2-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-1H-isoindole-1,3(2H)-dione | 386218-05-9

• 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: 2-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-1H-isoindole-1,3(2H)-dione
• 英文别名: 2-(4-(4-(4-chlorophenyl)piperazin-1-yl)butyl)isoindoline-1,3-dione；Phthalimide, N-[4-[4-(4-chlorophenyl)piperazin-1-yl]butyl]-；2-[4-[4-(4-chlorophenyl)piperazin-1-yl]butyl]isoindole-1,3-dione
• CAS: 386218-05-9
• 化学式: C₂₂H₂₄ClN₃O₂
• 分子量: 397.904
• InChiKey: OVUBTULZZRXHED-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.54
• 重原子数：
  28.0
• 可旋转键数：
  6.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  43.86
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  2-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-1H-isoindole-1,3(2H)-dione 在 HATU 、 盐酸羟胺 、 sodium acetate 、 一水合肼 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Design, synthesis and evaluation of bitopic arylpiperazinephenyl-1,2,4-oxadiazoles as preferential dopamine D3 receptor ligands

  摘要：

  The dopamine D3 receptor (D3R) was proposed as a therapeutic target for drug development to treat drug abuse and addiction and neuropsychiatric disorders. Several D3R-selective modulators over the dopamine D2 receptor (D2R) can avoid extrapyramidal symptoms (EPS) and hyperprolactinemia. However, few biased D3R ligands were identified or showed a narrow range of selectivity at the D3R over D2R because of their high sequence homology. Herein, we designed, synthesized and evaluated the binding affinity of a series of bitopic ligands: arypiperazine-phenyl-1,2,4-oxadiazoles. Compound 9e center dot HCl was the most potent and selective D3R modulator among these bitopic ligands. Molecular modeling revealed that D3R selectivity depends on the divergence of secondary binding pocket (SBP) in D3R and D2R. Specifically, non-conserved Tyr36, EL1 especially non-conserved Thr92 and Gly94, and EL2 Val180, Cys181 and Ser182 of D3R may contribute to D3R specificity over D2R. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.12.002
• 作为产物：
  描述：

  邻苯二甲酸亚胺 在 potassium carbonate 、 sodium iodide 作用下， 以 1,4-二氧六环 、 丙酮 为溶剂， 反应 40.0h， 生成 2-{4-[4-(4-chlorophenyl)piperazin-1-yl]butyl}-1H-isoindole-1,3(2H)-dione
  参考文献：
  名称：

  设计，合成和评估N-（4-（4-苯基哌嗪-1-基）丁基）-4-（噻吩-3-基）苯甲酰胺作为选择性多巴胺D3受体配体。

  摘要：

  为了探索多巴胺受体在药物成瘾中的作用并确定针对这种情况的潜在新疗法，我们正在进行的工作包括确定一系列N-（4-（4-苯基哌嗪-1-基）丁基）-4-（噻吩-3-基）苯甲酰胺D 3配体。该类别的成员对D 3和D 2具有高度选择性，并且我们鉴定了两种化合物（13g和13r），它们的大鼠体内IV药代动力学特性表明它们适用于评估物质使用失调的体内功效模型。

  DOI：

  10.1016/j.bmcl.2019.07.020

文献信息

• Design, synthesis, and evaluation of bitopic arylpiperazine-phthalimides as selective dopamine D₃ receptor agonists
  作者：Yongkai Cao、Ningning Sun、Jiumei Zhang、Zhiguo Liu、Yi-zhe Tang、Zhengzhi Wu、Kyeong-Man Kim、Seung Hoon Cheon

  DOI：10.1039/c8md00237a

  日期：——

  docking demonstrated that the orientation of Leu2.64 and Phe7.39 and the packing at the junction of helices may affect the specificity for D3R over D2R. Functional evaluation revealed that D3R-selective ligand 9i displayed a subpicomolar agonist activity at D3R with a 199-fold increase in potency compared to quinpirole. These results may be useful for the fragment-based design of bitopic compounds as selective

  多巴胺D 3受体（D 3 R）是公认的治疗神经系统疾病和神经精神疾病的治疗靶标。特别地，已经验证了可以消除与多巴胺D 2受体（D 2 R）治疗剂相关的副作用的D 3 R选择性配体。但是，信号通路的高度同源性以及D 2 R和D 3 R之间的序列相似性使D 3 R选择性配体的开发具有挑战性。在本文中，我们基于片段和分子对接启发设计，设计并合成了一系列哌嗪-邻苯二甲酰亚胺双位配体。化合物9i在这些双位配体中，被鉴定为最有选择性的D 3 R配体。与参考化合物1和2相比，其选择性分别提高了9倍和2倍，并且比化合物2的效价高21倍。分子对接表明亮氨酸的取向2.64和Phe 7.39和在螺旋的结填料可能影响d特异性3 R经由d 2 R.功能评价揭示，d 3 R-选择性配体9i中在显示亚皮摩尔激动剂活性d 3与喹吡罗相比，R的效价提高了199倍。这些结果可能对双主题化合物作为选择性D 3 R配体的基于片段的设计有用。
• An Interactive SAR Approach to Discover Novel Hybrid Thieno Probes as Ligands for D2-Like Receptors with Affinities in the Subnanomolar Range
  作者：Mohamed A. O. Abdel-Fattah、Jochen Lehmann、Ashraf H. Abadi

  DOI：10.1002/cbdv.201300204

  日期：2013.12

  ,3-dione derivatives was synthesized to serve as probes for dopaminergic receptors. Among this series, compound 6a showed the highest affinity towards D4 and D3 receptors with Ki values in the low nanomolar range, and D2/D4- and D2/D3-selectivity indices of 72 and 20, respectively. Optimization rounds were adopted and led to the D4-selective ligand thiophene-2-carboxamide 9a with a Ki (D4) value of

  合成了一系列的[（苯基哌嗪基）烷基]-异吲哚-1,3-二酮衍生物，用作多巴胺能受体的探针。在该系列中，化合物6a对D4和D3受体的亲和力最高，Ki值在低纳摩尔范围内，D2 / D4-和D2 / D3-选择性指数分别为72和20。采用最优化回合，得到Ki（D4）值为0.62 nM的D4选择性配体噻吩-2-羧酰胺9a，其丁基类似物10a的Ki（D4）和Ki（D3）值为0.03和0.26 nM。对接实验揭示了独特的D4残基Arg186在操纵配体D4亚型受体选择性中的重要性。
• NOVEL SELECTIVE LIGAND FOR DOPAMINE D3 RECEPTOR, PREPARATION METHOD THEREFOR, AND PHARMACEUTICAL APPLICATION THEREOF
  申请人：Shenzhen Linglan Bio-Pharmaceutical Technology Co., Ltd

  公开号：US20200087264A1

  公开（公告）日：2020-03-19

  The present invention provides a novel ligand for the dopamine D3 receptor and a preparation method therefor. The compound, and a pharmaceutically acceptable salt and a pharmaceutical composition or a pharmaceutical preparation thereof are used for the treatment and prevention of schizophrenia, neurodegenerative diseases, particularly Parkinson's disease, drug dependence, drug addiction, anxiety, depression, etc. The novel ligand of the dopamine D3 receptor features a high affinity, a high specificity, and a high functional selectivity. The compound and the pharmaceutically acceptable salt and the pharmaceutical composition or the pharmaceutical preparation thereof can be used to study the distribution and function of dopamine D2 subtype receptors and mechanism of diseases associated with dysfunction of dopamine D2-like receptors, and can also be used for the disease modification of hyperprolactinemia, extrapyramidal symptoms, and levodopa-associated movement disorder or dyskinesia.