D₂ Receptor ( Ki = 3.9 nM ); D₃ Receptor ( Ki = 0.5 nM ); D₄ Receptor ( Ki = 1.3 nM )

体外活性：普拉克索是一种用于治疗帕金森病症状的新型化学多巴胺激动剂，具有抗氧化活性，并且对缺氧缺血和甲基苯丙胺模型中的黑质多巴胺神经元具有神经保护作用。当与 SH-SY5Y 细胞孵育以及灌注到大鼠纹状体时，普拉克索均可降低甲基吡啶鎓离子 (MPP+) 产生的氧自由基水平。普拉克索还表现出对钙和磷酸盐或 MPP+ 诱导的线粒体过渡孔开放的浓度依赖性抑制。普拉克索剂量依赖性地降低多巴胺代谢物的水平，而纹状体多巴胺水平保持不变。普拉克索在这两种模型中都发挥作用，减少多巴胺周转的升高，以及减少 MAO 活性增加导致的羟自由基产生的升高，而 MAO 活性可能导致黑质纹状体神经元的氧化损伤。 Pramipexole (4-100 mM) 显着减弱 DA 或 L-DOPA 诱导的细胞毒性和细胞凋亡，这种作用不能被 D3 拮抗剂 U-99194 A 或 D2 拮抗剂雷氯必利阻断。 Pramipexole 还以剂量依赖性方式保护 MES 23.5 细胞免受过氧化氢诱导的细胞毒性。普拉克索可以有效抑制黑色素的形成，黑色素是DA或L-DOPA在无细胞系统中氧化产生的最终产物。

普拉克索（0.001-1 mg/kg sc）可降低小鼠的探索性运动活动。普拉克索（1 mg/kg，口服）能够显着降低增加的 DA 周转率，但仅降低 16%。

普拉克索是一种强效多巴胺受体激动剂，对帕金森病有很高的疗效，其血脑屏障（BBB）转运的主要特征是使用永生化大鼠脑毛细血管内皮细胞（RBEC）1作为体外BBB模型。[（14）C]RBEC1对普拉克索的摄取取决于温度和pH值，但不取决于钠离子浓度或膜电位。包括吡拉明在内的几种有机阳离子抑制了摄取。普拉克索和吡拉明之间存在相互抑制作用。此外，预加载未标记的普拉克索刺激了[（14）C]普拉克索的摄取。对RBEC1中的有机阳离子转运蛋白（rOCT1-3、rOCTN1-2）进行RT-PCR分析。rOCTN2的mRNA水平最高，其次是rOCTN1，而rOCT1、rOCT2和rOCT3的表达可以忽略不计。通过原位大鼠脑灌注技术测量的[（14）C]普拉克索的脑摄取被未标记的普拉克索显著抑制。这些结果表明，普拉克索至少部分是由有机阳离子敏感转运蛋白通过血脑屏障转运的。RBEC1中的普拉克索转运是pH依赖性的，但钠和膜电位无关[2]。

抗帕金森病药物罗匹尼罗和普拉克索是D3受体（D3R-）的多巴胺能（DA）激动剂，用作治疗难治性抑郁症（TRD）的辅助疗法。虽然确切的抗抑郁作用机制尚不清楚，但已有人提出D3R在恢复TRD中受损的神经可塑性中的作用。由于D3R激动剂在人类DA神经元上高度表达，我们使用人类诱导多能干细胞（hiPSCs）的翻译模型研究了罗匹尼罗和普拉克索对结构可塑性的影响。将来自健康供体的两个hiPSC克隆分化为中脑DA神经元。在培养3天后，罗匹宁和普拉克索产生了树突分枝和胞体大小的剂量依赖性增加，这种作用被选择性D3R拮抗剂SB277011-A和S33084以及mTOR途径激酶抑制剂LY294002和雷帕霉素拮抗。所有治疗均能有效减轻D3R依赖性p70S6激酶磷酸化的增加。BDNF的免疫中和、TrkB受体的抑制和MEK-ERK信号传导的阻断同样阻止了罗匹尼罗诱导的结构可塑性，表明BDNF和D3R信号通路之间存在关键的相互作用。从两个hiPSC克隆中获得的DA神经元所获得的数据高度相似，这为它们表征通过多巴胺能机制起作用的药物的可靠性奠定了基础[3]。

Male Wistar rats weighing 250-300 g (16-18 weeks old)
0.25 mg/kg, 1 mg/kg
Intraperitoneal injection

