(+/-)-1-methyl-4-hydroxy-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (+/-)-1-methyl-4-hydroxy-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
• 英文别名: 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone；(4c-hydroxy-1-methyl-4t-p-tolyl-[3r]piperidyl)-p-tolyl ketone；(4c-Hydroxy-1-methyl-4t-p-tolyl-[3r]piperidyl)-p-tolyl-keton；[(3S,4R)-4-hydroxy-1-methyl-4-(4-methylphenyl)piperidin-3-yl]-(4-methylphenyl)methanone
• 化学式: C₂₁H₂₅NO₂
• 分子量: 323.435
• InChiKey: SWFNNRQTSSTAGB-CTNGQTDRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (+/-)-1-methyl-4-hydroxy-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone 在 二异丁基氢化铝 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 2.5h， 以64%的产率得到3-[hydroxy(4-methylphenyl)methyl]-1-methyl-4-(4-methylphenyl)piperidin-4-ol
  参考文献：
  名称：

  通过3D数据库药效基团搜索发现了一种新型的多巴胺转运蛋白抑制剂4-羟基-1-甲基-4-（4-甲基苯基）-3-哌啶基4-甲基苯基酮，作为潜在的可卡因拮抗剂。分子建模，构效关系和行为药理研究。

  摘要：

  一种新型的，相当有效的多巴胺转运蛋白（DAT）抑制剂4-羟基-1-甲基-4-（4-甲基苯基）-3-哌啶基4-甲基苯基酮（3，结合时的K（i）值为492和360 nM通过3D数据库药效比搜索发现了对可卡因具有明显的功能拮抗作用，并且在三个转运蛋白位点（多巴胺，5-羟色胺和去甲肾上腺素）具有与可卡因不同的体外药理学特征，对多巴胺具有明显的拮抗作用。通过结构-活性关系和分子建模研究，我们发现疏水性和构象偏好是决定DAT位点亲和力的两个附加重要参数。铅化合物（3）的化学修饰产生了高亲和力的类似物（6，结合亲和力和多巴胺再摄取抑制的K（i）值分别为11和55 nM。在行为药理学测试中，6部分模拟了可卡因在提高小鼠运动能力中的作用，但在大鼠中却缺乏类似可卡因的判别刺激作用。综上所述，这些数据表明6代表了有希望的线索，可作为进一步评估可卡因滥用治疗的潜在方法。

  DOI：

  10.1021/jm990516x
• 作为产物：
  描述：

  对甲基苯乙酮 在 sodium hydroxide 作用下， 生成 (+/-)-1-methyl-4-hydroxy-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone
  参考文献：
  名称：

  1,3,4-TRISUBSTITUTED PIPERIDINE DERIVATIVES FROM MANNICH BASES

  摘要：

  DOI：

  10.1021/jo01157a022

文献信息

• Molecular Modeling, Structure–Activity Relationships and Functional Antagonism Studies of 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-Methylphenyl Ketones as a Novel Class of Dopamine Transporter Inhibitors
  作者：Shaomeng Wang、Sukumar Sakamuri、Istvan J. Enyedy、Alan P. Kozikowski、Wahiduz A. Zaman、Kenneth M. Johnson

  DOI：10.1016/s0968-0896(01)00090-6

  日期：2001.7

  We previously disclosed the discovery of 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidul 4-methylphenyl ketone (3) as a novel class of dopamine transporter (DAT) inhibitors and showed that (+/-)-3 has a significant functional antagonism against cocaine in vitro. Our previous preliminary structure activity relationship study led to identification of a more potent DAT inhibitor [(+/-)-4] but this compound failed to show any significant functional antagonism To search for more potent analogues than 3 but still displaying significant functional antagonism, further SARs, molecular modeling studies and in vitro pharmacological evaluation of this novel class of DAT inhibitors were performed. Sixteen new analogues were synthesized in racemic form and evaluated as DAT inhibitors. It was found that seven new analogues are reasonably potent DAT inhibitors with K-i values of 0.041-0.30 and 0.052-0.16 muM in [H-3]mazindol binding and inhibition of DA reuptake. Chiral isomers of several potent DAT inhibitors were obtained through chiral HPLC separation and evaluated as inhibitors at all the three monoamine transporter sites. In general, the (-)-isomer is more active than the (+)-isomer in inhibition of DA reuptake and all the (-)-isomers are selective inhibitors at the DAT site. Evaluation of cocaine's effect on dopamine uptake in the presence and absence of (+)-3 and (-)-3 showed that (-)-3 is responsible For the functional antagonism obtained with the original lead (+/-)-3. Out of the new compounds synthesized, analogue (+/-)-20, which is 8- and 3-fold more potent than (+/-)-3 in binding and inhibition of DA reuptake. appeared to hare improved functional antagonism as compared to (+/-)-3. (C) 2001 Elsevier Science Ltd. All rights reserved.
• Discovery of a Novel Dopamine Transporter Inhibitor, 4-Hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-Methylphenyl Ketone, as a Potential Cocaine Antagonist through 3D-Database Pharmacophore Searching. Molecular Modeling, Structure−Activity Relationships, and Behavioral Pharmacological Studies
  作者：Shaomeng Wang、Sukumar Sakamuri、Istvan J. Enyedy、Alan P. Kozikowski、Olivier Deschaux、Bidhan C. Bandyopadhyay、Srihari R. Tella、Wahiduz A. Zaman、Kenneth M. Johnson

  DOI：10.1021/jm990516x

  日期：2000.2.1

  fairly potent dopamine transporter (DAT) inhibitor, 4-hydroxy-1-methyl-4-(4-methylphenyl)-3-piperidyl 4-methylphenyl ketone (3, K(i) values of 492 and 360 nM in binding affinity and inhibition of dopamine reuptake, respectively), with significant functional antagonism against cocaine and a different in vitro pharmacological profile from cocaine at the three transporter sites (dopamine, serotonin, and

  一种新型的，相当有效的多巴胺转运蛋白（DAT）抑制剂4-羟基-1-甲基-4-（4-甲基苯基）-3-哌啶基4-甲基苯基酮（3，结合时的K（i）值为492和360 nM通过3D数据库药效比搜索发现了对可卡因具有明显的功能拮抗作用，并且在三个转运蛋白位点（多巴胺，5-羟色胺和去甲肾上腺素）具有与可卡因不同的体外药理学特征，对多巴胺具有明显的拮抗作用。通过结构-活性关系和分子建模研究，我们发现疏水性和构象偏好是决定DAT位点亲和力的两个附加重要参数。铅化合物（3）的化学修饰产生了高亲和力的类似物（6，结合亲和力和多巴胺再摄取抑制的K（i）值分别为11和55 nM。在行为药理学测试中，6部分模拟了可卡因在提高小鼠运动能力中的作用，但在大鼠中却缺乏类似可卡因的判别刺激作用。综上所述，这些数据表明6代表了有希望的线索，可作为进一步评估可卡因滥用治疗的潜在方法。
• 1,3,4-TRISUBSTITUTED PIPERIDINE DERIVATIVES FROM MANNICH BASES
  作者：JOHN T. PLATI、ROBERT A. SCHMIDT、WILHELM WENNER

  DOI：10.1021/jo01157a022

  日期：1949.9