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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
Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.
2000 Jul
Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.
2000 Nov
Vanoxerine National Institute on Drug Abuse.
2000 Oct
Subtle differences in the discriminative stimulus effects of cocaine and GBR-12909.
2001 Apr
Effect of acute ethanol on striatal dopamine neurotransmission in ambulatory rats.
2001 Apr
Cocaine or selective block of dopamine transporters influences multisecond oscillations in firing rate in the globus pallidus.
2001 Jul
Dopaminergic role in stimulant-induced wakefulness.
2001 Mar 1
A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule.
2001 Mar 1
Design, synthesis, and characterization of a novel, 4-[2-(diphenylmethoxy)ethyl]-1-benzyl piperidine-based, dopamine transporter photoaffinity label.
2001 Mar 9
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells.
2001 May
The role of dopamine in the locomotor stimulant effects and tolerance to these effects of caffeine.
2001 May-Jun
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
Behavioral responses to dopamine agonists in adult rats exposed to cocaine during the preweaning period.
2001 Sep
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
Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys.
2002 Jan
Effects of dopamine agonists and antagonists on locomotor activity in male and female rats.
2002 Jul
Effects of GBR 12909, WIN 35,428 and indatraline on cocaine self-administration and cocaine seeking in rats.
2002 Mar
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
Dopaminergic transmission in the rat striatum in vivo in conditions of pharmacological modulation.
2002 Mar-Apr
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
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
1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum.
2003 Jan
Self-biting induced by activation of L-type calcium channels in mice: dopaminergic influences.
2003 Jan-Feb
Norepinephrine in the prefrontal cortex is critical for amphetamine-induced reward and mesoaccumbens dopamine release.
2003 Mar 1
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
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists.
2004
Alpha2-adrenoceptor mediated co-release of dopamine and noradrenaline from noradrenergic neurons in the cerebral cortex.
2004 Feb
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine.
2004 Feb
Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice.
2004 Jul
Cocaine-like discriminative stimulus effects of heroin: modulation by selective monoamine transport inhibitors.
2004 Jul
Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging.
2004 Jun
Regional differences in extracellular dopamine and serotonin assessed by in vivo microdialysis in mice lacking dopamine and/or serotonin transporters.
2004 Oct
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
MINOR
METABOLIC ENZYME -> SUBSTRATE
MAJOR
METABOLIC ENZYME -> SUBSTRATE
MINOR
SALT/SOLVATE -> PARENT
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ACTIVE MOIETY