4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol | 944344-37-0

• 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-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
• 英文别名: 4-Amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)-butan-2-ol；4-amino-1-[4-(2,3-dichlorophenyl)piperazin-1-yl]butan-2-ol
• CAS: 944344-37-0
• 化学式: C₁₄H₂₁Cl₂N₃O
• 分子量: 318.246
• InChiKey: ZGOOMUKHQJASFX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  20
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  52.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 反应 12.5h， 生成 4-(((9H-fluoren-2-yl)methyl)amino)-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
  参考文献：
  名称：

  N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity

  摘要：

  N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, > 1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by > 100-fold (e.g., D3R K-i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.

  DOI：

  10.1021/jm200288r
• 作为产物：
  描述：

  1-(2,3-二氯苯基)哌嗪 在 肼 作用下， 以 乙醇 为溶剂， 反应 3.0h， 生成 4-amino-1-(4-(2,3-dichlorophenyl)piperazin-1-yl)butan-2-ol
  参考文献：
  名称：

  N-(3-Fluoro-4-(4-(2-methoxy or 2,3-dichlorophenyl)piperazine-1-yl)butyl)arylcarboxamides as Selective Dopamine D3 Receptor Ligands: Critical Role of the Carboxamide Linker for D3 Receptor Selectivity

  摘要：

  N-(3-Fluoro-4-(4-(2,3-dichloro- or 2-methoxyphenyl)piperazine-1-yl)butyl)arylcarboxamides were prepared and evaluated for binding and function at dopamine D3 receptors (D3Rs) and dopamine D2 receptors (D2Rs). In this series, we discovered some of the most D3R selective compounds reported to date (e.g., 8d and 8j, > 1000-fold D3R-selective over D2R). In addition, chimeric receptor studies further identified the second extracellular (E2) loop as an important contributor to D3R binding selectivity. Further, compounds lacking the carbonyl group in the amide linker were synthesized, and while these amine-linked analogues bound with similar affinities to the amides at D2R, this modification dramatically reduced binding affinities at D3R by > 100-fold (e.g., D3R K-i for 15b = 393 vs for 8j = 2.6 nM), resulting in compounds with significantly reduced D3R selectivity. This study supports a pivotal role for the D3R E2 loop and the carbonyl group in the 4-phenylpiperazine class of compounds and further reveals a point of separation between structure-activity relationships at D3R and D2R.

  DOI：

  10.1021/jm200288r

文献信息

• Toward Understanding the Structural Basis of Partial Agonism at the Dopamine D₃ Receptor
  作者：Mayako Michino、Comfort A. Boateng、Prashant Donthamsetti、Hideaki Yano、Oluyomi M. Bakare、Alessandro Bonifazi、Michael P. Ellenberger、Thomas M. Keck、Vivek Kumar、Clare Zhu、Ravi Verma、Jeffrey R. Deschamps、Jonathan A. Javitch、Amy Hauck Newman、Lei Shi

  DOI：10.1021/acs.jmedchem.6b01148

  日期：2017.1.26

  Both dopamine D3 receptor (D3R) partial agonists and antagonists have been implicated as potential medications for substance use disorders. In contrast to antagonists, partial agonists may cause fewer side effects since they maintain some dopaminergic tone and may be less disruptive to normal neuronal functions. Here, we report three sets of 4-phenylpiperazine stereoisomers that differ considerably

  多巴胺D 3受体（D 3 R）部分激动剂和拮抗剂均被认为是药物滥用障碍的潜在药物。与拮抗剂相比，部分激动剂可保持较少的多巴胺能基调，因此对副作用的影响较小，并且对正常神经元功能的破坏较小。在这里，我们报告三套4-苯基哌嗪立体异构体，它们的功效差异很大：（R）-对映异构体是拮抗剂/弱部分激动剂，而（S）-对映异构体则更为有效。为了研究部分激动剂的结构基础，我们从D 3的非活性状态开始进行了比较微秒级的分子动力学模拟R与这些对映异构体复合。对模拟结果的分析揭示了由结合的（S）-对映异构体而不是（R）-对映异构体诱导的配体结合位点附近的常见结构重排，其为部分活化的受体构象的特征。这些与部分激动剂结合的受体模型可用于具有定制功效特征的化合物的基于结构的设计。
• Novel Dual-Target μ-Opioid Receptor and Dopamine D₃ Receptor Ligands as Potential Nonaddictive Pharmacotherapeutics for Pain Management
  作者：Alessandro Bonifazi、Francisco O. Battiti、Julie Sanchez、Saheem A. Zaidi、Eric Bow、Mariia Makarova、Jianjing Cao、Anver Basha Shaik、Agnieszka Sulima、Kenner C. Rice、Vsevolod Katritch、Meritxell Canals、J. Robert Lane、Amy Hauck Newman

