VANOXERINE HYDROCHLORIDE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C28H32F2N2O.2ClH
Molecular Weight	523.485
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

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

InChI

InChIKey=MIBSKSYCRFWIRU-UHFFFAOYSA-N

InChI=1S/C28H32F2N2O.2ClH/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;2*1H

HIDE SMILES / InChI

Molecular Formula	ClH
Molecular Weight	36.461
Charge	0
Count

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

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 530	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 530	16.2 nM [IC50]
Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584	Antagonist 2737	2.32 µM [IC50]
Dopamine transporter 172 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078	Inhibitor 8146	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 530	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 651	Unknown Approved Use Unknown
Cocaine addiction 26 Sources: https://clinicaltrials.gov/ct2/show/NCT00218049	Primary	Phase I 422	Unknown Approved Use Unknown
Depression 232 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2530094	Primary	Not Provided 505	Unknown Approved Use Unknown
Parkinson's disease 223 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817928	Primary	Not Provided 505	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
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
Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats.	2001 Apr	11259524
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
Chronic GBR 12909 administration differentially alters prodynorphin gene expression compared to cocaine.	2001 Feb 16	11226394
Negative interaction of dopamine D2 receptor antagonists and GBR 12909 and GBR 12935 dopamine uptake inhibitors in the nucleus accumbens.	2001 Feb 23	11230993
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.	2001 May	11411492
Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine.	2001 May	11401007
Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene.	2001 May 1	11312315
Effects of repeated GBR 12909 administration on brain stimulation reward.	2001 May 11	11426842
The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine.	2001 May-Jun	11420069
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
The dopamine transporter in mesencephalic cultures is refractory to physiological changes in membrane voltage.	2001 Oct 1	11567046
Similar enhancement of the discriminative stimulus effects of cocaine and GBR 12909 by heroin in squirrel monkeys.	2001 Sep	11605088
Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period.	2001 Sep	11566139
Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes.	2001 Sep	11502731
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
Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.	2002 Jan	11752114
Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines.	2002 Jan 15	11784783
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.	2002 Jul	12062575
Studies, using in vivo microdialysis, on the effect of the dopamine uptake inhibitor GBR 12909 on 3,4-methylenedioxymethamphetamine ('ecstasy')-induced dopamine release and free radical formation in the mouse striatum.	2002 Jun	12065608
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 GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats.	2002 Mar	11889495
Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.	2002 Mar-Apr	11942697
Characterization of nicotinic agonist-induced [(3)H]dopamine release from synaptosomes prepared from four mouse brain regions.	2002 May	11961070
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.	2002 May 17	11988230
GBR-12909 effect on dopamine outflow depends on phosphorylation in the caudate nucleus of the rat.	2002 Nov	12211084
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens.	2002 Oct	12208558
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
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
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture.	2003 Aug	12871774
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
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
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
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
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.	2004 Aug 23	15306127
Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells.	2004 Aug 5	15265589
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
Cocaine-like discriminative stimulus effects of heroin: modulation by selective monoamine transport inhibitors.	2004 Jul	14985417
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

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 `Sun Dec 18 06:52:29 UTC 2022` Edited by `admin` on `Sun Dec 18 06:52:29 UTC 2022`
Record UNII	MWO1IP03EV
Record Status	`Validated (UNII)`
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Name

Type

Language

VANOXERINE HYDROCHLORIDE

Common Name

English

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

Systematic Name

English

Code System Code Type Description

CAS

67469-78-7