondingly).

Substance Class	Chemical Created by `admin` on `Sat Jun 26 07:39:55 UTC 2021` Edited by `admin` on `Sat Jun 26 07:39:55 UTC 2021`
Record UNII	90X28IKH43
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

VANOXERINE

Official Name

English

GBR 12909

Code

English

1-(2-(BIS(P-FLUOROPHENYL)METHOXY)ETHYL)-4-(3-PHENYLPROPYL)PIPERAZINE

Common Name

English

VANOXERINE [INN]

Common Name

English

GBR-12909

Code

English

Classification Tree Code System Code

NCI_THESAURUS

C66884