4-(2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide

• 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: 4-(2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide
• 英文别名: 6-[4-(2-nitrophenyl)piperazin-1-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)hexanamide
• 化学式: C₂₆H₃₄N₄O₃
• 分子量: 450.581
• InChiKey: ZBUOQRCOVPVZEE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  81.4
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  6-溴己酰氯 在 sodium hydroxide 、 potassium carbonate 作用下， 以 乙腈 为溶剂， 生成 4-(2-nitrophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide
  参考文献：
  名称：

  Structure−Activity Relationship Study on N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a Class of 5-HT₇ Receptor Agents. 2

  摘要：

  Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D-2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH(CH3)(2), N(CH3)(2), CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (K-i = 0.13-1.1 nM, EC50 = 0.90-1.77 mu M), showing selectivity over 5-HT1A, 5-HT2A, and D-2 receptors.

  DOI：

  10.1021/jm070487n

文献信息

• Structure−Affinity Relationship Study on <i>N</i>-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-Piperazinealkylamides, a New Class of 5-Hydroxytryptamine₇ Receptor Agents
  作者：Marcello Leopoldo、Francesco Berardi、Nicola A. Colabufo、Marialessandra Contino、Enza Lacivita、Mauro Niso、Roberto Perrone、Vincenzo Tortorella

  DOI：10.1021/jm049702f

  日期：2004.12.1

  A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin (5-hydroxytryptamine, 5-HT) 5-HT7, 5-HT1A, and 5-HT2A receptors was measured by in vitro binding assays. In relation to 5-HT7 receptor affinity, receptor binding studies indicated that (i) the optimal alkyl chain length was five methylenes, (ii) an unsubstituted 1,2,3,4-tetrahydronaphthalenyl nucleus was preferred, and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a crucial role. Several compound with high affinity for 5-HT7 receptors were identified. Among them, 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (28), 4-(2-acetylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (34), 4-(2-methylthlophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (44), 4-(2-hydroxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (46), and 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT7 receptor-mediated relaxation of substance P-induced guinea pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists and compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist. Among the compounds presented here, it emerged that 44 was identified as a potent 5-HT7 receptor agonist (K-i = 0.22 nM, EC50 = 2.56 muM), endowed with selectivity over 5-HT1A and 5-HT2A receptors (200-fold and > 1000-fold, respectively).
• Structure−Activity Relationship Study on <i>N</i>-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides, a Class of 5-HT₇ Receptor Agents. 2
  作者：Marcello Leopoldo、Enza Lacivita、Marialessandra Contino、Nicola A. Colabufo、Francesco Berardi、Roberto Perrone

  DOI：10.1021/jm070487n

  日期：2007.8.1

  Here we report the synthesis of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides 16-29 that were designed to elucidate both structure-affinity and -activity relationships for the 5-HT7 receptor, by targeting the substituent in 2-position of the aryl linked to the piperazine ring. The affinities of 16-29 for 5-HT7, 5-HT1A, 5-HT2A, and D-2 receptors were assessed by radioligand binding assays. The intrinsic activities at the 5-HT7 receptor of the most potent compounds were determined. A series of substituents covering a wide range of electronic, steric, and polar properties was evaluated, revealing a key role on 5-HT7 receptor affinity and intrinsic activity. Certain lipophilic substituents (SCH3, CH(CH3)(2), N(CH3)(2), CH3, Ph) led to high-affinity agonists, whereas OH and NHCH3 substituents switched intrinsic activity toward antagonism. 4-[2-(1-Methylethyl)phenyl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (19), 4-(2-diphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (21), and 4-(2-dimethylaminophenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (22) were identified as potent 5-HT7 receptor agonists (K-i = 0.13-1.1 nM, EC50 = 0.90-1.77 mu M), showing selectivity over 5-HT1A, 5-HT2A, and D-2 receptors.