4-amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butane-2-ol | 944344-38-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 4-amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butane-2-ol
• 英文别名: 4-amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butan-2-ol；4-amino-1-(4-(2-methoxy-phenyl)-piperazin-1-yl)-butan-2-ol；4-Amino-1-(4-(2-methoxyphenyl)-piperazin-1-yl)-butan-2-ol；4-amino-1-[4-(2-methoxyphenyl)piperazin-1-yl]butan-2-ol
• CAS: 944344-38-1
• 化学式: C₁₅H₂₅N₃O₂
• 分子量: 279.382
• InChiKey: LXVGLTSZDZTLJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  62
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butane-2-ol 、 9H-芴-2-羧基 酸 以45%的产率得到N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)-butyl)-9H-fluorene-2-carboxamide
  参考文献：
  名称：

  N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）丁基）芳基羧酰胺的杂环类似物，具有功能化的连接链，作为新的多巴胺D3受体配体：潜在的药物滥用治疗剂。

  摘要：

  多巴胺D3受体拮抗剂和部分激动剂已显示出可卡因和其他滥用药物引起的药物寻找作用。化合物6 [PG01037，（N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）-反式-丁-2-烯基）-4-吡啶-2-基苯甲酰胺）]及相关类似物目前正在对成瘾性动物模型进行评估。在这些研究中，已观察到体外结合亲和力，体内占有率和行为效能之间的差异。这项研究的目的是检查（1）丁基酰胺连接链上的2-吡啶基苯基部分的修饰和（2）与2-芴基酰胺或2-吡啶基苯基酰胺和2-甲氧基系统偶联的丁基酰胺连接链上的羟基，乙酰基和环丙基取代基-或2,3-二氯取代的苯基哌嗪来测量对结合亲和力，D2 / D3选择性的影响，亲脂性和功能。通常，如在竞争结合测定中所测量的，这些修饰在人多巴胺D3（hD3）受体（Ki = 1-5 nM）上具有良好的耐受性。几种类似物对多巴胺D3的选择性比D2和D4受体高100倍以上。此外，尽管所有带有烯烃连接

  DOI：

  10.1021/jm0704200
• 作为产物：
  描述：

  2-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)isoindoline-1,3-dione 在 肼 作用下， 以 乙醇 为溶剂， 反应 0.33h， 以69%的产率得到4-amino-1-(4-(2-methoxyphenyl)piperazin-1-yl)butane-2-ol
  参考文献：
  名称：

  N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）丁基）芳基羧酰胺的杂环类似物，具有功能化的连接链，作为新的多巴胺D3受体配体：潜在的药物滥用治疗剂。

  摘要：

  多巴胺D3受体拮抗剂和部分激动剂已显示出可卡因和其他滥用药物引起的药物寻找作用。化合物6 [PG01037，（N-（4-（4-（2,3-二氯苯基）哌嗪-1-基）-反式-丁-2-烯基）-4-吡啶-2-基苯甲酰胺）]及相关类似物目前正在对成瘾性动物模型进行评估。在这些研究中，已观察到体外结合亲和力，体内占有率和行为效能之间的差异。这项研究的目的是检查（1）丁基酰胺连接链上的2-吡啶基苯基部分的修饰和（2）与2-芴基酰胺或2-吡啶基苯基酰胺和2-甲氧基系统偶联的丁基酰胺连接链上的羟基，乙酰基和环丙基取代基-或2,3-二氯取代的苯基哌嗪来测量对结合亲和力，D2 / D3选择性的影响，亲脂性和功能。通常，如在竞争结合测定中所测量的，这些修饰在人多巴胺D3（hD3）受体（Ki = 1-5 nM）上具有良好的耐受性。几种类似物对多巴胺D3的选择性比D2和D4受体高100倍以上。此外，尽管所有带有烯烃连接

  DOI：

  10.1021/jm0704200

文献信息

• 4-PHENYLPIPERAZINE DERIVATIVES WITH FUNCTIONALIZED LINKERS AS DOPAMINE D3 RECEPTOR SELECTIVE LIGANDS AND METHODS OF USE
  申请人：Newman Amy Hauck

  公开号：US20100267737A1

  公开（公告）日：2010-10-21

  Dopamine D 3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D 3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D 3 receptors and achieve high selectivity over D 2 and D 4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知可以调节可卡因和其他滥用物质引起的强化和寻药效应。通过在4-苯基哌嗪类配体的丁酰胺链中引入功能基团，可以获得改进的D3受体亲和力和选择性，以及水溶性。公开了一系列链连接衍生物，其中引入了OH或OAc基团等功能基团。一般来说，这些修饰在D3受体上很好地耐受，并实现了对D2和D4受体的高选择性。
• 4-phenylpiperazine derivatives with functionalized linkers as dopamine D3 receptor selective ligands and methods of use
  申请人：Newman Amy Hauck

  公开号：US08748608B2

  公开（公告）日：2014-06-10

  Dopamine D3 receptor antagonists and partial agonists are known to modulate the reinforcing and drug-seeking effects induced by cocaine and other abused substances. By introducing functionality into the butylamide linking chain of the 4-phenylpiperazine class of ligands, improved D3 receptor affinity and selectivity, as well as water solubility, is achieved. A series of linking-chain derivatives are disclosed wherein functionality such as OH or OAc groups have been introduced into the linking chain. In general, these modifications are well tolerated at D3 receptors and achieve high selectivity over D2 and D4 receptors.

