3β-(4-methylphenyl)-2β-[isoxazol-5-yl]tropane

• 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: 3β-(4-methylphenyl)-2β-[isoxazol-5-yl]tropane
• 英文别名: 5-[(1R,2S,3S,5S)-8-methyl-3-(4-methylphenyl)-8-azabicyclo[3.2.1]octan-2-yl]-1,2-oxazole
• 化学式: C₁₈H₂₂N₂O
• 分子量: 282.385
• InChiKey: LLTFLCBWDZIXGL-LHHMISFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  29.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  乙醛肟 、 (1R,2S,3S,5S)-8-甲基-3-(4-甲基苯基)-8-氮杂双环[3.2.1]辛烷-2-羧酸甲酯 在 正丁基锂 、 硫酸 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 87.0h， 以28%的产率得到3β-(4-methylphenyl)-2β-[isoxazol-5-yl]tropane
  参考文献：
  名称：

  Synthesis, Monoamine Transporter Binding Properties, and Behavioral Pharmacology of a Series of 3β-(Substituted phenyl)-2β-(3‘-substituted isoxazol-5-yl)tropanes

  摘要：

  Several 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol- 5- yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC50 values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2beta-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED50 values for 2beta-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3beta-(4-methylphenyl)-2beta-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3beta-(4-methylphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED50 values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.

  DOI：

  10.1021/jm030453p

文献信息

• Synthesis, Monoamine Transporter Binding Properties, and Behavioral Pharmacology of a Series of 3β-(Substituted phenyl)-2β-(3‘-substituted isoxazol-5-yl)tropanes
  作者：F. Ivy Carroll、Neil Pawlush、Michael J. Kuhar、Gerald T. Pollard、James L. Howard

  DOI：10.1021/jm030453p

  日期：2004.1.1

  Several 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol- 5- yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC50 values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2beta-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED50 values for 2beta-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3beta-(4-methylphenyl)-2beta-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3beta-(4-methylphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED50 values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.