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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 of VANOXERINE

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

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).

Originator

Curator's Comment:: https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT171&dq=Drug+Discovery+for+the+Treatment+of+Addiction:+Medicinal+Chemistry+Strategies&hl=en&sa=X&ved=0ahUKEwjZjoCeuM_UAhVFVT4KHeFnAvwQ6AEIKDAA#v=onepage&q=VANOXERINE&f=false

Approval Year

Targets

Targets

Primary TargetPharmacologyConditionPotency
Target ID: Q12809|||Q9BUT7
Gene ID: 3757.0
Gene Symbol: KCNH2
Target Organism: Homo sapiens (Human)
9.3 nM [IC50]
Target ID: Q13936|||Q13922|||Q13930|||Q4VMI9
Gene ID: 775.0
Gene Symbol: CACNA1C
Target Organism: Homo sapiens (Human)
16.2 nM [IC50]
Target ID: Nicotinic acetylcholine receptor
2.32 µM [IC50]
0.7 nM [Ki]
Target ID: Q14524|||E9PFW7
Gene ID: 6331.0
Gene Symbol: SCN5A
Target Organism: Homo sapiens (Human)
34.6 nM [IC50]
Conditions

Conditions

ConditionModalityTargetsHighest PhaseProduct
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Primary
Unknown

Approved Use

Unknown
Doses

Doses

DosePopulationAdverse events​
400 mg single, oral (unknown)
Studied dose
Dose: 400 mg
Route: oral
Route: single
Dose: 400 mg
Sources:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
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:
AEs

AEs

AESignificanceDosePopulation
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:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
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:
unhealthy
n = 26
Health Status: unhealthy
Condition: atrial fibrillation
Sex: M+F
Food Status: UNKNOWN
Population Size: 26
Sources:
Sourcing

Sourcing

Vendor/AggregatorIDURL
PubMed

PubMed

TitleDatePubMed
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
A comparison of the patterns of striatal Fos-like immunoreactivity induced by various dopamine agonists in rats.
2000 Aug 4
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
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.
2001 Apr
Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys.
2001 Apr
Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity.
2001 Apr 27
[3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel probes for the dopamine transporter.
2001 Dec 17
Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus.
2001 Jul
Cocaine and amphetamine increase extracellular dopamine in the nucleus accumbens of mice lacking the dopamine transporter gene.
2001 May 1
Differential sensitivity to acute administration of cocaine, GBR 12909, and fluoxetine in mice selectively bred for hyperactive wheel-running behavior.
2001 Nov
Repeated cocaine administration into the rat ventral tegmental area produces behavioral sensitization to a systemic cocaine challenge.
2001 Nov 29
Synthesis and biological evaluation of tropane-like 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909) analogues.
2001 Nov 8
Mechanisms of MPP(+) incorporation into cerebellar granule cells.
2001 Sep 15
Drug addiction. Part III. Pharmacotherapy of addiction.
2001 Sep-Oct
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
Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites.
2002 Dec
New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.
2002 Dec 15
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.
2002 Jul
Persistent antagonism of methamphetamine-induced dopamine release in rats pretreated with GBR12909 decanoate.
2002 Jun
Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction.
2002 Jun-Aug
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat.
2002 May 17
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens.
2002 Oct
Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.
2003
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture.
2003 Aug
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
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
Behavioral effects of rimcazole analogues alone and in combination with cocaine.
2003 May 9
Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity.
2003 Sep
Agents in development for the management of cocaine abuse.
2004
A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding.
2004
Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS.
2004 Aug 23
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.
2004 Feb
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
Dopamine transporter-mediated cytotoxicity of beta-carbolinium derivatives related to Parkinson's disease: relationship to transporter-dependent uptake.
2004 May
Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission.
2004 May
Drug discrimination in methamphetamine-trained monkeys: effects of monoamine transporter inhibitors.
2004 Nov
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.
2004 Oct
Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT).
2004 Sep
Patents

Patents

Sample Use Guides

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
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
  • Download
Name Type Language
VANOXERINE
INN  
INN  
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
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
Code System Code Type Description
DRUG BANK
DB03701
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
FDA UNII
90X28IKH43
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
NCI_THESAURUS
C81084
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
PUBCHEM
3455
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
INN
6307
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
CAS
67469-69-6
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
MESH
C043425
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
EPA CompTox
67469-69-6
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
ChEMBL
CHEMBL281594
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
EVMPD
SUB00023MIG
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
WIKIPEDIA
VANOXERINE
Created by admin on Sat Jun 26 07:39:55 UTC 2021 , Edited by admin on Sat Jun 26 07:39:55 UTC 2021
PRIMARY
Related Record Type Details
METABOLIC ENZYME -> SUBSTRATE
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METABOLIC ENZYME -> SUBSTRATE
MAJOR
METABOLIC ENZYME -> SUBSTRATE
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SALT/SOLVATE -> PARENT
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ACTIVE MOIETY