Dopamine reuptake (Ki = 1 nM)[1]

Vanoxerine diHClide (GBR-12909 diHClide) 是一种低倍有效的去甲肾上腺素和血清素补充剂，可抑制营养物多巴胺 (DA)，IC50 在低纳摩尔范围内 [2]。另一种具有 IKr、INa 和 L 型钙通道作用的壁混合离子通道阻断剂是 -12909 二盐酸盐 [3]。

通过小鼠的动态活动来评估多巴胺摄取抑制剂GBR-12909（GBR）的行为效应。单次腹腔注射和口服超过10mg/kg的GBR显著增加了活动能力。仅以10mg/kg的剂量重复服用GBR，对其增加行走的作用产生了相反的耐受性。然而，GBR（10至20mg/kg）和甲基苯丙胺（2mg/kg）在两个方向上都诱导了交叉反向耐受。此外，5mg/kg的GBR显著增强了甲基苯丙胺、可卡因、丙咪嗪、吗啡、东莨菪碱和咖啡因的作用。酪氨酸羟化酶的辅酶R-THBP也增强了GBR的作用。相比之下，氟哌啶醇、氯丙嗪、丁苯那嗪、奥替品、利血平和α-甲基对酪氨酸显著降低了10mg/kg GBR的步行增加作用。另一方面，阿扑吗啡、蓝桉素、毒扁豆碱、匹罗卡品、N6-（L-2-苯基异丙基）-腺苷和纳洛酮对GBR的作用仅略有和/或几乎没有改变。大鼠而非小鼠的神经化学实验表明，GBR对多巴胺能系统的作用比去甲肾上腺素能或5-羟色胺能系统更为显著。然而，GBR的行为特征与甲基苯丙胺和可卡因相似，后者对多巴胺能和去甲肾上腺素能系统的选择性作用不如GBR[2]。

研究了GBR 12909（1-（2-双（4-氟苯基）-甲氧基）-乙基）-4-（3-苯基-丙基）哌嗪）的神经化学特征。GBR 12909是突触体多巴胺摄取的强效选择性抑制剂（KI=1 nM），对组胺H1受体的亲和力低20倍，对去甲肾上腺素和5-HT摄取载体、多巴胺D-1、D-2、5-HT2、5-HT1A和α1受体以及电压依赖性钠通道的亲和力高100倍以上。GBR 12909（3微M）对毒蕈碱、α2、β1+2、γ-氨基丁酸（GABA）和苯二氮卓受体以及胆碱和GABA摄取载体没有影响。体外摄取实验证实了GBR 12909的选择性多巴胺摄取抑制特征。GBR 12909以竞争方式抑制体外摄取，可卡因和哌醋甲酯也是如此。[3H]GBR 12935结合被GBR 12909以及多巴胺、可卡因和哌醋甲酯竞争性抑制。[3H]GBR 12935结合的非速率分析排除了多巴胺载体复合物上存在变构结合位点。相反，这些数据支持GBR 12909通过与载体蛋白本身上的多巴胺结合位点结合来抑制多巴胺摄取的观点，从而阻断载体过程。总之，GBR 12909是体内和体外多巴胺摄取的高选择性抑制剂。目前，GBR 12909是唯一具有这种神经化学特征的化合物。GBR 12909对这种神经元系统的选择性作用使其成为一种有趣的实验工具和潜在的抗抑郁药[3]。

Animal/Disease Models: Male mice (6 weeks old ddY strain) [3]
Doses: 2.5, 5, 10, 20 mg/kg Varnosline hydrochloride (2.5-20 mg/kg; intraperitoneal (ip) injection) Dramatically increases walking activity [ 3].
Route of Administration: intraperitoneal (ip) injection.
Experimental Results: The walking activity of mice increased in a dose-dependent manner, with the maximum increase 30 minutes after administration.

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]. 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.
[3]. Andersen PH. The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action. Eur J Pharmacol.

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.

C28H34CL2F2N2O

523.4852

522.201

C, 64.24; H, 6.55; Cl, 13.54; F, 7.26; N, 5.35; O, 3.06

67469-78-7

Vanoxerine;67469-69-6

3455

Typically exists as White to off-white solid at room temperature

542.7ºC at 760 mmHg

221 °C

282ºC

6.801

15.71

0

5

10

33

498

0

Cl[H].Cl[H].FC1C([H])=C([H])C(=C([H])C=1[H])C([H])(C1C([H])=C([H])C(=C([H])C=1[H])F)OC([H])([H])C([H])([H])N1C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])C([H])([H])C1([H])[H]

MIBSKSYCRFWIRU-UHFFFAOYSA-N

InChI=1S/C28H32F2N2O.2ClH/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,4,7,16-22H22*1H

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

Vanoxerine DiHCl; GBR 12909; Vanoxerine dihydrochloride; GBR 12909 dihydrochloride; Vanoxerine hydrochloride; GBR-12909 dihydrochloride; Vanoxeamine; Vanoxerine dihydrochloride(GBR12909); 1-(2-(bis(4-fluorophenyl)methoxy)ethyl)-4-(3-phenylpropyl)piperazine dihydrochloride; GBR-12909; GBR12909.

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中，避免吸湿/受潮。

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

DMSO : ~9.4 mg/mL (~17.96 mM)
H2O : ~1 mg/mL (~1.91 mM)

配方 1 中的溶解度: ≥ 2.08 mg/mL (3.97 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (3.97 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (3.97 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。