2-[4-[4-(m-aminophenyl)piperazine-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole | 188915-13-1

• 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: 2-[4-[4-(m-aminophenyl)piperazine-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole
• 英文别名: 2-[4-[4-(m-aminophenyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole；2-{4-[4-(m-aminophenyl)piperazin-1-yl]butyl}-1,3-dioxoperhydropyrrolo[1,2-c]imidazole；2-[4-[4-(3-Aminophenyl)piperazin-1-yl]butyl]-5,6,7,7a-tetrahydropyrrolo[1,2-c]imidazole-1,3-dione
• CAS: 188915-13-1
• 化学式: C₂₀H₂₉N₅O₂
• 分子量: 371.483
• InChiKey: UEPIRTWFGGUUDL-UHFFFAOYSA-N

物化性质

• 沸点：
  565.9±60.0 °C(Predicted)
• 密度：
  1.29±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  73.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  异丁酰氯 、 2-[4-[4-(m-aminophenyl)piperazine-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole 在 吡啶 作用下， 反应 1.5h， 以62%的产率得到2-(4-{4-[m-(2-methylpropanamido)phenyl]piperazin-1-yl}butyl)-1,3-dioxoperhydropyrrolo[1,2-c]imidazole
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

  摘要：

  A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT1A and alpha(1) receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha(1) selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and alpha(1) receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and alpha(1) receptors. A comparison of these models gives an additional understanding for 5-HT1A/alpha(1) selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/alpha(1) selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha(1) receptor are more restricted (optimum volume of substituent 11-25 Angstrom(3)). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT1A/alpha(1) selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.

  DOI：

  10.1021/jm960744g
• 作为产物：
  描述：

  2-[4-[4-(m-nitrophenyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 反应 2.0h， 以93%的产率得到2-[4-[4-(m-aminophenyl)piperazine-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole
  参考文献：
  名称：

  Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

  摘要：

  A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT1A and alpha(1) receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha(1) selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and alpha(1) receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and alpha(1) receptors. A comparison of these models gives an additional understanding for 5-HT1A/alpha(1) selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/alpha(1) selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha(1) receptor are more restricted (optimum volume of substituent 11-25 Angstrom(3)). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT1A/alpha(1) selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.

  DOI：

  10.1021/jm960744g

文献信息

• Design, Synthesis and Pharmacological Evaluation of 5-Hydroxytryptamine_1aReceptor Ligands to Explore the Three-Dimensional Structure of the Receptor
  作者：Marı́a L. López-Rodrı́guez、Bruno Vicente、Xavier Deupi、Sergio Barrondo、Mireia Olivella、M. José Morcillo、Bellinda Behamú、Juan A. Ballesteros、Joan Sallés、Leonardo Pardo

  DOI：10.1124/mol.62.1.15

  日期：2002.7.1

  In this work, we evaluate the structural differences of transmembrane helix 3 in rhodopsin and the 5-hydroxytryptamine 1A (5-HT1A) receptor caused by their different amino acid sequence. Molecular dynamics simulations of helix 3 in the 5-HT1A receptor tends to bend toward helix 5, in sharp contrast to helix 3 in rhodopsin, which is properly located within the position observed in the crystal structure. The relocation of the central helix 3 in the helical bundle facilitates the experimentally derived interactions between the neurotransmitters and the Asp residue in helix 3 and the Ser/Thr residues in helix 5. The different amino acid sequence that forms helix 3 in rhodopsin (basically the conserved Gly3.36Glu3.37 motif in the opsin family) and the 5-HT1A receptor (the conserved Cys3.36Thr3.37 motif in the neurotransmitter family) produces these structural divergences. These structural differences were experimentally checked by designing and testing ligands that contain comparable functional groups but at different interatomic distance. We have estimated the position of helix 3 relative to the other helices by systematically changing the distance between the functional groups of the ligands ( 1 and 2 ) that interact with the residues in the receptor. Thus, ligand 1 optimally interacts with a model of the 5-HT1A receptor that matches rhodopsin template, whereas ligand 2 optimally interacts with a model that possesses the proposed conformation of helix 3. The lack of affinity of 1 ( K i > 10,000 nM) and the high affinity of 2 ( K i = 24 nM) for the 5-HT1A receptor binding sites, provide experimental support to the proposed structural divergences of helix 3 between the 5-HT1A receptor and rhodopsin.