  DOI：10.1021/acs.jmedchem.1c00611

  日期：2021.6.10

  safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D3 receptor (D3R) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without

  对更安全的疼痛管理疗法和减少滥用倾向的需求激发了一种新的药物设计，该药物设计保留了 μ-阿片受体 (MOR) 介导的镇痛作用，同时最大限度地减少了成瘾倾向。我们最近证明，用高选择性拮抗剂/部分激动剂靶向多巴胺 D 3受体 (D 3 R) 可以减少阿片类药物的自我给药和在啮齿动物模型中恢复药物寻求，而不会降低镇痛作用。将 D 3 R 确定为治疗阿片类药物使用障碍的靶点促使产生一类呈现双位或二价结构的配体的想法，允许 MOR 和 D 3的双靶点结合R. 使用计算辅助药物设计和体外结合试验的结构-活性关系研究导致基于不同的结构模板和支架，具有中等（亚微摩尔) 到高（低纳摩尔/亚纳摩尔）结合亲和力。基于生物发光共振能量转移的功能研究揭示了 MOR 激动剂-D 3 R 拮抗剂/部分激动剂的功效，这表明具有维持镇痛作用并降低阿片类药物滥用倾向的潜力。
• Heterocyclic Analogues of <i>N</i>-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with Functionalized Linking Chains as Novel Dopamine D3 Receptor Ligands:  Potential Substance Abuse Therapeutic Agents
  作者：Peter Grundt、Katherine M. Prevatt、Jianjing Cao、Michelle Taylor、Christina Z. Floresca、Ji-Kyung Choi、Bruce G. Jenkins、Robert R. Luedtke、Amy Hauck Newman

  DOI：10.1021/jm0704200

  日期：2007.8.1

  Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylben zamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding

  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
• Scaffold Hybridization Strategy Leads to the Discovery of Dopamine D₃ Receptor-Selective or Multitarget Bitopic Ligands Potentially Useful for Central Nervous System Disorders
  作者：Alessandro Bonifazi、Amy H. Newman、Thomas M. Keck、Silvia Gervasoni、Giulio Vistoli、Fabio Del Bello、Gianfabio Giorgioni、Pegi Pavletić、Wilma Quaglia、Alessandro Piergentili

  DOI：10.1021/acschemneuro.1c00368

  日期：2021.10.6

  multitarget behavior has been highlighted for the 5,5-diphenyl-1,4-dioxane and 1,4-benzodioxane derivatives 6 and 9, respectively, which displayed potent D2R antagonism, 5-HT1AR and D4R agonism, as well as potent D3R partial agonism. They also behaved as low-potency 5-HT2AR antagonists and 5-HT2CR partial agonists. Such a profile might be a promising starting point for the discovery of novel antipsychotic agents

  在寻找靶向多巴胺 D 3受体 (D 3 R) 的新型双位化合物时，N -(2,3-二氯苯基)哌嗪核（主要药效团）已与 6,6- 或 5,5-二苯基连接-1,4-二恶烷-2-甲酰胺或 1,4-苯并二恶烷-2-甲酰胺支架（二级药效团）由未取代或 3-F-/3-OH-取代的丁基链构成。这种支架杂交策略导致发现了可能对中枢神经系统疾病有用的有效的 D 3 R 选择性或多靶标配体。特别地，6,6-二苯基-1,4-二恶烷衍生物3显示出D 3R 优先分布，而 5,5-二苯基-1,4-二恶烷和 1,4-苯二恶烷衍生物6和9分别显示出有效的 D 2 R 拮抗作用，5-HT 的多靶点行为1A R 和 D 4 R 激动，以及有效的 D 3 R 部分激动。它们还表现为低效 5-HT 2A R 拮抗剂和 5-HT 2C R 部分激动剂。这样的概况可能是发现新型抗精神病药物的一个有希望的起点。
• 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。