Tetrabenazine
(Synonyms: (+)-丁苯那嗪; (+)-TBZ; (3R,11bR)-TBZ; (3R,11bR)-Tetrabenazine) 目录号 : GC13672
丁苯那嗪是美国食品和药物管理局唯一批准的亨廷顿舞蹈病药物，适用于治疗与亨廷顿舞蹈病相关的舞蹈症。
Cas No.:58-46-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Neuro-2a neuroblastoma cell line |
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Preparation Method |
Neuro-2a cells were incubated for 24h with tetrabenazine solution, tetrabenazine loaded nanoemulsion and placebo. |
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Reaction Conditions |
2.4/4.8/9.6 ng/mL Tetrabenazine for 24h |
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Applications |
Tetrabenazine loaded nanoemulsion showed 100.00±1.23%, 100.00±2.01% and 100.00±2.09% cell viability when treated at the dose of 4.8ng/mL, 2.4ng/mL and 9.6ng/Ml. |
| Animal experiment [2]: | |
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Animal models |
Wistar rats (200-250g) of age 11-12 weeks |
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Preparation Method |
Tetrabenazine solution was administered intravenously to group 1 (dose 1.25mg/day dissolved in 1mL of normal saline solution). Second group of animals received tetrabenazine nanoemulsion administered intranasally (dose equivalent to 1.25mg/day). Dosage volume administered to each nostril was 25µL. Rats were sacrificed humanely by cervical dislocation method at different time intervals (0.5, 1, 6 and 12h) after collecting blood from retino-orbital vein in precoated EDTA tube. |
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Dosage form |
Group 1：1.25mg/day Tetrabenazine in 1mL saline; iv |
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Applications |
The superiority of tetrabenazine nanoemulsion for delivering of tetrabenazine via intranasal route bypassing BBB. |
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References: [1].Arora A, Kumar S, Ali J, Baboota S. Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study. Chem Phys Lipids. 2020 Aug;230:104917. doi: 10.1016/j.chemphyslip.2020.104917. Epub 2020 May 19. PMID: 32439327. |
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Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, indicated for treatment of chorea associated with Huntington's disease[1,3,4]. It reversibly inhibits central vesicular monoamine transporter (VMAT) transporter type 2 which acts on the various monoaminergic systems in the brain, e.g., dopamine, serotonin and noradrenaline[5] Tetrabenazine binds predominately to VMAT2 and has been shown to reversibly inhibit monoamine uptake in pre-synaptic vesicles, resulting in monoamine depletion of serotonin, dopamine, and nor-epinephrine [6] thereby reducing chorea[7].
In Neuro-2a neuroblastoma cell line, Tetrabenazine loaded nanoemulsion showed 100.00±1.23%, 100.00±2.01% and 100.00±2.09% cell viability when treated at the dose of 4.8ng/mL, 2.4ng/mL and 9.6ng/Ml[2]. When used bovine chromaffin cells (BCCs) challenged with repeated pulses of high K+ Upon repeated K+ pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to tetrabenazine, responses were mildly augmented and decay rate delayed[8].
In rat, The superiority of tetrabenazine nanoemulsion for delivering of tetrabenazine via intranasal route bypassing BBB[2]. In mice, Cold-water immersion-induced acute stress diminished the locomotor activity, exploratory behaviour, motor activity and social behaviour along with increase in the plasma corticosterone levels. Administration of tetrabenazine (1 and 2 mg/kg, i.p.), abolished the acute stress-induced behavioural and biochemical changes in a dose-dependent manner[9].
References:
[1]. Peter D, Vu T, et,al.Chimeric vesicular monoamine transporters identify structural domains that influence substrate affinity and sensitivity to tetrabenazine. J Biol Chem. 1996 Feb 9;271(6):2979-86. doi: 10.1074/jbc.271.6.2979. PMID: 8621690.
[2]. Arora A, Kumar S, et,al. Intranasal delivery of tetrabenazine nanoemulsion via olfactory region for better treatment of hyperkinetic movement associated with Huntington's disease: Pharmacokinetic and brain delivery study. Chem Phys Lipids. 2020 Aug;230:104917. doi: 10.1016/j.chemphyslip.2020.104917. Epub 2020 May 19. PMID: 32439327.