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A dopamine D2 receptor agonist, pramipexole, has been found to elicit neuroprotection in patients with Parkinson's disease and restless leg syndrome. Recent evidence has shown that pramipexole mediates its neuroprotection through mitochondria. Considering this, we examined the possible mitochondrial role of pramipexole in promoting neuroprotection following an ischemic stroke of rat. Male Wistar rats underwent transient middle cerebral artery occlusion (tMCAO) and then received pramipexole (0.25 mg and 1 mg/kg body weight) at 1, 6, 12 and 18 h post-occlusion. A panel of neurological tests and 2,3,5-triphenyl tetrazolium chloride (TTC) staining were performed at 24 h after the surgery. Flow cytometry was used to detect the mitochondrial membrane potential, and mitochondrial levels of reactive oxygen species (ROS) and Ca2+, respectively. Mitochondrial oxidative phosphorylation was analyzed by oxygraph (oxygen electrode). Western blotting was used to analyze the expression of various proteins such as Bax, Bcl-2 and cytochrome c Pramipexole promoted the neurological recovery as shown by the panel of neurobehavioral tests and TTC staining. Post-stroke treatment with pramipexole reduced levels of mitochondrial ROS and Ca2+ after ischemia. Pramipexole elevated the mitochondrial membrane potential and mitochondrial oxidative phosphorylation. Western blotting showed that pramipexole inhibited the transfer of cytochrome c from mitochondria to cytosol, and hence inhibited the mitochondrial permeability transition pore. Thus, our results have demonstrated that post-stroke administration of pramipexole induces the neurological recovery through mitochondrial pathways in ischemia/reperfusion injury[5].

[1]. A review of the receptor-binding and pharmacokinetic properties of dopamine agonists. Clin Ther, 2006. 28(8): p. 1065-78.

[2]. Blood-brain barrier transport of pramipexole, a dopamine D2 agonist. Life Sci. 2007 Apr 3;80(17):1564-71.

[3]. Ropinirole and Pramipexole Promote Structural Plasticity in Human iPSC-Derived Dopaminergic Neurons via BDNF and mTOR Signaling. Neural Plast. 2018; 2018: 4196961.

[4]. Attenuation of levodopa-induced toxicity in mesencephalic cultures by pramipexole. J Neural Transm (Vienna). 1997;104(2-3):209-28.

[5]. Pramipexole prevents ischemic cell death via mitochondrial pathways in ischemic stroke. Dis Model Mech. 2019 Aug 1; 12(8): dmm033860.

Pramipexole is a member of the class of benzothiazoles that is 4,5,6,7-tetrahydro-1,3-benzothiazole in which the hydrogens at the 2 and 6-pro-S-positions are substituted by amino and propylamino groups, respectively. It has a role as an antiparkinson drug, a dopamine agonist, an antidyskinesia agent and a radical scavenger. It is a member of benzothiazoles and a diamine. It is a conjugate base of a pramipexole(2+).
Pramipexole is a drug used to treat the symptoms of Parkinson's Disease (PD). It is a non-ergot dopamine agonist drug that is efficacious in treating various Parkinson's symptoms such as tremor, rigidity, and bradykinesia (slow movement). It was first approved by the FDA in 1997. Parkinson's Disease is one of the most common neurodegenerative disorders and causes a high level of disability in patients, leading to increased difficulty in performing activities of daily living due to symptoms that progress over time. The prevalence of Parkinson's Disease worldwide has increased from approximately 2.5 million in 1990 to about 6.1 million in 2016. This increase may be attributed to an aging population along with other contributing factors. In addition to the above FDA approval for Parkinson's Disease, pramipexole was also approved by the FDA in 2006 for the treatment of Restless Legs Syndrome (RLS). RLS is a sleep-related disorder characterized by unpleasant sensations in the lower extremities, often accompanied by an uncontrollable urge to move the legs.

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Pramipexole is a Nonergot Dopamine Agonist. The mechanism of action of pramipexole is as a Dopamine Agonist.
Pramipexole is a selective dopamine receptor agonist used in the therapy of Parkinson disease. Pramipexole therapy is associated with a low rate of transient serum enzyme elevations during treatment, but has not been implicated in cases of clinically apparent acute liver injury.
Pramipexole is a medication indicated for treating Parkinson's disease and restless legs syndrome (RLS). It is also sometimes used off-label as a treatment for cluster headache or to counteract the problems with low libido experienced by some users of SSRI antidepressant drugs. Pramipexole has shown robust effects on pilot studies in bipolar disorder. Pramipexole is classified as a non-ergoline dopamine agonist.
A benzothiazole derivative and dopamine agonist with antioxidant properties that is used in the treatment of PARKINSON DISEASE and RESTLESS LEGS SYNDROME.