  多巴胺D3受体拮抗剂和部分激动剂已知能够调节可卡因和其他滥用物质引起的强化和寻药效应。通过在4-苯基哌嗪类配体的丁酰胺连接链中引入功能基团，可以获得改良的D3受体亲和力和选择性，以及水溶性。披露了一系列连接链衍生物，其中引入了OH或OAc基团等功能基团。一般来说，这些修饰在D3受体上很容易耐受，并实现了对D2和D4受体的高选择性。
• High Affinity Dopamine D₃ Receptor (D₃R)-Selective Antagonists Attenuate Heroin Self-Administration in Wild-Type but not D₃R Knockout Mice
  作者：Comfort A. Boateng、Oluyomi M. Bakare、Jia Zhan、Ashwini K. Banala、Caitlin Burzynski、Elie Pommier、Thomas M. Keck、Prashant Donthamsetti、Jonathan A. Javitch、Rana Rais、Barbara S. Slusher、Zheng-Xiong Xi、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.5b00776

  日期：2015.8.13

  The dopamine D-3 receptor (D3R) is a promising target for the development of pharmacotherapeutics to treat substance use disorders. Several D3R-selective antagonists are effective in animal models of drug abuse, especially in models of relapse. Nevertheless, poor bioavailability, metabolic instability, and/or predicted toxicity have impeded success in translating these drug candidates to clinical use. Herein, we report a series of D3R-selective 4-phenylpiperazines with improved metabolic stability. A subset of these compounds was evaluated for D3R functional efficacy and off-target binding at selected 5-HT receptor subtypes, where significant overlap in SAR with D3R has been observed. Several high affinity D3R antagonists, including compounds 16 (K-i = 0.12 nM) and 32 (K-i = 0.35 nM), showed improved metabolic stability compared to the parent compound, PG648 (6). Notably, 16 and the classic D3R antagonist SB277011A (2) were effective in reducing selfadministration of heroin in wild-type but not D3R knockout mice.
• Synthesis and evaluation of fluoro substituted pyridinylcarboxamides and their phenylazo analogues for potential dopamine D3 receptor PET imaging
  作者：Natascha Nebel、Simone Maschauer、Amelie L. Bartuschat、Stefanie K. Fehler、Harald Hübner、Peter Gmeiner、Torsten Kuwert、Markus R. Heinrich、Olaf Prante、Carsten Hocke

  DOI：10.1016/j.bmcl.2014.10.043

  日期：2014.12

  A series of fluoro substituted pyridinylcarboxamides and their phenylazo analogues with high affinity and selectivity for the dopamine D3 receptor was synthesized by the use of 6-fluoropyridine-3-carbonyl chloride (1) and fluorophenylazocarboxylic ester (2). Several of these compounds (9a-e and 10a-h) have been evaluated in vitro, among which 9b, 10a, 10c and 10d proved to have at least single-digit nanomolar affinity for D3. They also exhibit considerable selectivity over the other dopamine receptor subtypes and noteworthy selectivity over the structurally related serotonin receptor subtypes 5-HT1A and 5-HT2, offering potential radiotracers for positron emission tomography. (C) 2014 Elsevier Ltd. All rights reserved.
• <i>N</i>-(4-(4-(2,3-Dichloro- or 2-methoxyphenyl)piperazin-1-yl)butyl)heterobiarylcarboxamides with Functionalized Linking Chains as High Affinity and Enantioselective D3 Receptor Antagonists
  作者：Amy Hauck Newman、Peter Grundt、George Cyriac、Jeffrey R. Deschamps、Michelle Taylor、Rakesh Kumar、David Ho、Robert R. Luedtke

  DOI：10.1021/jm900095y

  日期：2009.4.23

  In the present report, the D3 receptor pharmacophore is modified in the 2,3-diCl- and 2-OCH3-phenylpiperazine class of compounds with the goal to improve D3 receptor affinity and selectivity. This extension of structure-activity relationships (SAR) has resulted in the identification of the first enantioselective D3 antagonists (R- and S-22) to be reported, wherein enantioselectivity is more pronounced at D3 than at D2, and that a binding region on the second extracellular loop (E2) may play a role in both enantioselectivity and D3 receptor selectivity. Moreover, we have discovered some of the most D3-selective compounds reported to date that show high affinity (K-i = 1 nM) for D3 and similar to 400-fold selectivity over the D2 receptor subtype. Several of these analogues showed exquisite selectivity for D3 receptors over >60 other receptors, further underscoring their value as in vivo research tools. These lead compounds also have appropriate physical characteristics for in vivo exploration and therefore will be useful in determining how intrinsic activity at D3 receptors tested in vitro is related to behaviors in animal models of addiction and other neuropsychiatric disorders.