1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐 | 23007-85-4

• 物质功能分类: 医药中间体
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐
• 中文别名: MPTP盐酸盐；MPTP,1-甲基-4-苯基-1,2,3,6-四氢嘧啶；1-甲基-4-苯基-1,2,3,6-四氢嘧啶盐酸盐
• 英文名称: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride
• 英文别名: MPTP hydrochloride；MPTP*HCl；MPTP；1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine；hydron;1-methyl-4-phenyl-3,6-dihydro-2H-pyridine;chloride
• CAS: 23007-85-4
• 化学式: C₁₂H₁₅N*ClH
• 分子量: 209.719
• InChiKey: KOWJANGMTAZWDT-UHFFFAOYSA-N

物化性质

• 熔点：
  249.0 to 254.0 °C
• 溶解度：
  DMSO（少许）、甲醇（少许）、水（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.35
• 重原子数：
  14
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.333
• 拓扑面积：
  3.2
• 氢给体数：
  1
• 氢受体数：
  1

安全信息

• 危险等级：
  6.1(b)
• 危险品标志：
  T
• 危险类别码：
  R39/23/24/25,R25
• 危险品运输编号：
  UN 2811
• 海关编码：
  2933399090
• 包装等级：
  III
• 危险类别：
  6.1(b)

制备方法与用途

应用

1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐是一种吡啶类衍生物，可用作医药中间体。

生物活性

MPTP HCl 是一种多巴胺能的神经毒素，在帕金森动物模型中能够选择性地破坏多巴胺能神经元，并诱导细胞凋亡。

体外研究

当N2AB-1和神经胶质瘤细胞暴露于不同浓度的MPTP时，其形态未发生改变；C6胶质细胞的增殖也未受到影响。然而，MPTP能够促进人类成神经细胞瘤M17细胞的凋亡及Tau蛋白磷酸化，显著提高了Ser262位点上的Tau磷酸化水平。此外，MPTP还导致了人类成神经细胞瘤M17细胞中胞内α-synuclein水平的提升，并通过激活PKA和GSK3β促进了脑内Tau的磷酸化。

体内研究

在MPTP处理的小鼠黑质致密部中，酪氨酸羟化酶阳性的多巴胺能神经元数量减少。此外，MPTP减少了小鼠中脑1型硫氧还蛋白还原酶的表达和活性，并降低了黑质致密部中该酶阳性细胞的数量。研究显示，MPTP可以在人体、非人类灵长类动物及啮齿类动物中引起类似帕金森病患者的神经化学、行为学和组织病理学改变。相对于灵长类动物而言，啮齿类动物对MPTP的反应较不敏感。MPTP可通过多种途径施用，如填喂法、定位注射等，但最常见且可重复的方式是全身用药，包括皮下、静脉、腹腔及肌内注射。作为一种亲脂性原毒素，MPTP能够透过血脑屏障，并在进入大脑后转化为1-甲基-4-苯基吡啶，进而对多巴胺能神经元产生毒性作用并持续消耗多巴胺，在纹状体中生成其代谢产物。

反应信息

• 作为反应物：
  描述：

  1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐 在 potassium permanganate 作用下， 以 丙酮 为溶剂， 反应 2.0h， 以85%的产率得到N-methyl-N-(3-oxo-3-phenylpropyl)formamide
  参考文献：
  名称：

  摘要：

  DOI：

  10.1023/a:1012495323470
• 作为产物：
  描述：

  1-甲基-4-苯基-4-羟基哌啶 在 盐酸 作用下， 以 水 为溶剂， 反应 5.0h， 生成 1-甲基-4-苯基-1,2,3,6-四氢吡啶盐酸盐
  参考文献：
  名称：

  Preferential Extracellular Generation of the Active Parkinsonian Toxin MPP⁺by Transporter-Independent Export of the Intermediate MPDP⁺

