VANOXERINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H32F2N2O
Molecular Weight	450.5633
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

FC1=CC=C(C=C1)C(OCCN2CCN(CCCC3=CC=CC=C3)CC2)C4=CC=C(F)C=C4

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	450.5633
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 6 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 537	9.3 nM [IC50]
Voltage-dependent L-type calcium channel subunit alpha-1C 4 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 537	16.2 nM [IC50]
Nicotinic acetylcholine receptor 10 Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584	Antagonist 2778	2.32 µM [IC50]
Dopamine transporter 180 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078	Inhibitor 8297	0.7 nM [Ki]
Sodium channel protein type 5 subunit alpha 9 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 537	34.6 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Atrial fibrillation 131 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817929	Primary	Phase III 656	Unknown Approved Use Unknown
Cocaine addiction 28 Sources: https://clinicaltrials.gov/ct2/show/NCT00218049	Primary	Phase I 428	Unknown Approved Use Unknown
Depression 235 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2530094	Primary	Not Provided 504	Unknown Approved Use Unknown
Parkinson's disease 226 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817928	Primary	Not Provided 504	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
Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice.	2002 Dec	12438556
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
Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys.	2002 Jul	12112412
Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.	2002 Jun-Aug	12175869
GBR-12909 effect on dopamine outflow depends on phosphorylation in the caudate nucleus of the rat.	2002 Nov	12211084
Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease.	2002 Oct	12151033
Piperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909): high affinity ligands for the dopamine transporter.	2002 Sep 12	12213078
Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates.	2002 Sep 13	12231385
Inhibition of vesicular uptake of monoamines by hyperforin.	2002 Sep 27	12215370
Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.	2003	12732244
1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3.	2003 Apr	12675912
Structure-activity relationship studies of highly selective inhibitors of the dopamine transporter: N-benzylpiperidine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine.	2003 Apr 10	12672246
Further exploration of 1-[2-[Bis-(4-fluorophenyl)methoxy]ethyl]piperazine (GBR 12909): role of N-aromatic, N-heteroaromatic, and 3-oxygenated N-phenylpropyl substituents on affinity for the dopamine and serotonin transporter.	2003 Apr 7	12657288
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
1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.	2003 Jan	12504872
S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats.	2003 Jan	12422372
Self-biting induced by activation of L-type calcium channels in mice: dopaminergic influences.	2003 Jan-Feb	12876427
Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.	2003 Mar 1	12629192
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
Inhibitory effect of the DA uptake blocker GBR 12909 on sodium channels of hippocampal neurons.	2003 Oct 27	14561926
Dopamine transporter as target for drug development of cocaine dependence medications.	2003 Oct 31	14612141
Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.	2003 Sep	12808005
Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter.	2003 Sep 1	12927856
Effects of dopamine indirect agonists and selective D1-like and D2-like agonists and antagonists on cocaine self-administration and food maintained responding in rats.	2004	15464142
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
Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain.	2004	14997015
An animal model with relevance to schizophrenia: sex-dependent cognitive deficits in osteogenic disorder-Shionogi rats induced by glutathione synthesis and dopamine uptake inhibition during development.	2004	14751276
In vivo evidence that genetic background controls impulse-dependent dopamine release induced by amphetamine in the nucleus accumbens.	2004 Apr	15056292
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.	2004 Aug 23	15306127
Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex.	2004 Aug 30	15262056
Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells.	2004 Aug 5	15265589
Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex.	2004 Feb	14756822
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.	2004 Feb	14756813
Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia.	2004 Feb	14751774
Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys.	2004 Jan	14563783
Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice.	2004 Jul	14985936
Cocaine-like discriminative stimulus effects of heroin: modulation by selective monoamine transport inhibitors.	2004 Jul	14985417
Effect of the mGluR5 antagonist 6-methyl-2-(phenylethynyl)pyridine (MPEP) on the acute locomotor stimulant properties of cocaine, D-amphetamine, and the dopamine reuptake inhibitor GBR12909 in mice.	2004 Jul	14726993
Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.	2004 Jun	14982963
Protection against cocaine toxicity in mice by the dopamine D3/D2 agonist R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol [(+)-PD 128,907].	2004 Mar	14711932
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
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
Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys.	2004 Sep	15064912

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 `Fri Dec 15 15:45:49 GMT 2023` Edited by `admin` on `Fri Dec 15 15:45:49 GMT 2023`
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