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
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
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 |
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/11249581
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
Primary Target | Pharmacology | Condition | Potency |
---|---|---|---|
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 |
9.3 nM [IC50] | ||
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 |
16.2 nM [IC50] | ||
Target ID: Nicotinic acetylcholine receptor Sources: https://www.ncbi.nlm.nih.gov/pubmed/17207584 |
2.32 µM [IC50] | ||
Target ID: CHEMBL238 Sources: https://www.ncbi.nlm.nih.gov/pubmed/12213078 |
0.7 nM [Ki] | ||
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 |
34.6 nM [IC50] |
Conditions
Condition | Modality | Targets | Highest Phase | Product |
---|---|---|---|---|
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
|||
Primary | Unknown Approved UseUnknown |
Doses
Dose | Population | Adverse 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%) Sources: torsades de pointe (serious, 3.85%) |
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: |
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: |
PubMed
Title | Date | PubMed |
---|---|---|
Interleukin-2 potentiates novelty- and GBR 12909-induced exploratory activity. | 2001 Apr 27 |
|
Effect of intracerebral 6-nitronoradrenaline, an endogenous catechol-O-methyltransferase (COMT) inhibitor, on striatal dopamine metabolism in anaesthetised rats. | 2001 Aug 15 |
|
Uptake of the dopaminergic neurotoxin, norsalsolinol, into PC12 cells via dopamine transporter. | 2001 Jun |
|
Norsalsolinol uptake into secretory vesicles via vesicular monoamine transporter and its secretion by membrane depolarization or purinoceptor stimulation in PC12 cells. | 2001 May |
|
Differential interaction of GBR 12909, a dopamine uptake inhibitor, with cocaine and methamphetamine in rats discriminating cocaine. | 2001 May |
|
Effects of repeated GBR 12909 administration on brain stimulation reward. | 2001 May 11 |
|
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 |
|
Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes. | 2001 Sep |
|
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 |
|
Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. | 2002 Dec |
|
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 |
|
The pharmacology of the acute hyperthermic response that follows administration of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') to rats. | 2002 Jan |
|
Interactions between cocaine and dopamine agonists on cardiovascular function in squirrel monkeys. | 2002 Jan |
|
Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys. | 2002 Jul |
|
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 |
|
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 |
|
Effects of catecholamine uptake blockers in the caudate-putamen and subregions of the medial prefrontal cortex of the rat. | 2002 May 17 |
|
GBR-12909 effect on dopamine outflow depends on phosphorylation in the caudate nucleus of the rat. | 2002 Nov |
|
Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens. | 2002 Oct |
|
Chronic cocaine increases kappa-opioid receptor density: lack of effect by selective dopamine uptake inhibitors. | 2002 Sep 1 |
|
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 |
|
Dopamine reuptake inhibition and failure to evoke dyskinesia in MPTP-treated primates. | 2002 Sep 13 |
|
Inhibition of vesicular uptake of monoamines by hyperforin. | 2002 Sep 27 |
|
1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. | 2003 Apr |
|
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 |
|
Paraquat leads to dopaminergic neural vulnerability in organotypic midbrain culture. | 2003 Aug |
|
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 |
|
Behavioral effects of rimcazole analogues alone and in combination with cocaine. | 2003 May 9 |
|
Inhibitory effect of the DA uptake blocker GBR 12909 on sodium channels of hippocampal neurons. | 2003 Oct 27 |
|
Dopamine transporter as target for drug development of cocaine dependence medications. | 2003 Oct 31 |
|
Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter. | 2003 Sep 1 |
|
A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding. | 2004 |
|
Terminally differentiated SH-SY5Y cells provide a model system for studying neuroprotective effects of dopamine agonists. | 2004 |
|
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 |
|
Noradrenaline transporter blockers raise extracellular dopamine in medial prefrontal but not parietal and occipital cortex: differences with mianserin and clozapine. | 2004 Feb |
|
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 |
|
Modification by dopaminergic drugs of choice behavior under concurrent schedules of intravenous saline and food delivery in monkeys. | 2004 Jan |
|
Pharmacological modulation of GABA(B) receptors affects cocaine-induced seizures in mice. | 2004 Jul |
|
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 |
|
Effects of dopamine transporter inhibitors on cocaine self-administration in rhesus monkeys: relationship to transporter occupancy determined by positron emission tomography neuroimaging. | 2004 Jun |
|
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 |
|
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 |
|
Methylphenidate restores ventral tegmental area dopamine neuron activity in prenatal ethanol-exposed rats by augmenting dopamine neurotransmission. | 2004 May |
|
Nitric oxide donors inhibit 5-hydroxytryptamine (5-HT) uptake by the human 5-HT transporter (SERT). | 2004 Sep |
Patents
Sample Use Guides
In Vivo Use Guide
Sources: https://www.ncbi.nlm.nih.gov/pubmed/2150527
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
Sources: https://www.ncbi.nlm.nih.gov/pubmed/26616666
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
Edited
Fri Dec 15 15:45:49 GMT 2023
by
admin
on
Fri Dec 15 15:45:49 GMT 2023
|
Record UNII |
90X28IKH43
|
Record Status |
Validated (UNII)
|
Record Version |
|
-
Download
Name | Type | Language | ||
---|---|---|---|---|
|
Official Name | English | ||
|
Code | English | ||
|
Common Name | English | ||
|
Common Name | English | ||
|
Code | English |
Classification Tree | Code System | Code | ||
---|---|---|---|---|
|
NCI_THESAURUS |
C66884
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
Code System | Code | Type | Description | ||
---|---|---|---|---|---|
|
DB03701
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
90X28IKH43
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
C81084
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
3455
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
6307
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
67469-69-6
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
C043425
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
DTXSID8045143
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
64089
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
CHEMBL281594
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
SUB00023MIG
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
VANOXERINE
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY | |||
|
100000079072
Created by
admin on Fri Dec 15 15:45:49 GMT 2023 , Edited by admin on Fri Dec 15 15:45:49 GMT 2023
|
PRIMARY |
Related Record | Type | Details | ||
---|---|---|---|---|
|
TARGET -> INHIBITOR |
BINDING
IC50
|
||
|
TARGET -> INHIBITOR |
Potent blocker of cardiac hERG, Na and Ca channels; (2) block is strongly frequency-dependent especially for Na and Ca channels;has characteristics of a potentially effective and safe antiarrhythmic.
IC50
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
MINOR
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
MAJOR
|
||
|
METABOLIC ENZYME -> SUBSTRATE |
MINOR
|
||
|
SALT/SOLVATE -> PARENT |
|
||
|
TARGET -> INHIBITOR |
BINDING
IC50
|
||
|
BINDER->LIGAND |
BINDING
|
Related Record | Type | Details | ||
---|---|---|---|---|
|
ACTIVE MOIETY |
|