(1S,3S,6R,10S)-(Z)-9-(3,4-dichlorobenzylidene)-10-(E-styryl)-7-azatricyclo[3.2.1.0^3,7]decane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚里西啶
• 英文名称: (1S,3S,6R,10S)-(Z)-9-(3,4-dichlorobenzylidene)-10-(E-styryl)-7-azatricyclo[3.2.1.0^3,7]decane
• 英文别名: (1S,2S,3R,6S,9Z)-9-[(3,4-dichlorophenyl)methylidene]-2-[(E)-2-phenylethenyl]-7-azatricyclo[4.3.1.03,7]decane
• 化学式: C₂₄H₂₃Cl₂N
• 分子量: 396.359
• InChiKey: RFQGECOOEGPNDP-QHZODLNISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  (1S,3R,6S)-2-(hydroxymethyl)-(Z)-9-(3,4-dichlorophenylmethylene)-7-azatricyclo[4.3.1.0^3,7]decane 在 正丁基锂 、 草酰氯 、 二甲基亚砜 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 16.0h， 生成 (1S,3S,6R,10S)-(Z)-9-(3,4-dichlorobenzylidene)-10-(E-styryl)-7-azatricyclo[3.2.1.0^3,7]decane
  参考文献：
  名称：

  Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites:  Synthesis of (Z)-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes as a Novel Class of Serotonin Transporter Inhibitors

  摘要：

  A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo [4.3.1.0(3,7)] decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of different substituents on the phenyl ring indicated that the substitution pattern plays an important role in the monoamine transporter activity. Most compounds in this series possessed a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character of the substituent did not affect uptake inhibition as dramatically as observed in some benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl analogues 8d and 8j exhibited the highest potency at the SERT with a K-i value of 10 nM. In the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were discovered. Compound So has a K-i value of 2.3 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a Ki value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are also better than those of fluoxetine. Second, a variety of functional modifications on the ester moiety were investigated. Substitution by other esters or amides as well as alkenes did not increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone 28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent is believed to be required for high activity. The most potent and selective ligand is compound 23, which displayed a K-i value of 0.06 nM and has essentially no activity at the DAT or NET. The present results have important implications for drug addiction as well as a number of psychiatric diseases.

  DOI：

  10.1021/jm0105373

文献信息

• Further Studies on Conformationally Constrained Tricyclic Tropane Analogues and Their Uptake Inhibition at Monoamine Transporter Sites:  Synthesis of (<i>Z</i>)-9-(Substituted arylmethylene)-7-azatricyclo[4.3.1.0^3,7]decanes as a Novel Class of Serotonin Transporter Inhibitors
  作者：Ao Zhang、Guochun Zhou、Alexander Hoepping、Jayanta Mukhopadhyaya、Kenneth M. Johnson、Mei Zhang、Alan P. Kozikowski

  DOI：10.1021/jm0105373

  日期：2002.4.1

  A novel series of conformationally constrained tricyclic tropane analogues, (Z)-9-(substituted arylmethylene)-7-azatricyclo [4.3.1.0(3,7)] decanes, were prepared, and their abilities to inhibit high-affinity uptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) into rat brain nerve endings (synaptosomes) were evaluated. First, a systematic screening of a variety of different substituents on the phenyl ring indicated that the substitution pattern plays an important role in the monoamine transporter activity. Most compounds in this series possessed a very low activity at the DA transporter (DAT) but a good to excellent affinity for the 5-HT transporter (SERT). In the case of para-substituted phenyl analogues, the electronic character of the substituent did not affect uptake inhibition as dramatically as observed in some benztropine analogues. Among these compounds, the 4-bromophenyl and 4-isopropylphenyl analogues 8d and 8j exhibited the highest potency at the SERT with a K-i value of 10 nM. In the 3,4-disubstituted phenyl series, even more potent and highly selective compounds were discovered. Compound So has a K-i value of 2.3 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 2360, and a NET/SERT uptake ratio of 200. Compound 8p exhibited a Ki value of 1.8 nM for uptake inhibition at the SERT, a DAT/SERT uptake ratio of 1740, and a NET/SERT uptake ratio of 151. These compounds are 3-4-fold more potent than the antidepressant medication fluoxetine, and the selectivities for SERT over DAT and NET are also better than those of fluoxetine. Second, a variety of functional modifications on the ester moiety were investigated. Substitution by other esters or amides as well as alkenes did not increase potency, while most of the acetates or benzoates (16-21, 23, and 24) and the ketone 28 exhibited significantly improved activity. A good hydrogen-bonding ability of the substituent is believed to be required for high activity. The most potent and selective ligand is compound 23, which displayed a K-i value of 0.06 nM and has essentially no activity at the DAT or NET. The present results have important implications for drug addiction as well as a number of psychiatric diseases.