4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinepentanamide

• 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-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinepentanamide
• 英文别名: 5-(4-(2-methoxyphenyl)piperazin-1-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pentanamide；5-[4-(2-methoxyphenyl)piperazin-1-yl]-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pentanamide
• 化学式: C₂₆H₃₅N₃O₂
• 分子量: 421.583
• InChiKey: COFRSTRKYJRGFB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  31
• 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：
  44.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-氯代戊酰氯 在 sodium hydroxide 、 potassium carbonate 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 生成 4-(2-methoxyphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinepentanamide
  参考文献：
  名称：

  Structure−Affinity Relationship Study on N-(1,2,3,4-Tetrahydronaphthalen-1-yl)-4-Aryl-1-Piperazinealkylamides, a New Class of 5-Hydroxytryptamine₇ Receptor Agents

  摘要：

  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).

  DOI：

  10.1021/jm049702f

文献信息

• N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-phenyl-1-piperazinealkylamide derivatives, and therapeutic use thereof as 5-HT7 receptor ligands
  申请人：Leopoldo Marcello

  公开号：US20070117811A1

  公开（公告）日：2007-05-24

  A series of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinealkylamides was prepared and their affinity for serotonin 5-HT 7 , 5-HT 1A , and 5-HT 2A receptors was measured using in vitro binding assays. In relation to 5-HT 7 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 selected for further substitutions; and (iii) the substitution pattern of the aryl ring linked to the piperazine ring played a significant role. Several compound with high affinity for 5-HT 7 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-methylthiophenyl)-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), 4-(2-methylphenyl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1-piperazinehexanamide (49) were assayed for the 5-HT 7 receptor mediated relaxation of substance P-induced guinea-pig ileum contraction. Compounds 28, 44, and 49 behaved as full agonists, compound 34 as a partial agonist, whereas derivative 46 acted as an antagonist.

  一系列N-(1,2,3,4-四氢萘基)-4-芳基-1-哌嗪烷基酰胺被制备，并利用体外结合实验测定它们对5-HT7、5-HT1A和5-HT2A受体的亲和力。关于5-HT7受体亲和力，受体结合研究表明：(i) 最佳的烷基链长度为五个亚甲基；(ii) 选择未取代的1,2,3,4-四氢萘基核进行进一步取代；(iii) 与哌嗪环相连的芳基环的取代模式起着重要作用。鉴定了几种对5-HT7受体具有高亲和力的化合物。其中，4-(2-甲氧基苯基)-N-(1,2,3,4-四氢萘基)-1-哌嗪己酰胺（28）、4-(2-乙酰基苯基)-N-(1,2,3,4-四氢萘基)-1-哌嗪己酰胺（34）、4-(2-甲硫基苯基)-N-(1,2,3,4-四氢萘基)-1-哌嗪己酰胺（44）、4-(2-羟基苯基)-N-(1,2,3,4-四氢萘基)-1-哌嗪己酰胺（46）、4-(2-甲基苯基)-N-(1,2,3,4-四氢萘基)-1-哌嗪己酰胺（49）被用于评估对5-HT7受体介导的物质P诱导的豚鼠回肠收缩的松弛作用。化合物28、44和49表现为全激动剂，化合物34表现为部分激动剂，而衍生物46表现为拮抗剂。
• US7488730B2
  申请人：——

  公开号：US7488730B2

  公开（公告）日：2009-02-10
• 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).