  在这项研究中，我们评估了因氨基酸序列不同而导致的犀牛蛋白和5-羟色胺1A（5-HT1A）受体跨膜螺旋3的结构差异。分子动力学模拟显示，5-HT1A 受体中的螺旋 3 趋向于向螺旋 5 弯曲，这与斜视素中的螺旋 3 形成鲜明对比，后者正确地位于晶体结构中观察到的位置。螺旋 3 在螺旋束中的中心位置有利于神经递质与螺旋 3 中的 Asp 残基和螺旋 5 中的 Ser/Thr 残基之间的相互作用。形成螺旋 3 的氨基酸序列在犀牛蛋白（基本上是视蛋白家族中的 Gly3.36Glu3.37 保守基团）和 5-HT1A 受体（神经递质家族中的 Cys3.36Thr3.37 保守基团）中不同，从而产生了这些结构差异。通过设计和测试含有相似功能基团但原子间距离不同的配体，我们在实验中检验了这些结构差异。我们通过系统地改变与受体残基相互作用的配体（1 和 2）的功能基团之间的距离，估算出了螺旋 3 相对于其他螺旋的位置。因此，配体 1 与符合犀牛蛋白模板的 5-HT1A 受体模型的相互作用最佳，而配体 2 与具有拟议的螺旋 3 构象的模型的相互作用最佳。配体 1 与 5-HT1A 受体结合位点的亲和力不足（K i > 10,000 nM），而配体 2 与 5-HT1A 受体结合位点的亲和力较高（K i = 24 nM），这为 5-HT1A 受体和视网膜视蛋白之间的螺旋 3 结构差异提供了实验支持。
• Design and synthesis of 2-[4-[4-(m-(ethylsulfonamido)-phenyl)piperazin-1-yl]butyl]-1,3-dioxoperhydropyrrolo[1,2-c]imidazole (EF-7412) using neural networks. A selective derivative with mixed antagonist properties
  作者：María L López-Rodríguez、M JoséMorcillo、Esther Fernández、M Luisa Rosado、Luis Orensanz、M Eugenia Beneytez、Jorge Manzanares、JoséA Fuentes、Klaus-Jürgen Schaper

  DOI：10.1016/s0960-894x(99)00254-1

  日期：1999.6

  A test series of 32 phenylpiperazines III with affinity for 5-HT1A and alpha(1) receptors was subjected to QSAR analysis using artificial neural networks (ANNs), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha(1) selectivity. Good models and predictive power were obtained for 5-HT1A and alpha(1) receptors. A comparison of these models gives information for the design of the new ligand EF-7412 (5-HT1A:K-i (nM)= 27; alpha(1):K-i (nM) > 1000). This derivative displayed affinity for dopamine D-2 receptor (K-i=22 nM) and is selective for all other receptor examined (5-HT2A, 5-HT3, 5-HT3, 5-HT4 and Bz). EF-7412 acts an antagonist in vivo in pre- and postsynaptic 5-MT1A receptor sites and as an antagonist in dopamine D-2 receptor. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 5. Study of the Physicochemical Influence of the Pharmacophore on 5-HT_1A/α₁-Adrenergic Receptor Affinity:  Synthesis of a New Derivative with Mixed 5-HT_1A/D₂ Antagonist Properties
  作者：María L. López-Rodríguez、M. José Morcillo、Esther Fernández、Esther Porras、Luis Orensanz、M Eugenia Beneytez、Jorge Manzanares、Jose Angel Fuentes

  DOI：10.1021/jm000929u

  日期：2001.1.1

  In this paper we have designed and synthesized a test series of 32 amide arylpiperazine derivatives VI in order to gain insight into the physicochemical influence of the pharmacophores of 5-HT1A and alpha (1)-adrenergic receptors. The training set was designed applying a fractional factorial design using six physicochemical descriptors. The amide moiety is a bicyclohydantoin or a diketopiperazine (X = -(CH2)(3)-, -(CH2)(4)-; m = 0, 1), the spacer length is 3 or 4 methylene units, which are the optimum values for both receptors, and the aromatic substituent R occupies the ortho- or meta-position and has been selected from a database of 387 substituents using the EDISFAR program. The 5-HT1A and alpha (1)-adrenergic receptor binding affinities of synthesized compounds VI (1-32) have been determined. This data set has been used to derive classical quantitative structure-activity relationships (QSAR) and neural-networks models for both receptors (following paper). A comparison of these models gives information for the design of the new ligand EF-7412 (46) (5-HT1A: K-i = 27 nM; alpha (1): K-i > 1000 nM). This derivative displays affinity for the dopamine D-2 receptor (K-i = 22 nM) and is selective versus all other receptors examined (5-HT2A, 5-HT3, 5-HT4 and Bz; K-i > 1000 nM). EF-7412 (46) acts as an antagonist in vivo in pre- and postsynaptic 5-HT1A receptor sites and; as an antagonist in the dopamine D-2 receptor. Thus, EF-7412 (46) is a derivative with mixed 5-HT1A/D-2 antagonist properties and this derivative could be useful as a pharmacological tool.