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
Approval Year
Targets
| Primary Target | Pharmacology | Condition | Potency |
|---|---|---|---|
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] | ||
Target ID: CHEMBL238 |
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
| 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 |
|---|---|---|
| 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 |
|
| Age-related changes in the striatal dopaminergic system in the living brain: a multiparametric PET study in conscious monkeys. | 2002 Jul |
|
| Effects of dopamine agonists and antagonists on locomotor activity in male and female rats. | 2002 Jul |
|
| Preclinical evaluation of GBR12909 decanoate as a long-acting medication for methamphetamine dependence. | 2002 Jun |
|
| 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 |
|
| Dopamine re-uptake inhibitor GBR-12909 induction of aberrant behaviors in animal models of dopamine dysfunction. | 2002 Jun-Aug |
|
| Effect of daily dosing duration of direct and indirect dopamine receptor agonists: cocaine cross-tolerance following chronic regimens. | 2002 Oct |
|
| Pharmacologic thresholds for self-injurious behavior in a genetic mouse model of Lesch-Nyhan disease. | 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 |
|
| Role of alpha-synuclein in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice. | 2003 |
|
| 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. | 2003 Apr |
|
| 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 |
|
| 1-methyl-4-phenylpyridinium (MPP+) decreases mitochondrial oxidation-reduction (REDOX) activity and membrane potential (Deltapsi(m)) in rat striatum. | 2003 Jan |
|
| S-[18F]fluoromethyl-(+)-McN5652, a PET tracer for the serotonin transporter: evaluation in rats. | 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 |
|
| Differential regulation of the endocannabinoids anandamide and 2-arachidonylglycerol within the limbic forebrain by dopamine receptor activity. | 2003 Sep |
|
| Novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter. | 2003 Sep 1 |
|
| 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 |
|
| Agents in development for the management of cocaine abuse. | 2004 |
|
| A novel modulatory mechanism of sodium currents: frequency-dependence without state-dependent binding. | 2004 |
|
| Role of serotonin on cocaine-mediated effects on prodynorphin gene expression in the rat brain. | 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 |
|
| In vivo evidence that genetic background controls impulse-dependent dopamine release induced by amphetamine in the nucleus accumbens. | 2004 Apr |
|
| Effects of the selective norepinephrine uptake inhibitor nisoxetine on prodynorphin gene expression in rat CNS. | 2004 Aug 23 |
|
| Characterization of dopamine transport in crude synaptosomes prepared from rat medial prefrontal cortex. | 2004 Aug 30 |
|
| Effects of iptakalim on rotenone-induced cytotoxicity and dopamine release from PC12 cells. | 2004 Aug 5 |
|
| 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 |
|
| 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 |
|
| 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 |
|
| Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys. | 2004 Sep |
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
Edited
Fri Dec 16 18:05:24 UTC 2022
by
admin
on
Fri Dec 16 18:05:24 UTC 2022
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| Record UNII |
90X28IKH43
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| Record Status |
Validated (UNII)
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| Record Version |
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NCI_THESAURUS |
C66884
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90X28IKH43
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C81084
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3455
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67469-69-6
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C043425
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DTXSID8045143
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64089
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CHEMBL281594
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SUB00023MIG
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VANOXERINE
Created by
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METABOLIC ENZYME -> SUBSTRATE |
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METABOLIC ENZYME -> SUBSTRATE |
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METABOLIC ENZYME -> SUBSTRATE |
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SALT/SOLVATE -> PARENT |
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ACTIVE MOIETY |
