endo-8-(1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol | 1065220-06-5

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: endo-8-(1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol
• 英文别名: 3-(4-chlorophenyl)-8-(1H-indol-3-ylmethyl)-8-azabicyclo[3.2.1]octan-3-ol
• CAS: 1065220-06-5
• 化学式: C₂₂H₂₃ClN₂O
• 分子量: 366.89
• InChiKey: AXPWNFAVTPIWHV-NGRWLJPCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.84
• 重原子数：
  26.0
• 可旋转键数：
  3.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  39.26
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为反应物：
  描述：

  endo-8-(1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 、 草酸 以 乙醇 、 丙酮 为溶剂， 以39%的产率得到endo-8-(1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol oxalate
  参考文献：
  名称：

  Structure−Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol

  摘要：

  Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K-i(D2R/MR) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K-i(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K-i(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.

  DOI：

  10.1021/jm800532x
• 作为产物：
  描述：

  芦竹碱 、 (3-endo)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol 在 吡啶 作用下， 反应 16.0h， 以58%的产率得到endo-8-(1H-indol-3-ylmethyl)-3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol
  参考文献：
  名称：

  Structure−Activity Relationships for a Novel Series of Dopamine D2-like Receptor Ligands Based on N-Substituted 3-Aryl-8-azabicyclo[3.2.1]octan-3-ol

  摘要：

  Discovering dopamine D2-like receptor subtype-selective ligands has been a focus of significant investigation. The D2R-selective antagonist 3-[4-(4-chlorophenyl)-4-hydroxypiperidinyl]methylindole (1, L741,626; K-i(D2R/MR) = 11.2:163 nM) has previously provided a lead template for chemical modification. Herein, analogues have been synthesized where the piperidine was replaced by a tropane ring that reversed the selectivity seen in the parent compound, in human hD2(L)R- or hD3R-transfected HEK 293 cells (31, K-i(D2R/D3R) = 33.4: 15.5 nM). Further exploration of both N-substituted and aryl ring-substituted analogues resulted in the discovery of several high affinity D2R/D3R ligands with 3-benzofurylmethyl-substituents (e.g., 45, K-i(D2R/D3R) = 1.7:0.34 nM) that induced high affinity not achieved in similarly N-substituted piperidine analogues and significantly (470-fold) improved D3R binding affinity compared to the parent ligand 1. X-ray crystallographic data revealed a distinctive spatial arrangement of pharmacophoric elements in the piperidinol vs tropine analogues, providing clues for the diversity in SAR at the D2 and D3 receptor subtypes.

  DOI：

  10.1021/jm800532x

文献信息

• Synthesis and evaluation of ligands for D2-like receptors: The role of common pharmacophoric groups
  作者：Donald M.N. Sikazwe、Nancy T. Nkansah、Ramazan Altundas、Xue Y. Zhu、Bryan L. Roth、Vincent Setola、Seth Y. Ablordeppey

  DOI：10.1016/j.bmc.2008.12.054

  日期：2009.2

  Arylcycloalkylamines, such as phenyl piperidines and piperazines and their arylalkyl substituents, constitute pharmacophoric groups exemplified in several antipsychotic agents. A review of previous reports indicates that arylalkyl substituents can improve the potency and selectivity of the binding affinity at D-2-like receptors. In this paper, we explored the contributions of two key pharmacophoric groups, that is, 40-fluorobutyrophenones and 3-methyl-7-azaindoles, to the potency and selectivity of synthesized agents at D-2-like receptors. Preliminary observation of binding affinities indicates that there is little predictability of specific effects of the arylalkyl moieties but the composite structure is responsible for selectivity and potency at these receptors. Published by Elsevier Ltd.