Dopamine reuptake (Ki = 1 nM)[1]

Vanoxerine (GBR-12909) is several times less effective as an inhibitor of norepinephrine and 5-HT uptake, and it inhibits dopamine (DA) uptake with an IC50 in the low nanomolar range [2]. Another oral mixed ion channel blocker with IKr, INa, and L-type calcium channel action is vanoxerine (GBR-12909) [3].

Vanoxerine (GBR-12909) (2.5-20 mg/kg; i.p.) greatly boosts the amount of walking that occurs [3].

The neurochemical profile of GBR 12909 (1-(2-bis(4-fluorphenyl)-methoxy)-ethyl)-4-(3-phenyl-propyl)pipera zine) was investigated. GBR 12909 was a potent and selective inhibitor of synaptosomal dopamine uptake (KI = 1 nM), with a 20-fold lower affinity for the histamine H1-receptor and a more than 100-fold affinity for the noradrenaline and 5-HT uptake carriers, the dopamine D-1, D-2, 5-HT2, 5-HT1A and alpha 1-receptors and voltage-dependent sodium channels. GBR 12909 (3 microM) was without effect on muscarinic, alpha 2, beta 1 + 2, gamma-aminobutyric acid (GABA) and benzodiazepine receptors, and on choline and GABA uptake carriers. The selective dopamine uptake inhibitory profile of GBR 12909 was confirmed by ex vivo uptake experiments. GBR 12909 inhibited uptake in vitro in a competitive manner as did cocaine and methylphenidate. [3H]GBR 12935 binding was competitively inhibited by GBR 12909 as well as by dopamine, cocaine and methylphenidate. Off-rate analysis of the [3H]GBR 12935 binding excluded the presence of allosteric binding sites on the dopamine carrier complex. Instead, the data favored the notion that GBR 12909 inhibits dopamine uptake by binding to the dopamine binding site on the carrier protein itself, thereby blocking the carrier process. In conclusion, GBR 12909 is a highly selective inhibitor of dopamine uptake, both in vivo and in vitro. At the moment GBR 12909 is the only compound with this neurochemical profile. The selective effect of GBR 12909 on this neuronal system makes it an interesting experimental tool and a potential antidepressant agent[2].

Animal/Disease Models: Male mice (6 weeks old ddY strain) [3]
Doses: 2.5, 5, 10, 20 mg/kg
Route of Administration: intraperitoneal (ip) injection
Experimental Results: The ambulation activity of mice increased in a dose-dependent manner. After administration Maximum increase is reached in 30 minutes.

Absorption, Distribution and Excretion
At doses of 25, 75 or 125 mg, vanoxerine had a corresponding Cmax of 17.9, 81.1 and 236.5 nmol/L and a corresponding AUC of 81, 365 and 1116 h⋅nmol/L when given orally to healthy male volunteers (n=14). In this same set of subjects, tmax was reached at 0.91, 0.93 and 1.13 h at oral doses of 25, 75 or 125 mg, respectively. The oral bioavailability of this drug depends on food intake. Compared with those fasting, the bioavailability of vanoxerine in volunteers taking a low-fat and a high-fat meal was 76% and 255% higher, respectively.
The majority of vanoxerine is excreted in urine, bile and feces.
Vanoxerine is capable of crossing the blood-brain barrier and distributing to several organs such as fat tissue, lungs, liver and the gastrointestinal tract. Vanoxerine has a large volume of distribution.
At 25, 75 and 125 mg/day, vanoxerine had a corresponding oral clearance of 660, 478 and 250 L/h.

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Metabolism / Metabolites
_In vitro_ studies suggest that vanoxerine is mostly metabolized by CYP3A4. CYP2C8 and CYP2E1 may also contribute to the metabolism of this drug. CYP3A4 selective-inhibitors may interact with vanoxerine.
Vanoxerine has known human metabolites that include 4-[3-[4-[2-[Bis(4-fluorophenyl)methoxy]ethyl]piperazino]propyl]phenol and 1-Phenyl-3-[4-[2-(4,4'-difluorobenzhydryloxy)ethyl]piperazino]-1-propanol.

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Biological Half-Life
The mean elimination half-life of vanoxerine was 53.5 h at 75 mg/day and 66 h at 125 mg/day.

Protein Binding
The plasma protein binding of vanoxerine is 99% at 0.1, 0.4 and 1 μM.

