2-phenylspiro[1,5-dihydroimidazole-4,3'-quinuclidine] | 1350363-85-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: 2-phenylspiro[1,5-dihydroimidazole-4,3'-quinuclidine]
• 英文别名: 2-Phenylspiro[1,4-dihydroimidazole-5,3'-1-azabicyclo[2.2.2]octane]
• CAS: 1350363-85-7
• 化学式: C₁₅H₁₉N₃
• 分子量: 241.336
• InChiKey: PFFDUVATZBBEFV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  27.6
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  苯甲亚胺酸甲酯盐酸盐 、 3-aminomethyl-1-azabicyclo<2.2.2>octyl-3-amine 以 甲醇 为溶剂， 反应 0.08h， 以28%的产率得到2-phenylspiro[1,5-dihydroimidazole-4,3'-quinuclidine]
  参考文献：
  名称：

  Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands

  摘要：

  AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and alpha 7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac. Bt, and the alpha 7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the alpha 7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-pi interactions. The use of AChBPs structure as a surrogate to predict binding affinity to alpha 7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a alpha 7 homology model, Bt or Ac crystal structure is used. (C) 2011 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2011.09.033

文献信息

• Discovery of novel α7 nicotinic acetylcholine receptor ligands via pharmacophoric and docking studies of benzylidene anabaseine analogs
  作者：David C. Kombo、Anatoly A. Mazurov、Joseph Chewning、Philip S. Hammond、Kartik Tallapragada、Terry A. Hauser、Jason Speake、Daniel Yohannes、William S. Caldwell

  DOI：10.1016/j.bmcl.2011.11.090

  日期：2012.1

  Based on pharmacophore elucidation and docking studies on interactions of benzylidene anabaseine analogs with AChBPs and alpha 7 nAChR, novel spirodiazepine and spiroimidazoline quinuclidine series have been designed. Binding studies revealed that some of hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the alpha 7 nAChR subtype in comparison with most potent metabolite of GTS-21, 3-(4-hydroxy-2-methoxybenzylidene)-anabaseine. Hydrophobicity and rigidity of the ligand also contribute into its binding affinity. We also describe alternative pharmacophoric features equidistant from the carbonyl oxygen atom of the conserved Trp-148 of the principal face, which may be exploited to further design diverse focused libraries targeting the alpha 7 nAChR. (C) 2011 Elsevier Ltd. All rights reserved.
• Docking studies of benzylidene anabaseine interactions with α7 nicotinic acetylcholine receptor (nAChR) and acetylcholine binding proteins (AChBPs): Application to the design of related α7 selective ligands
  作者：David C. Kombo、Anatoly Mazurov、Kartik Tallapragada、Philip S. Hammond、Joseph Chewning、Terry A. Hauser、Montserrat Vasquez-Valdivieso、Daniel Yohannes、Todd T. Talley、Palmer Taylor、William S. Caldwell

  DOI：10.1016/j.ejmech.2011.09.033

  日期：2011.11

  AChBPs isolated from Lymnaea stagnalis (Ls), Aplysia californica (Ac) and Bulinus truncatus (Bt) have been extensively used as structural prototypes to understand the molecular mechanisms that underlie ligand-interactions with nAChRs [1]. Here, we describe docking studies on interactions of benzylidene anabaseine analogs with AChBPs and alpha 7 nAChR. Results reveal that docking of these compounds using Glide software accurately reproduces experimentally-observed binding modes of DMXBA and of its active metabolite, in the binding pocket of Ac. In addition to the well-known nicotinic pharmacophore (positive charge, hydrogen-bond acceptor, and hydrophobic aromatic groups), a hydrogen-bond donor feature contributes to binding of these compounds to Ac. Bt, and the alpha 7 nAChR. This is consistent with benzylidene anabaseine analogs with OH and NH2 functional groups showing the highest binding affinity of these congeners, and the position of the ligand shown in previous X-ray crystallographic studies of ligand-Ac complexes. In the predicted ligand-Ls complex, by contrast, the ligand OH group acts as hydrogen-bond acceptor. We have applied our structural findings to optimizing the design of novel spirodiazepine and spiroimidazoline quinuclidine series. Binding and functional studies revealed that these hydrogen-bond donor containing compounds exhibit improved affinity and selectivity for the alpha 7 nAChR subtype and demonstrate partial agonism. The gain in affinity is also due to conformational restriction, tighter hydrophobic enclosures, and stronger cation-pi interactions. The use of AChBPs structure as a surrogate to predict binding affinity to alpha 7 nAChR has also been investigated. On the whole, we found that molecular docking into Ls binding site generally scores better than when a alpha 7 homology model, Bt or Ac crystal structure is used. (C) 2011 Elsevier Masson SAS. All rights reserved.