3-aminomethyl-1-azabicyclo<2.2.2>octyl-3-amine | 125889-79-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 奎宁环
• 英文名称: 3-aminomethyl-1-azabicyclo<2.2.2>octyl-3-amine
• 英文别名: 3-(aminomethyl)quinuclidin-3-amine；3-amino-3-(aminomethyl)quinuclidine；3-(aminomethyl)-1-azabicyclo[2.2.2]octan-3-amine
• CAS: 125889-79-4
• 化学式: C₈H₁₇N₃
• 分子量: 155.243
• InChiKey: KZXAUAPHHGXSBG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.2
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  55.3
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-aminomethyl-1-azabicyclo<2.2.2>octyl-3-amine 在 三氯化磷 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 4.0h， 生成 2'-(4-pyridyl)-1-azabicyclo<2.2.2>octane-3-spiro-4'(5')-imidazoline
  参考文献：
  名称：

  Synthesis of 2′-Arylazabicyclo-3-spiro-4′(5′)-imidazolines

  摘要：

  本文描述了一种通过氮杂双环1,2-二胺与芳基亚氨盐反应合成一系列2′-芳基-3-氮杂双环螺-4′(5′)-咪唑啉的方法。在二胺的合成过程中，如氨基腈与LiAlH4的还原反应等竞争性反应导致一些异常产物的生成。在Pinner合成法中，不稳定的吡啶型亚氨盐被其N-氧化衍生物所稳定化。

  DOI：

  10.1055/s-1994-25584
• 作为产物：
  描述：

  3-羟基喹洛啉-3-甲腈 在 ammonium hydroxide 、 lithium aluminium tetrahydride 作用下， 以 乙醚 、 乙醇 为溶剂， 反应 60.0h， 生成 3-aminomethyl-1-azabicyclo<2.2.2>octyl-3-amine
  参考文献：
  名称：

  Synthesis of 2′-Arylazabicyclo-3-spiro-4′(5′)-imidazolines

  摘要：

  本文描述了一种通过氮杂双环1,2-二胺与芳基亚氨盐反应合成一系列2′-芳基-3-氮杂双环螺-4′(5′)-咪唑啉的方法。在二胺的合成过程中，如氨基腈与LiAlH4的还原反应等竞争性反应导致一些异常产物的生成。在Pinner合成法中，不稳定的吡啶型亚氨盐被其N-氧化衍生物所稳定化。

  DOI：

  10.1055/s-1994-25584

文献信息

• [EN] QUINUCLIDINE, 1-AZABICYCLO[2.2.1]HEPTANE, 1-AZABICYCLO [3.2.1]OCTANE, and 1-AZABICYCLO[3.2.2]NONANE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS<br/>[FR] COMPOSÉS DE QUINUCLIDINE, 1-AZABICYCLO[2.2.1]HEPTANE, 1-AZABICYCLO [3.2.1]OCTANE, ET 1-AZABICYCLO[3.2.2]NONANE UTILES COMME LIGANDS DU RÉCEPTEUR ALPHA-7 NICOTINIQUE DE L'ACÉTYLCHOLINE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2013177024A1

  公开（公告）日：2013-11-28

  The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  本公开提供I式化合物，包括其盐，以及使用该化合物的组合物和方法。这些化合物是尼古丁酸α7受体的配体，可用于治疗中枢神经系统的各种疾病，尤其是情感和神经退行性疾病。
• QUINUCLIDINE, 1-AZABICYCLO[2.2.1]HEPTANE, 1-AZABICYCLO [3.2.1]OCTANE, and 1-AZABICYCLO[3.2.2]NONANE COMPOUNDS AS ALPHA-7 NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US20150322089A1

  公开（公告）日：2015-11-12

  The disclosure provides compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands for the nicotinic α7 receptor and may be useful for the treatment of various disorders of the central nervous system, especially affective and neurodegenerative disorders.

  本披露提供了公式I的化合物及其盐，以及使用该化合物的组合物和方法。这些化合物是尼古丁α7受体的配体，可用于治疗中枢神经系统的各种疾病，特别是情感和神经退行性疾病。
• 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.
• (−)-Spiro[1-azabicyclo[2.2.2]octane-3,5‘-oxazolidin-2‘-one], a Conformationally Restricted Analogue of Acetylcholine, Is a Highly Selective Full Agonist at the α7 Nicotinic Acetylcholine Receptor
  作者：George Mullen、James Napier、Michael Balestra、Thomas DeCory、Gregory Hale、John Macor、Robert Mack、James Loch、Ed Wu、Alexander Kover、Patrick Verhoest、Anthony Sampognaro、Eifion Phillips、Yanyi Zhu、Robert Murray、Ronald Griffith、James Blosser、David Gurley、Anthony Machulskis、John Zongrone、Alan Rosen、Jack Gordon

  DOI：10.1021/jm000249r

  日期：2000.11.1

  Neuronal nicotinic acetylcholine receptors are members of the ligand-gated ion channel receptor superfamily and may play important roles in modulating neurotransmission, cognition, sensory gating, and anxiety. Because of its distribution and abundance in the CNS, the alpha7 nicotinic receptor is a strong candidate to be involved in some of these functions. In this paper we describe the synthesis and in vitro profile of AR-R17779, (-)-spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one] (4a), a potent full agonist at the rat alpha7 nicotinic receptor, which is highly selective for the rat alpha7 nicotinic receptor over the alpha4 beta2 subtype. Preliminary SAR of AR-R17779 presented here indicate that there is little scope for modification of this rigid molecule as even minor changes result in significant loss of the alpha7 nicotinic receptor affinity.
• 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.