JJC 2-010 | 569353-92-0

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: JJC 2-010
• 英文别名: 1-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-3-ol；(+/-)-3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol；3-(4-(3-(Bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol；3-[4-[3-(4-fluoro-N-(4-fluorophenyl)anilino)propyl]piperazin-1-yl]-1-phenylpropan-1-ol
• CAS: 569353-92-0
• 化学式: C₂₈H₃₃F₂N₃O
• 分子量: 465.586
• InChiKey: HPCHCQKXJNQWHO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  34
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  30
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-苯基丁酰氯 、 JJC 2-010 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropyl phenylbutanoate
  参考文献：
  名称：

  Dual DAT/σ1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol

  摘要：

  Ester analogs of (+/-) 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma 1 receptors, and compared to GBR 12909 and several known sigma 1 receptor ligands. Most of these compounds demonstrated high affinity (K(i) = 4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma 1 receptors was observed and most of the ester analogs of the more active S- enantiomer showed comparable binding affinities at both DAT and sigma 1 receptors with a maximal 16-fold DAT/sigma 1 selectivity. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2008.08.065
• 作为产物：
  描述：

  4,4'-二氟二苯胺 在 lithium aluminium tetrahydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 丙酮 、 苯 为溶剂， 反应 7.0h， 生成 JJC 2-010
  参考文献：
  名称：

  Dual Probes for the Dopamine Transporter and σ₁ Receptors:  Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents

  摘要：

  Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K-i = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues. (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K-i = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K-i = 77 and 124 nM, respectively, 17; K-i = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.

  DOI：

  10.1021/jm030008u

文献信息

• Dual Probes for the Dopamine Transporter and σ₁ Receptors:  Novel Piperazinyl Alkyl-bis(4‘-fluorophenyl)amine Analogues as Potential Cocaine-Abuse Therapeutic Agents
  作者：Jianjing Cao、Santosh S. Kulkarni、Stephen M. Husbands、Wayne D. Bowen、Wanda Williams、Theresa Kopajtic、Jonathan L. Katz、Clifford George、Amy Hauck Newman

  DOI：10.1021/jm030008u

  日期：2003.6.1

  Both dopamine uptake inhibitors and sigma(1) receptor antagonists have been implicated as potential pharmacotherapeutics for the treatment of cocaine abuse. While the dopamine uptake inhibitors may share with cocaine neurochemical mechanisms underlying reinforcing properties, sigma(1) antagonists have been shown to attenuate some behavioral actions and toxic side effects associated with cocaine overdose. Rimcazole, a sigma(1) receptor antagonist that binds to the DAT (K-i = 224 nM), is not behaviorally cocaine-like and attenuates some of the behavioral actions of cocaine. To determine the roles of both DAT and sigma(1) receptors in the behavioral actions of rimcazole, a series of analogues was synthesized. Initial studies identified two analogues. (1 and 4) that showed high to moderate affinities for both DAT and sigma(1) receptors and failed to show cocaine-like discriminative stimulus (DS) effects. A second series of bis(4'-fluorophenyl)amine analogues have now been prepared in which the most potent DAT compound, 19 (K-i = 8.5 nM), was selective over serotonin transporter (SERT/DAT = 94), norepinephrine transporter (NET/DAT = 63), and sigma(1) receptor binding (sigma(1)/DAT = 44). In addition, two other analogues 10 and 17 showed superior selectivity for DAT over SERT (170- and 140-fold, respectively) and DAT over NET (219- and 190-fold, respectively) but were essentially equipotent at DAT and sigma(1) receptors (10; K-i = 77 and 124 nM, respectively, 17; K-i = 28 and 13 nM, respectively). CoMFA studies at both DAT and sigma(1) receptors were performed to examine structural requirements for optimal binding at these two targets as well as to assess differences between them. Behavioral evaluation of analogues with varying affinities for both DAT and sigma(1) receptors may provide a novel approach toward designing medications for cocaine abuse.
• Dual DAT/σ1 receptor ligands based on 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol
  作者：Jianjing Cao、Theresa Kopajtic、Jonathan L. Katz、Amy Hauck Newman

  DOI：10.1016/j.bmcl.2008.08.065

  日期：2008.10

  Ester analogs of (+/-) 3-(4-(3-(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-1-phenylpropan-1-ol were synthesized and evaluated for binding at DAT, SERT, NET, and sigma 1 receptors, and compared to GBR 12909 and several known sigma 1 receptor ligands. Most of these compounds demonstrated high affinity (K(i) = 4.3-51 nM) and selectivity for the DAT among the monoamine transporters. S- and R-1-(4-(3(bis(4-fluorophenyl)amino)propyl)piperazin-1-yl)-3-phenylpropan-2-ol were also prepared wherein modest enantioselectivity was demonstrated at the DAT. However, no enantioselectivity at sigma 1 receptors was observed and most of the ester analogs of the more active S- enantiomer showed comparable binding affinities at both DAT and sigma 1 receptors with a maximal 16-fold DAT/sigma 1 selectivity. Published by Elsevier Ltd.