[1]. Rothman RB, et al. Dopamine transport inhibitors based on GBR12909 and benztropine as potential medications to treat cocaine addiction. Biochem Pharmacol. 2008 Jan 1;75(1):2-16.
[2]. Andersen PH. The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol.
[3]. Hirate K, et al. Characteristics of the ambulation-increasing effect of GBR-12909, a selective dopamine uptakeinhibitor, in mice. Jpn J Pharmacol. 1991 Apr;55(4):501-11.

Vanoxerine is an N-alkylpiperazine that consists of piperazine bearing 2-bis(4-fluorophenyl)methoxy]ethyl and 3-phenylpropyl groups at positions 1 and 4 respectively. Potent, competitive inhibitor of dopamine uptake (Ki = 1 nM for inhibition of striatal dopamine uptake). Has > 100-fold lower affinity for the noradrenalin and 5-HT uptake carriers. Also a potent sigma ligand (IC50 = 48 nM). Centrally active following systemic administration. It has a role as a dopamine uptake inhibitor. It is a N-alkylpiperazine, an organofluorine compound, a tertiary amino compound and an ether. It is a conjugate base of a vanoxerine(2+).
Vanoxerine is a highly selective dopamine transporter antagonist. It was synthesized in the late 1970s and developed as a potential treatment for depression. Vanoxerine was later evaluated as a potential treatment for cocaine addiction due to its ability to block dopamine reuptake with a slower dissociation rate than cocaine. Although several studies have suggested that the profile of vanoxerine is safer than that of cocaine, other studies have found that vanoxerine has at least moderate potential to be abused by humans. More recently, vanoxerine was tested as a potential anti-arrhythmic and anti-atrial fibrillatory agent due to its ability to block the hKV11.1 (hERG) cardiac potassium channel. Vanoxerine is an investigational drug and has not been approved for therapeutic use.

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Drug Indication
Vanoxerine has not been approved for therapeutic use.

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Mechanism of Action
Vanoxerine is a highly selective dopamine transporter antagonist. Due to its ability to inhibit dopamine reuptake, it has been suggested that vanoxerine may be beneficial in treating cocaine addiction. Cocaine increases the amount of dopamine in the synapse by attaching and blocking the dopamine transporter. Compared to cocaine, vanoxerine has a higher affinity for the dopamine transporter and a slower dissociation rate, without the stimulant profile of cocaine. The use of vanoxerine to treat conditions characterized by low levels of dopamine, such as Parkinson's disease and depression, has also been investigated. Vanoxerine is also a potent blocker of the hKV11.1 (hERG) cardiac potassium channel. Even at low concentrations, vanoxerine is capable of blocking calcium and sodium currents without having a significant effect on QT interval, action potential waveforms and transmural dispersion of repolarization. Because of this, the anti-arrhythmic and anti-atrial fibrillatory properties of vanoxerine have been investigated.

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Pharmacodynamics
Vanoxerine inhibits dopamine reuptake by binding and blocking the dopamine transporter. The use of vanoxerine has been evaluated as a potential substitute of cocaine in the treatment of drug addiction. In primates, the intravenous administration of vanoxerine reduced cocaine self-administration at 1 mg/kg and eliminated it at 3 mg/kg. The stimulant profile of cocaine was not detected in healthy volunteers (n=8) receiving vanoxerine for 2 weeks, suggesting a lack of abuse potential of vanoxerine. However, other studies have found that vanoxerine has at least moderate potential to be abused by humans. The antiarrhythmic potential of vanoxerine has also been assessed. A clinical study evaluating the efficacy of vanoxerine on the conversion of atrial fibrillation (AF) or atrial flutter (AFL) to normal sinus rhythm reported that, within 24 hours, a significant proportion of symptomatic AF/AFL patients treated with 200, 300 and 400 mg of vanoxerine converted to sinus rhythm. In studies that evaluated doses ranging from 25 to 300 mg, vanoxerine was considered to be safe and tolerable.

C28H32F2N2O

334.71454

450.248

C, 74.64; H, 7.16; F, 8.43; N, 6.22; O, 3.55

67469-69-6

Vanoxerine dihydrochloride;67469-78-7

3455

Typically exists as solid at room temperature

1.135g/cm3

542.7ºC at 760 mmHg

282ºC

1.561

5.197

0

5

10

33

498

0

FC1=CC=C(C(C2=CC=C(F)C=C2)OCCN3CCN(CCCC4=CC=CC=C4)CC3)C=C1

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

1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine

GBR12,909; GBR-12909; Vanoxerine; 67469-69-6; Gbr 12909; Vanoxerine [INN]; ...; 67469-69-9 (free base); GBR12909; GBR 12909; I-893; I 893; I893.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)