(2Z)-2-[[1-[(4-chlorophenyl)methyl]indol-3-yl]methylidene]-1-azabicyclo[2.2.2]octan-3-one | 1001020-47-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (2Z)-2-[[1-[(4-chlorophenyl)methyl]indol-3-yl]methylidene]-1-azabicyclo[2.2.2]octan-3-one
• CAS: 1001020-47-8
• 化学式: C₂₃H₂₁ClN₂O
• 分子量: 376.886
• InChiKey: XFZIJYAWPYEUFH-XKZIYDEJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  25.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2Z)-2-[[1-[(4-chlorophenyl)methyl]indol-3-yl]methylidene]-1-azabicyclo[2.2.2]octan-3-one 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 以83%的产率得到(2Z)-2-[[1-[(4-chlorophenyl)methyl]indol-3-yl]methylidene]-1-azabicyclo[2.2.2]octan-3-ol
  参考文献：
  名称：

  Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents

  摘要：

  Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radio sensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential too] to provide outstanding local-regional control for refractory disease. (Z)-(+/-)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-oI (2) and (Z)-(+/-)-2-(N-benzenesulfonylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-()-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-oI (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structure-activity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R-1 = H, R 2 = 4-Cl), which potently inhibited (93% inhibition at 50 mu M) the growth of HT-29 cells after a 41 degrees C/2 h exposure. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2007.10.035
• 作为产物：
  描述：

  (Z)-2-(1H-indol-3-ylmethylene)quinuclidin-3-one 、 alkaline earth salt of/the/ methylsulfuric acid 在 苄基三乙基氯化铵 、 sodium hydroxide 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 (2Z)-2-[[1-[(4-chlorophenyl)methyl]indol-3-yl]methylidene]-1-azabicyclo[2.2.2]octan-3-one
  参考文献：
  名称：

  Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs

  摘要：

  Our laboratory recently reported that a group of novel indole quinuclidine analogs bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/G -proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analog exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogs acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist 0-2050. All proposed cannabinoid type-1 receptor antagonists attenuated aclenyly1 cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogs demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoicl receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. (C) 2014 Elsevier B.V. All rights reserved

  DOI：

  10.1016/j.ejphar.2014.05.007

文献信息

• Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents
  作者：Vijayakumar N. Sonar、Y. Thirupathi Reddy、Konjeti R. Sekhar、Soumya Sasi、Michael L. Freeman、Peter A. Crooks

  DOI：10.1016/j.bmcl.2007.10.035

  日期：2007.12

  Use of ionizing radiation is essential for the management of many human cancers, and therapeutic hyperthermia has been identified as a potent radio sensitizer. Radiation therapy combined with adjuvant hyperthermia represents a potential too] to provide outstanding local-regional control for refractory disease. (Z)-(+/-)-2-(N-Benzylindol-3-ylmethylene)quinuclidin-3-oI (2) and (Z)-(+/-)-2-(N-benzenesulfonylindol-3-ylmethylene)quinuclidin-3-ol (4) were initially identified as potent thermal sensitizers that could lower the threshold needed for thermal sensitivity to radiation treatment. To define the structural requirements of the molecule that are essential for thermal sensitization, we have synthesized and evaluated a series of (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one (9), and (Z)-()-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-oI (10) analogs that incorporate a variety of substituents in both the indole and N-benzyl moieties. These systematic structure-activity relationship (SAR) studies were designed to further the development and optimization of potential clinically useful thermal sensitizing agents. The most potent analog was compound 10 (R-1 = H, R 2 = 4-Cl), which potently inhibited (93% inhibition at 50 mu M) the growth of HT-29 cells after a 41 degrees C/2 h exposure. (c) 2007 Elsevier Ltd. All rights reserved.
• Evaluation of (Z)-2-((1-benzyl-1H-indol-3-yl)methylene)-quinuclidin-3-one analogues as novel, high affinity ligands for CB1 and CB2 cannabinoid receptors
  作者：Nikhil Reddy Madadi、Narsimha Reddy Penthala、Lisa K. Brents、Benjamin M. Ford、Paul L. Prather、Peter A. Crooks

  DOI：10.1016/j.bmcl.2013.02.025

  日期：2013.4

  A small library of N-benzyl indolequinuclidinone (IQD) analogs has been identified as a novel class of cannabinoid ligands. The affinity and selectivity of these IQDs for the two established cannabinoid receptor subtypes, CB1 and CB2, was evaluated. Compounds 8 (R = R-2 = H, R-1 = F) and 13 (R = COOCH3, R-1 = R-2 = H) exhibited high affinity for CB2 receptors with K-i values of 1.33 and 2.50 nM, respectively, and had lower affinities for the CBI receptor (K-i values of 9.23 and 85.7 nM, respectively). Compound 13 had the highest selectivity of all the compounds examined, and represents a potent cannabinoid ligand with 34-times greater selectivity for CB2R over CB1R. These findings are significant for future drug development, given recent reports demonstrating beneficial use of cannabinoid ligands in a wide variety of human disease states including drug abuse, depression, schizophrenia, inflammation, chronic pain, obesity, osteoporosis and cancer. (C) 2013 Elsevier Ltd. All rights reserved.
• Characterization of the intrinsic activity for a novel class of cannabinoid receptor ligands: Indole quinuclidine analogs
  作者：Lirit N. Franks、Benjamin M. Ford、Nikhil R. Madadi、Narsimha R. Penthala、Peter A. Crooks、Paul L. Prather

  DOI：10.1016/j.ejphar.2014.05.007

  日期：2014.8

  Our laboratory recently reported that a group of novel indole quinuclidine analogs bind with nanomolar affinity to cannabinoid type-1 and type-2 receptors. This study characterized the intrinsic activity of these compounds by determining whether they exhibit agonist, antagonist, or inverse agonist activity at cannabinoid type-1 and/or type-2 receptors. Cannabinoid receptors activate Gi/G -proteins that then proceed to inhibit activity of the downstream intracellular effector adenylyl cyclase. Therefore, intrinsic activity was quantified by measuring the ability of compounds to modulate levels of intracellular cAMP in intact cells. Concerning cannabinoid type-1 receptors endogenously expressed in Neuro2A cells, a single analog exhibited agonist activity, while eight acted as neutral antagonists and two possessed inverse agonist activity. For cannabinoid type-2 receptors stably expressed in CHO cells, all but two analogs acted as agonists; these two exceptions exhibited inverse agonist activity. Confirming specificity at cannabinoid type-1 receptors, modulation of adenylyl cyclase activity by all proposed agonists and inverse agonists was blocked by co-incubation with the neutral cannabinoid type-1 antagonist 0-2050. All proposed cannabinoid type-1 receptor antagonists attenuated aclenyly1 cyclase modulation by cannabinoid agonist CP-55,940. Specificity at cannabinoid type-2 receptors was confirmed by failure of all compounds to modulate adenylyl cyclase activity in CHO cells devoid of cannabinoid type-2 receptors. Further characterization of select analogs demonstrated concentration-dependent modulation of adenylyl cyclase activity with potencies similar to their respective affinities for cannabinoicl receptors. Therefore, indole quinuclidines are a novel structural class of compounds exhibiting high affinity and a range of intrinsic activity at cannabinoid type-1 and type-2 receptors. (C) 2014 Elsevier B.V. All rights reserved