C-(5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine | 912342-44-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 香豆素
• 英文名称: C-(5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine
• 英文别名: (7-Methoxy-3-oxatricyclo[6.4.1.04,13]trideca-4(13),5,7-trien-9-yl)methanamine
• CAS: 912342-44-0
• 化学式: C₁₄H₁₉NO₂
• 分子量: 233.31
• InChiKey: IYUCMLOTRIBKPG-UHFFFAOYSA-N

物化性质

• 熔点：
  225 °C (decomp)
• 沸点：
  334.338±42.00 °C(Press: 760.00 Torr)(predicted)
• 密度：
  1.123±0.06 g/cm3(Temp: 25 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  44.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  C-(5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine 在 溴 作用下， 以 甲醇 为溶剂， 生成 syn-C-(3-bromo-5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine 、 anti-C-(3-bromo-5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine
  参考文献：
  名称：

  1-Aminomethylbenzocycloalkanes:  Conformationally Restricted Hallucinogenic Phenethylamine Analogues as Functionally Selective 5-HT_2A Receptor Agonists

  摘要：

  A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT2A receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT2A receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT2A receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT2A receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.

  DOI：

  10.1021/jm060656o
• 作为产物：
  描述：

  2-溴-4-甲氧基苯酚 在 镍 偶氮二异丁腈 、 氨 、 氢气 、 三正丁基氢锡 、 potassium carbonate 、 三氟乙酸 、 三氟乙酸酐 、 zinc(II) iodide 作用下， 以 乙醇 、 二氯甲烷 、 丙酮 、 苯 为溶剂， 20.0 ℃ 、413.68 kPa 条件下， 反应 63.0h， 生成 C-(5-methoxy-1,6,7,8,9,9a-hexahydro-2-oxabenzo[cd]azulen-6-yl)methylamine
  参考文献：
  名称：

  1-Aminomethylbenzocycloalkanes:  Conformationally Restricted Hallucinogenic Phenethylamine Analogues as Functionally Selective 5-HT_2A Receptor Agonists

  摘要：

  A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT2A receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT2A receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT2A receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT2A receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.

  DOI：

  10.1021/jm060656o

文献信息

• 1-Aminomethylbenzocycloalkanes:  Conformationally Restricted Hallucinogenic Phenethylamine Analogues as Functionally Selective 5-HT_2A Receptor Agonists
  作者：Thomas H. McLean、Jason C. Parrish、Michael R. Braden、Danuta Marona-Lewicka、Alejandra Gallardo-Godoy、David E. Nichols

  DOI：10.1021/jm060656o

  日期：2006.9.1

  A series of conformationally restricted analogues of the hallucinogenic phenethylamine 1 (2,5-dimethoxy4-bromophenethylamine, 2C-B) was synthesized to test several hypotheses concerning the bioactive conformation of phenethylamine ligands upon binding to the 5-HT2A receptor. These benzocycloalkane analogues were assayed for their receptor binding affinity and ability to activate downstream signaling pathways, and one exceptional compound was selected for testing in an in vivo drug discrimination model of hallucinogenesis. All compounds were examined in silico by virtual docking into a homology model of the 5-HT2A receptor. On the basis of these docking experiments, it was predicted that the R enantiomer of benzocyclobutene analogue 2 would be the most potent. Subsequent chemical resolution and X-ray crystallography confirmed this prediction, as (R)-2 proved to be equipotent to LSD in rats trained to discriminate LSD from saline. Thus, we propose that the conformation of 2 mimics the active binding conformation of the more flexible phenethylamine type hallucinogens. In addition, (R)-2 is one of the most potent and selective compounds yet discovered in the in vivo drug discrimination assay. Further, 2 was found to be a functionally selective agonist at the 5-HT2A receptor, having 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. If hallucinogenic effects are correlated with arachidonic acid production, such functionally selective 5-HT2A receptor agonists may lack the intoxicating properties of hallucinogens such as LSD.