  摘要：

  Aims: 1-Methyl-4-phenyl-tetrahydropyridine (MPTP) is among the most widely used neurotoxins for inducing experimental parkinsonism. MPTP causes parkinsonian symptoms in mice, primates, and humans by killing a subpopulation of dopaminergic neurons. Extrapolations of data obtained using MPTP-based parkinsonism models to human disease are common; however, the precise mechanism by which MPTP is converted into its active neurotoxic metabolite, 1-methyl-4-phenyl-pyridinium (MPP+), has not been fully elucidated. In this study, we aimed to address two unanswered questions related to MPTP toxicology: (1) Why are MPTP-converting astrocytes largely spared from toxicity? (2) How does MPP+ reach the extracellular space? Results: In MPTP-treated astrocytes, we discovered that the membrane-impermeable MPP+, which is generally assumed to be formed inside astrocytes, is almost exclusively detected outside of these cells. Instead of a transporter-mediated export, we found that the intermediate, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP+), and/or its uncharged conjugate base passively diffused across cell membranes and that MPP+ was formed predominately by the extracellular oxidation of MPDP+ into MPP+. This nonenzymatic extracellular conversion of MPDP+ was promoted by O-2, a more alkaline pH, and dopamine autoxidation products. Innovation and Conclusion: Our data indicate that MPTP metabolism is compartmentalized between intracellular and extracellular environments, explain the absence of toxicity in MPTP-converting astrocytes, and provide a rationale for the preferential formation of MPP+ in the extracellular space. The mechanism of transporter-independent extracellular MPP+ formation described here indicates that extracellular genesis of MPP+ from MPDP is a necessary prerequisite for the selective uptake of this toxin by catecholaminergic neurons.

  DOI：

  10.1089/ars.2015.6297

文献信息

• CELL DELIVERY COMPOSITIONS
  申请人：——

  公开号：US20010006817A1

  公开（公告）日：2001-07-05

  The present invention provides improved cell delivery compositions. In particular, the invention provides biocompatible endosomolytic agents. In a preferred embodiment, the endosomolytic agents are also biodegradable and can be broken down within cells into components that the cells can either reuse or dispose of. Preferred endosomolytic agents include cationic polymers, particularly those comprised of biomolecules, such as histidine, polyhistidine, polylysine or any combination thereof. Other exemplary endosomolytic agents include, but are not limited to, other imidazole containing compounds such as vinylimidazole and histamine. More particularly preferred are those agents having multiple proton acceptor sites and acting as a “proton sponge”, disrupting the endosome by osmolytic action. In preferred embodiments, the endosomolytic agent comprises a plurality of proton acceptor sites having pKas within the range of 4 to 7, which endosomal lysing component is polycationic at pH 4. The present invention also contemplates the use of these endosomolytic agents as delivery agents by complexation with the desired compound to be delivered. Thus, the present invention also acts as a cell delivery system comprising an endosomolytic agent, a delivery agent, and a compound to be delivered.

  本发明提供了改进的细胞递送组合物。具体而言，本发明提供了生物相容的内体溶解剂。在一个优选实施例中，内体溶解剂也是可生物降解的，可以在细胞内分解为细胞可以重新利用或处置的组分。优选的内体溶解剂包括阳离子聚合物，特别是由生物分子组成的聚组氨酸，如组氨酸、多组氨酸、多赖氨酸或二者的任意组合。其他示例性的内体溶解剂包括但不限于其他含咪唑醇基的化合物，如乙烯咪唑和组胺。更具体优选的是那些具有多个质子受体位点并作为“质子海绵”起作用的剂，通过渗透调节作用破坏内体。在优选实施例中，内体溶解剂包括具有pKa在4到7范围内的多个质子受体位点的内体溶解组分，在pH 4时为多阳离子性的。本发明还考虑了将这些内体溶解剂作为递送剂通过与要递送的化合物结合的复合物的使用。因此，本发明还作为一个细胞递送系统，包括一个内体溶解剂、一个递送剂和一个要递送的化合物。
• BIODEGRADABLE STEALTH POLYMERIC PARTICLES FABRICATED USING THE MACROMONOMER APPROACH BY FREE RADICAL DISPERSION POLYMERIZATION
  申请人：AKALA Emmanuel

  公开号：US20120129797A1

  公开（公告）日：2012-05-24

  The present invention is directed to a crosslinked or non-crosslinked polymer particle, wherein the crosslinked polymer particle comprises a copolymer of poly(alklyene glycol-graft-lactate) that is crosslinked by at least one hydrolysable monmer. Another embodiment of the present invention is a polymer particle comprising a crosslinked polymer particle that is a product of starting materials comprising (a) a hydrophilic monomer, (b) a hydrophobic monomer, and (c) a hydrolysable crosslinking agent. Another embodiment of the present invention is a polymer particle comprising, a crosslinked copolymer comprises structures represented by Formulas (I), (II), and (III), where Formulas (I), (II) and (III) are defined in the specification. Yet other embodiments of the present invention include a method of preparing a methacrylate terminated macromonomer, a method of preparing a crosslinking agent, and a method of preparing a therapeutic agent loaded nanosphere by dispersion polymerization.