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Absorption: The bioavailability of pramipexole is higher than 90%, indicating a high level of absorption.
Route of Elimination: The main route of pramipexole elimination, with 90% of a pramipexole dose found in the urine, almost entirely as unchanged drug.
Volume of Distribution: This drug is extensively distributed in the body with a volume of distribution of approximately 500 L.
Clearance: Renal clearance is about 400 mL/min, indicating heavy secretion by the renal tubules.

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Pramipexole is extensively distributed, having a volume of distribution of about 500 L. Protein binding is less than 20% in plasma; with albumin accounting for most of the protein binding in human serum. Pramipexole distributes into red blood cells as indicated by an erythrocyte to plasma ratio of approximately 2.0 and a blood to plasma ratio of approximately 1.5. Consistent with the large volume of distribution in humans, whole body autoradiography and brain tissue levels in rats indicated that pramipexole was widely distributed throughout the body, including the brain.
Biological Half-Life: About 8.5-12 hours.
The terminal elimination half-life was about 8.5 hours in young volunteers (mean age 30 years) and about 12 hours in elderly volunteers (mean age 70 years).

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The exact mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown at this time. It is thought, however, that the ability of pramipexole to cause stimulation of the dopamine receptors in the striatum of the brain, a region that receives a vast array of neurological input and is responsible for a wide variety of functions, may be involved. Studies performed in animals show that pramipexole influences striatal neuronal transmission rates following activation of dopamine receptors. Pramipexole is considered a non-ergot dopamine agonist that shows specificity and strong activity at the D2 subfamily of dopamine receptors in vitro, binding selectively and dopamine D2 receptors and showing a preference for the dopamine D3 receptor subtype rather than other subtypes. The clinical significance of this binding specificity is unknown.
The purpose of this study was to determine the binding sites of pramipexole in extrastriatal dopaminergic regions because its antidepressive effects have been speculated to occur by activating the dopamine D(2) receptor subfamily in extrastriatal areas. Dynamic positron emission tomography (PET) scanning using (11)C-FLB 457 for quantification of D(2)/D(3) receptor subtype was performed on 15 healthy volunteers. Each subject underwent two PET scans before and after receiving a single dose of pramipexole (0, 0.125, or 0.25 mg). The study demonstrated that pramipexole significantly binds to D(2)/D(3) receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus at a dose of 0.25 mg. These regions have been indicated to have some relation to depression and may be part of the target sites where pramipexole exerts its antidepressive effects.
Pramipexole dihydrochloride, a synthetic benzothiazolamine derivative, is a nonergot-derivative dopamine receptor agonist. In in vitro binding studies, pramipexole demonstrated high binding specificity for and intrinsic activity at dopamine D2 receptors compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide), having a higher affinity for the D3 receptor subtype than for the D2 or D4 subtypes. Pramipexole binds with moderate affinity to alpha2-adrenergic receptors but has little or no affinity for alpha1- or beta-adrenergic, acetylcholine, dopamine D1, or serotonin (5-hydroxytryptamine (5-HT)) receptors.

C10H17N3S

211.33

211.11

C, 56.84; H, 8.11; N, 19.88; S, 15.17

104632-26-0

Pramipexole dihydrochloride; 104632-25-9; Dexpramipexole dihydrochloride; 104632-27-1; Pramipexole dihydrochloride hydrate; 191217-81-9; Dexpramipexole;104632-28-2; Pramipexole-d5; 1217975-28-4

119570

White to off-white solid powder

1.2±0.1 g/cm3

378.0±42.0 °C at 760 mmHg

288-290°C

182.4±27.9 °C

0.0±0.9 mmHg at 25°C

1.583

1.42

79.18

CCCN[C@H]1CCC2=C(C1)SC(=N2)N

FASDKYOPVNHBLU-ZETCQYMHSA-N

InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1

(6S)-6-N-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine

2934.99.03.00

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)

配方 1 中的溶解度: 10 mg/mL (47.32 mM) 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; 超声助溶。
例如，若需制备1 mL的工作液，可将100 μL 100.0 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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配方 2 中的溶解度: ≥ 2.5 mg/mL (11.83 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 25.0 mg/mL澄清DMSO储备液加入到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 3 中的溶解度: ≥ 2.5 mg/mL (11.83 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 25.0 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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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。