trans-2-(3-pyridylmethyl)quinuclidin-3-ol

• 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: trans-2-(3-pyridylmethyl)quinuclidin-3-ol
• 英文别名: 2-(pyridin-3-ylmethyl)quinuclidin-3-ol；(2S,3R)-2-(pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]octan-3-ol
• 化学式: C₁₃H₁₈N₂O
• 分子量: 218.299
• InChiKey: CKDDUULIRPQPSS-QWHCGFSZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  36.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  trans-2-(3-pyridylmethyl)quinuclidin-3-ol 在 potassium tert-butylate 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 2.0h， 生成 trans-5-[6-[2-(3-pyridylmethyl)quinuclidin-3-yl]oxypyridazin-3-yl]-1H-indole
  参考文献：
  名称：

  作为潜在镇咳剂的新型 α7 烟碱型乙酰胆碱受体调节剂

  摘要：

  设计了一系列新的 α7 烟碱型乙酰胆碱受体 (nAChR) 调节剂，并评估了其在体内化学诱发咳嗽的豚鼠模型中的镇咳活性。所有测试剂量（9.5、3 和 1 mg/kg）的化合物16显着（p < 0.01）减少咳嗽的累积次数，并显示与阳性对照（30 mg/kg 的可待因）相似的结果。在三种不同的给药途径（腹膜内、口服和吸入）中，化合物16在吸入剂量低至 0.4 mg/kg 时对豚鼠产生显着的镇咳作用 ( p < 0.05)。α7 nAChR 调节剂可为急性和慢性咳嗽患者提供一种新型的非麻醉性治疗方法。

  DOI：

  10.1016/j.bmcl.2022.129067
• 作为产物：
  描述：

  3-奎宁环酮 在 palladium on activated charcoal 氢氧化钾 、 氢气 、 aluminum isopropoxide 作用下， 生成 trans-2-(3-pyridylmethyl)quinuclidin-3-ol
  参考文献：
  名称：

  2-(Arylmethyl)-3-substituted quinuclidines as selective α7 nicotinic receptor ligands

  摘要：

  A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha 7 over other nAChRs (e.g., the alpha A beta 2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha 7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-81), has potent agonistic activity for the alpha 7 nAChR (EC50 = 33 nM, I-max = 1.0), at concentrations below those that result in desensitization. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.02.045

文献信息

• [EN] NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS<br/>[FR] LIGANDS DU RECEPTEUR NICOTINIQUE DE L'ACETYLCHOLINE
  申请人：PHILIP MORRIS PRODUCTS SA

  公开号：WO2023213740A1

  公开（公告）日：2023-11-09

  FTR3159/PCT (P/85142.WO01) - 74 - NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS Abstract Compounds of general formula (I), pharmaceutical compositions comprising the compound, uses of the compositions, and methods of manufacturing the compound are disclosed. The compounds are nicotinic acetylcholine receptor (nAChR) ligands, and may be used in the prevention and/or 5 suppression of coughs. (I). [Figure 2A] 10

  FTR3159/PCT (P/85142.WO01) - 74 - 尼古丁乙酰胆碱受体配体 摘要 本发明公开了通式(I)的化合物、包含该化合物的药物组合物、组合物的用途以及该化合物的制造方法。这些化合物是烟碱乙酰胆碱受体（nAChR）配体，可用于预防和/或抑制咳嗽。(I).[图 2A] 10
• Surface Plasmon Resonance Biosensor Based Fragment Screening Using Acetylcholine Binding Protein Identifies Ligand Efficiency Hot Spots (LE Hot Spots) by Deconstruction of Nicotinic Acetylcholine Receptor α7 Ligands
  作者：Gerdien E. de Kloe、Kim Retra、Matthis Geitmann、Per Källblad、Tariq Nahar、René van Elk、August B. Smit、Jacqueline E. van Muijlwijk-Koezen、Rob Leurs、Hubertus Irth、U. Helena Danielson、Iwan J. P. de Esch

  DOI：10.1021/jm100834y

  日期：2010.10.14

  The soluble acetylcholine binding protein (AChBP) is a homologue of the ligand-binding domain of the nicotinic acetylcholine receptors (nAChR). To guide future fragment-screening using surface plasmon resonance (SPR) biosensor technology as a label-free, direct binding, biophysical screening assay, a focused fragment library was generated based on deconstruction of a set of alpha 7 nAChR selective quinuclidine containing ligands with nanomolar affinities. The interaction characteristics of the fragments and the parent compounds with AChBP) were evaluated using an SPR biosensor assay. The data obtained from this direct binding assay correlated well with data from the reference radioligand displacement assay. Ligand efficiencies for different (structural) groups of fragments in the library were correlated to binding with distinct regions of the binding pocket, thereby identifying ligand efficiency hot spots (LE hot spots). These hot spots can be used to identity the most promising hit fragments in a large scale fragment library screen.
• 2-(Arylmethyl)-3-substituted quinuclidines as selective α7 nicotinic receptor ligands
  作者：Anatoly Mazurov、Jozef Klucik、Lan Miao、Teresa Y. Phillips、Angela Seamans、Jeffrey D. Schmitt、Terry A. Hauser、Raymond T. Johnson、Craig Miller

  DOI：10.1016/j.bmcl.2005.02.045

  日期：2005.4

  A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha 7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha 7 over other nAChRs (e.g., the alpha A beta 2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha 7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-81), has potent agonistic activity for the alpha 7 nAChR (EC50 = 33 nM, I-max = 1.0), at concentrations below those that result in desensitization. (c) 2005 Elsevier Ltd. All rights reserved.
• Novel α7 nicotinic acetylcholine receptor modulators as potential antitussive agents
  作者：Anatoly Mazurov、Jenny Ho、Tiffany Low、Julia Hoeng

  DOI：10.1016/j.bmcl.2022.129067

  日期：2023.1

  A novel series of α7 nicotinic acetylcholine receptor (nAChR) modulators was designed and evaluated for antitussive activity in an in vivo guinea pig model of chemically induced cough. Compound 16 at all tested doses (9.5, 3 and 1 mg/kg) significantly (p < 0.01) reduced the cumulative number of coughs and showed similar results to a positive control (codeine at 30 mg/kg). Among three different administration

  设计了一系列新的 α7 烟碱型乙酰胆碱受体 (nAChR) 调节剂，并评估了其在体内化学诱发咳嗽的豚鼠模型中的镇咳活性。所有测试剂量（9.5、3 和 1 mg/kg）的化合物16显着（p < 0.01）减少咳嗽的累积次数，并显示与阳性对照（30 mg/kg 的可待因）相似的结果。在三种不同的给药途径（腹膜内、口服和吸入）中，化合物16在吸入剂量低至 0.4 mg/kg 时对豚鼠产生显着的镇咳作用 ( p < 0.05)。α7 nAChR 调节剂可为急性和慢性咳嗽患者提供一种新型的非麻醉性治疗方法。