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 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 511	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 511	16.2 nM [IC50]
Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584	Antagonist 2575	2.32 µM [IC50]
Dopamine transporter 164 Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078	Inhibitor 7728	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 511	34.6 nM [IC50]

Conditions

Condition	Modality	Highest Phase	Product
Atrial fibrillation 130 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817929	Primary	Phase III 643	Unknown Approved Use Unknown
Cocaine addiction 20 Sources: https://clinicaltrials.gov/ct2/show/NCT00218049	Primary	Phase I 409	Unknown Approved Use Unknown
Depression 215 Sources: https://www.ncbi.nlm.nih.gov/pubmed/2530094	Primary	Not Provided 492	Unknown Approved Use Unknown
Parkinson's disease 219 Sources: https://www.ncbi.nlm.nih.gov/pubmed/19817928	Primary	Not Provided 492	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
Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.	2000 Jul	10958121
Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.	2000 Nov	11127425
Vanoxerine National Institute on Drug Abuse.	2000 Oct	11249581
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.	2001 Apr	11371002
Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats.	2001 Apr	11259524
Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus.	2001 Jul	11377917
Dopaminergic role in stimulant-induced wakefulness.	2001 Mar 1	11222668
A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule.	2001 Mar 1	11173166
Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label.	2001 Mar 9	11292062
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.	2001 May	11411492
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
Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period.	2001 Sep	11566139
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
Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.	2002 Jan	11752114
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.	2002 Jul	12062575
Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats.	2002 Mar	11889495
Development of long-acting dopamine transporter ligands as potential cocaine-abuse therapeutic agents: chiral hydroxyl-containing derivatives of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine and 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine.	2002 Mar 14	11882001
Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.	2002 Mar-Apr	11942697
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
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
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
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists.	2004	15111235
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
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
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
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.	2004 Oct	15226739

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