[3]. Kenney C, Hunter C, et,al. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov Disord. 2007 Jan;22(1):10-3. doi: 10.1002/mds.21161. PMID: 17078062.
[4]. Mestre TA, Ferreira JJ. An evidence-based approach in the treatment of Huntington's disease. Parkinsonism Relat Disord. 2012 May;18(4):316-20. doi: 10.1016/j.parkreldis.2011.10.021. Epub 2011 Dec 16. PMID: 22177624.
[5]. Thibaut F, Faucheux BA, et,al. Regional distribution of monoamine vesicular uptake sites in the mesencephalon of control subjects and patients with Parkinson's disease: a postmortem study using tritiated tetrabenazine. Brain Res. 1995 Sep 18;692(1-2):233-43. doi: 10.1016/0006-8993(95)00674-f. PMID: 8548309.
[6]. Pettibone DJ, Totaro JA, et,al. Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants. Eur J Pharmacol. 1984 Jul 20;102(3-4):425-30. doi: 10.1016/0014-2999(84)90562-4. PMID: 6489435.
[7]. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006 Feb 14;66(3):366-72. doi: 10.1212/01.wnl.0000198586.85250.13. PMID: 16476934.
[8]. de Pascual R, álvarez-Ortego N,et,al. Tetrabenazine Facilitates Exocytosis by Enhancing Calcium-Induced Calcium Release through Ryanodine Receptors. J Pharmacol Exp Ther. 2019 Oct;371(1):219-230. doi: 10.1124/jpet.119.256560. Epub 2019 Jun 17. PMID: 31209099.
[9].Kumar M, Singh N, et,al. Exploring the anti-stress effects of imatinib and tetrabenazine in cold-water immersion-induced acute stress in mice. Naunyn Schmiedebergs Arch Pharmacol. 2020 Sep;393(9):1625-1634. doi: 10.1007/s00210-020-01862-w. Epub 2020 Apr 14. PMID: 32291496.
丁苯那嗪是美国食品和药物管理局唯一批准的亨廷顿舞蹈病药物,适用于治疗与亨廷顿舞蹈病相关的舞蹈症[1,3,4]。它可逆地抑制 2 型中央囊泡单胺转运蛋白 (VMAT) 转运蛋白,后者作用于大脑中的各种单胺能系统,例如多巴胺、5-羟色胺和去甲肾上腺素[5] Tetrabenazine 主要与 VMAT2 结合并已被证明可逆地抑制突触前小泡中的单胺摄取,导致血清素、多巴胺和去甲肾上腺素的单胺消耗[6],从而减少舞蹈病[7]。\n
在 Neuro-2a 神经母细胞瘤细胞系中,负载 Tetrabenazine 的纳米乳剂以 4.8ng/mL、2.4ng/mL 和 9.6ng/mL 的剂量处理时显示出 100.00±1.23%、100.00±2.01% 和 100.00±2.09% 的细胞活力毫升[2]。当使用重复的高 K+ 脉冲攻击牛嗜铬细胞 (BCC) 时 在重复 K+ 脉冲下,胞吐儿茶酚胺释放反应逐渐衰减。然而,当细胞暴露于丁苯那嗪时,反应会轻度增强,衰减速率会延迟[8]。
在大鼠中,丁苯那嗪纳米乳剂通过鼻内途径绕过 BBB 递送丁苯那嗪的优势[2]。在小鼠中,冷水浸泡引起的急性应激会降低运动活动、探索行为、运动活动和社交行为,同时血浆皮质酮水平也会升高。施用丁苯那嗪（1 和 2 mg/kg,腹腔注射）,以剂量依赖性方式消除急性应激诱导的行为和生化变化[9]。
| Cas No. | 58-46-8 | SDF | |
| 别名 | (+)-丁苯那嗪; (+)-TBZ; (3R,11bR)-TBZ; (3R,11bR)-Tetrabenazine | ||
| 化学名 | 3-isobutyl-9,10-dimethoxy-3,4,6,7-tetrahydro-1H-pyrido[2,1-a]isoquinolin-2(11bH)-one | ||
| Canonical SMILES | CC(CC1CN2CCC3=CC(OC)=C(OC)C=C3C2CC1=O)C | ||
| 分子式 | C19H27NO3 | 分子量 | 317.42 |
| 溶解度 | ≥ 9mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.1504 mL | 15.752 mL | 31.504 mL |
| 5 mM | 0.6301 mL | 3.1504 mL | 6.3008 mL |
| 10 mM | 0.315 mL | 1.5752 mL | 3.1504 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Tetrabenazine
Background: Tetrabenazine (TBZ) depletes presynaptic dopamine in the CNS. It has been found to be beneficial in hyperkinetic movement disorders without carrying the extrapyramidal side effects that are characteristic of neuroleptics. Objective: To summarize current knowledge on the use of TBZ and draw conclusions about its efficacy and safety. Methods: PubMed literature searches using the term 'tetrabenazine' were carried out for the period prior to May 2009. Additional relevant studies referenced by these publications were included. Conclusions: Both short- and long-term studies have consistently yielded favorable results for the use of TBZ in the treatment of hyperkinetic movement in terms of efficacy and safety. TBZ is most effective in reducing chorea (including Huntington's disease associated chorea), tic associated with Tourette's syndrome and tardive dyskinesias. Furthermore, TBZ might also have potential for use in other hyperkinetic disorders (e.g., myoclonus and dystonia), for which future clinical trials are needed.
