(3S,5R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,5-dimethylpiperazine | 105685-10-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (3S,5R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,5-dimethylpiperazine
• CAS: 105685-10-7
• 化学式: C₁₄H₂₀N₂O₂
• 分子量: 248.325
• InChiKey: SWDHAFVKSKKELV-PHIMTYICSA-N

物化性质

• 沸点：
  390.6±42.0 °C(Predicted)
• 密度：
  1.095±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  18
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  33.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(4-氟苯甲酰)氮丙啶 、 (3S,5R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,5-dimethylpiperazine 以 丙酮 为溶剂， 生成 N-[2-[(2S,6R)-4-(2,3-dihydro-1,4-benzodioxin-5-yl)-2,6-dimethylpiperazin-1-yl]ethyl]-4-fluorobenzamide
  参考文献：
  名称：

  5-HT_1A- versus D₂-Receptor Selectivity of Flesinoxan and Analogous N ⁴-Substituted N ¹-Arylpiperazines

  摘要：

  We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D-2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [H-3]-8-OH-DPAT and [H-3]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N-4-substituent and the arylpiperazine region. Effects of N-4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D-2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N-4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N-4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N-4-substituents, selectivity for 5-HT1A versus D-2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N-4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N-4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the H-N4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N-4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D-2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D-2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D-2 receptors.

  DOI：

  10.1021/jm960496o
• 作为产物：
  描述：

  N-benzyliminodipropionic acid 在 palladium on activated charcoal dimethyl sulfide borane 、 氢气 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 生成 (3S,5R)-1-(2,3-dihydro-1,4-benzodioxin-5-yl)-3,5-dimethylpiperazine
  参考文献：
  名称：

  5-HT_1A- versus D₂-Receptor Selectivity of Flesinoxan and Analogous N ⁴-Substituted N ¹-Arylpiperazines

  摘要：

  We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D-2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [H-3]-8-OH-DPAT and [H-3]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N-4-substituent and the arylpiperazine region. Effects of N-4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D-2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N-4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N-4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N-4-substituents, selectivity for 5-HT1A versus D-2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N-4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N-4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the H-N4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N-4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D-2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D-2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D-2 receptors.

  DOI：

  10.1021/jm960496o

文献信息

• 5-HT_1A- versus D₂-Receptor Selectivity of Flesinoxan and Analogous <i>N</i> ⁴-Substituted <i>N</i> ¹-Arylpiperazines
  作者：Wilma Kuipers、Chris G. Kruse、Ineke van Wijngaarden、Piet J. Standaar、Martin Th. M. Tulp、Nora Veldman、Anthony L. Spek、Adriaan P. IJzerman

  DOI：10.1021/jm960496o

  日期：1997.1.1

  We investigated the structural requirements for high 5-HT1A affinity of the agonist flesinoxan and its selectivity versus D-2 receptors. For this purpose a series of arylpiperazine congeners of flesinoxan were synthesized and evaluated for their ability to displace [H-3]-8-OH-DPAT and [H-3]spiperone from their specific binding sites in rat frontal cortex homogenates and rat striatum, respectively. Variations were made in the N-4-substituent and the arylpiperazine region. Effects of N-4-substitution in the investigated compounds appeared to be quite similar for 5-HT1A- and D-2-receptor affinity. Lipophilicity at a distance of four carbon atoms from the piperazine N-4 atom seems to be the main contributing factor to affinity for both receptors. Our data show that the amide group in the flesinoxan N-4-substituent is unlikely to interact with the 5-HT1A receptor but, instead, acts as a spacer. In contrast to the structure-affinity relationships (SARs) of the N-4-substituents, selectivity for 5-HT1A versus D-2 receptors was gained by the arylpiperazine substitution pattern of flesinoxan. Restriction of flexibility of the N-4-(benzoylamino)ethyl substituent and its effect on 5-HT1A-receptor affinity and activity were also studied. Our data show that in the bioactive conformation, the N-4-[(p-fluorobenzoyl)amino]ethyl substituent is probably directed anti-periplanar relative to the H-N4 atom. These results were used to dock flesinoxan (1) and two of its congeners (27 and 33) into a model of the 5-HT1A receptor that we previously reported. Amino acid residues surrounding the N-4-[(p-fluorobenzoyl)amino]ethyl substituent of flesinoxan and its congeners are also present in D-2 receptors. In contrast, several residues that contact the benzodioxane moiety differ from those in D-2 receptors. These observations from the 3D model agree with the 5-HT1A SAR data and probably account for the selectivity of flesinoxan versus D-2 receptors.