  本发明涉及交联或非交联聚合物颗粒，其中交联聚合物颗粒包括聚（烷基二醇接枝乳酸酯）共聚物，该共聚物由至少一种可水解单体交联。本发明的另一实施例是聚合物颗粒，包括由起始材料制成的交联聚合物颗粒，该起始材料包括（a）亲水性单体，（b）疏水性单体和（c）可水解交联剂。本发明的另一实施例是聚合物颗粒，包括交联共聚物，其结构由式（I）、（II）和（III）表示，其中式（I）、（II）和（III）在说明书中有定义。本发明的其他实施例包括制备甲基丙烯酸酯末端的大分子单体的方法，制备交联剂的方法以及通过分散聚合制备治疗剂载药纳米球的方法。
• Dopamine analog amide
  申请人：——

  公开号：US20010056116A1

  公开（公告）日：2001-12-27

  The invention involves the formation of a prodrug from a fatty acid carrier and a neuroactive drug. The prodrug is stable in the environment of both the stomach and the bloodstream and may be delivered by ingestion. The prodrug passes readily through the blood brain barrier. Once in the central nervous system, the prodrug is hydrolyzed into the fatty acid carrier and the drug to release the drug. In a preferred embodiment, the carrier is 4, 7, 10, 13, 16, 19 docosahexa-enoic acid and the drug is dopamine. Both are normal components of the central nervous system. The covalent bond between the drug and the carrier preferably is an amide bond, which bond may survive the conditions in the stomach. Thus, the prodrug may be ingested and will not be hydrolyzed completely into the carrier molecule and drug molecule in the stomach.

  该发明涉及使用脂肪酸载体和神经活性药物形成前药。该前药在胃和血液流动环境中稳定，并可通过口服递送。该前药容易穿过血脑屏障。一旦进入中枢神经系统，前药被水解成脂肪酸载体和药物以释放药物。在首选实施方式中，载体是4,7,10,13,16,19二十二碳六烯酸，药物是多巴胺。两者都是中枢神经系统的正常成分。药物和载体之间的共价键通常是酰胺键，这种键可以在胃的条件下存活。因此，前药可以被摄入，并且不会在胃中完全水解成载体分子和药物分子。
• NOVEL CONJUGATES FOR TREATING NEURODEGENERATIVE DISEASES AND DISORDERS
  申请人：STEIN Gideon

  公开号：US20120277310A1

  公开（公告）日：2012-11-01

  A conjugate comprising L-DOPA covalently linked to at least one γ-aminobutyric acid (GABA) moiety, an ester and/or an addition salt thereof are disclosed, as well as uses thereof for treating a neurodegenerative disease or disorder.

  本发明揭示了一种共轭物，包括L-DOPA与至少一种γ-氨基丁酸（GABA）基团共价连接，以及它的酯和/或加成盐，以及它们在治疗神经退行性疾病或障碍方面的用途。
• Use of Cysteamine in Treating Parkinson's Disease
  申请人：Chan Bill Piu

  公开号：US20120309785A1

  公开（公告）日：2012-12-06

  The subject invention provides materials and methods for treating neurodegenerative diseases. In one embodiment of the invention, a cysteamine compound is administered to a patient to treat Parkinson's Disease and/or complications associated with Parkinson's Disease. In another embodiment, a cysteamine compound is administered to a patient to prevent the onset of Parkinson's Disease in an at-risk patient and/or treat or prevent the onset of Parkinson's Disease-associated symptoms.

  本发明提供了治疗神经退行性疾病的材料和方法。在本发明的一个实施例中，将半胱氨酸化合物用于治疗帕金森病及/或与帕金森病相关的并发症。在另一个实施例中，将半胱氨酸化合物用于预防有风险的患者患上帕金森病和/或治疗或预防与帕金森病相关的症状的发生。