Synthesis of Tetrabenazine and Its Derivatives, Pursuing Efficiency and Selectivity
Tetrabenazine is a US Food and Drug Administration (FDA)-approved drug that exhibits a dopamine depleting effect and is used for the treatment of chorea in Huntington's disease. Mechanistically, tetrabenazine binds and inhibits vesicular monoamine transporter type 2, which is responsible for importing neurotransmitters from the cytosol to the vesicles in neuronal cells. This transportation contributes to the release of neurotransmitters inside the cell to the synaptic cleft, resulting in dopaminergic signal transmission. The highly potent inhibitory activity of tetrabenazine has led to its advanced applications and in-depth investigation of prodrug design and metabolite drug discovery. In addition, the synthesis of enantiomerically pure tetrabenazine has been pursued. After a series of research studies, tetrabenazine derivatives such as valbenazine and deutetrabenazine have been approved by the US FDA. In addition, radioisotopically labeled tetrabenazine permits the early diagnosis of Parkinson's disease, which is difficult to treat during the later stages of this disease. These applications were made possible by the synthetic efforts aimed toward the efficient and asymmetric synthesis of tetrabenazine. In this review, various syntheses of tetrabenazine and its derivatives have been summarized.
Deuterium Tetrabenazine for Tardive Dyskinesia
Tardive dyskinesia remains a significant, potentially stigmatizing or crippling adverse effect for any patient treated with an antipsychotic medication. While second- and third-generation antipsychotics have exhibited lower annual incidence rates for tardive dyskinesia than classic or first-generation agents, 3.9% versus 5.5%, the estimated incidence rate is only modestly lower. When coupled with the fact that second- and third-generation antipsychotic medications have come to be employed in treating a wider range of disorders (e.g., autism spectrum disorders, mood disorders, personality disorders, etc.), it is clear that the population of patients exposed to the risk of tardive dyskinesia has expanded. On April 3, 2017, the U.S. Food and Drug Administration (FDA) approved a deuterated version of tetrabenazine (Xenozine?) for the treatment of the involuntary choreic movements associated with Huntington's disease. More recent data, however, have indicated that deuterium tetrabenazine or deutetrabenazine (Austedo?) is effective in treating tardive dyskinesia. Moreover, like the other derivative of tetrabenazine, valbenazine (Ingrezza?), deutetrabenazine offers less frequent dosing and a better short-term adverse effect profile than that of tetrabenazine. Longer use in a broader range of patients, however, will be required to identify risks and benefits not found in short-term trials, as well as optimal use parameters for treatment of tardive dyskinesia.