N-[2-(1H-indol-3-yl)ethyl]cyclobutancarboxamide | 19462-21-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-[2-(1H-indol-3-yl)ethyl]cyclobutancarboxamide
• 英文别名: N-cyclobutanoyltryptamine；N-Cyclobutylcarbonyltryptamin；N-[2-(1H-indol-3-yl)ethyl]cyclobutanecarboxamide
• CAS: 19462-21-6
• 化学式: C₁₅H₁₈N₂O
• mdl: MFCD03983935
• 分子量: 242.321
• InChiKey: XHRBVPGBQAVBGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  18
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  44.9
• 氢给体数：
  2
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  N-[2-(1H-indol-3-yl)ethyl]cyclobutancarboxamide 在 四(三苯基膦)钯 、 potassium acetate 、 sodium hydride 作用下， 以 四氢呋喃 、 二甲胺 为溶剂， 反应 19.0h， 生成 Cyclobutanecarboxylic acid [2-(6H-isoindolo[2,1-a]indol-11-yl)-ethyl]-amide
  参考文献：
  名称：

  Mapping the Melatonin Receptor. 6. Melatonin Agonists and Antagonists Derived from 6H-Isoindolo[2,1-a]indoles, 5,6-Dihydroindolo[2,1-a]isoquinolines, and 6,7-Dihydro-5H-benzo[c]azepino[2,1-a]indoles

  摘要：

  6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2,1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles (23, 25, 27, 30) have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human mt(1) and MT2 receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2,1-a]indoles (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolines (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6,7-5H-benzo[c]azepino[2,1-a]indoles (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT2 receptor but similar affinities at the mt(1) site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT2 receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT2 receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT2 receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT2 melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT2 receptor, while 25c is an MT2-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.

  DOI：

  10.1021/jm980684+
• 作为产物：
  描述：

  色胺 、 环丁基甲酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以80%的产率得到N-[2-(1H-indol-3-yl)ethyl]cyclobutancarboxamide
  参考文献：
  名称：

  Spadoni, Gilberto; Balsamini, Cesarino; Bedini, Annalida, Medicinal Chemistry Research, 1998, vol. 8, # 9, p. 487 - 498

  摘要：

  DOI：

文献信息

• Synthesis and structure–activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands
  作者：Véronique Leclerc、Eric Fourmaintraux、Patrick Depreux、Daniel Lesieur、Peter Morgan、H.Edward Howell、Pierre Renard、Daniel-Henri Caignard、Bruno Pfeiffer、Philippe Delagrange、Béatrice Guardiola-Lemaı̂tre、Jean Andrieux

  DOI：10.1016/s0968-0896(98)00147-3

  日期：1998.10

  synthesis of melatonin receptor ligands. In order to complete the structure-activity relationships and to obtain antagonists to the melatonin receptor, a new series of naphthalenic analogues of melatonin have been synthesized. Modifications include deletion of the 7-methoxy group, replacement of the ethylene moiety, replacement of the amidic function by bioisosteres, and replacement of the naphthalenic nucleus

  先前的论文报道了褪黑激素受体配体的合成。为了完成结构-活性关系并获得褪黑激素受体的拮抗剂，已经合成了一系列新的褪黑激素萘类似物。修饰包括7-甲氧基的缺失，乙烯部分的取代，生物等位基因的取代酰胺功能，以及其他双环取代的萘核。几乎所有的结构修饰都会导致对褪黑激素受体的亲和力下降。但是，Nn丙基脲衍生物（27）在该受体上是非常有效的配体（pKi = 14.3）。最有趣的是，甲氧基的缺失导致了该系列的第一个拮抗剂。该分子，化合物12
• Mapping the Melatonin Receptor. 6. Melatonin Agonists and Antagonists Derived from 6<i>H</i>-Isoindolo[2,1-<i>a</i>]indoles, 5,6-Dihydroindolo[2,1-<i>a</i>]isoquinolines, and 6,7-Dihydro-5<i>H</i>-benzo[<i>c</i>]azepino[2,1-<i>a</i>]indoles
  作者：Rüdiger Faust、Peter J. Garratt、Rob Jones、Li-Kuan Yeh、Andrew Tsotinis、Maria Panoussopoulou、Theodora Calogeropoulou、Muy-Teck Teh、David Sugden

  DOI：10.1021/jm980684+

  日期：2000.3.1

  6H-Isoindolo[2,1-a]indoles (5, 7, 10, 13), 5,6-dihydroindolo[2,1-a]isoquinolines (20, 21), and 6,7-dihydro-5H-benzo[c]azepino[2,1-a]indoles (23, 25, 27, 30) have been prepared as melatonin analogues to investigate the nature of the binding site of the melatonin receptor. The affinity of analogues was determined in a radioligand binding assay using cloned human mt(1) and MT2 receptor subtypes expressed in NIH 3T3 cells. Agonist and antagonist potency was measured using the pigment aggregation response of a clonal line of Xenopus laevis melanophores. The 2-methoxyisoindolo[2,1-a]indoles (7a-d) showed much higher binding affinities than the parent isoindoles (5a-e), and whereas 7a-c were agonists in the functional assay, 7d and 5a-e were antagonists. The 2-ethoxyisoindolo[2,1-a]indoles (10a-d) showed reduced binding affinities compared to their methoxy analogues, while the 5-chloro derivative 13 showed a considerable reduction in binding affinity and potency compared to 7a. The 10-methoxy-5,6-dihydroindolo[2,1-a]isoquinolines (21a-c) had higher binding affinities than the corresponding parent indoloisoquinolines (20a-c) in the human receptor subtypes, and the parent compounds were antagonists whereas the 10-methoxy derivatives were agonists in the functional assay. The N-cyclobutanecarbonyl derivatives of both the parent (20d) and 10-methoxyl (21d) series had similar binding affinities and were both antagonists with similar potencies. The 11-methoxy-6,7-5H-benzo[c]azepino[2,1-a]indoles (25a-d) had higher binding affinities than the corresponding parent compounds (23a-d) at the MT2 receptor but similar affinities at the mt(1) site; all of the compounds were antagonists in the functional assay. Changing 11-methoxy for 11-ethoxy decreased the binding affinity slightly, and this was more evident at the MT2 receptor. All of the derivatives investigated had either the same or a greater affinity for the human MT2 receptor compared to the mt(1) receptor (range 1:1-1:132). This suggests that the mt(1) and MT2 receptor pockets differ in their ability to accommodate alkyl groups in the indole nitrogen region of the melatonin molecule. Two compounds (7c and 25c) were tested in functional assays on recombinant mt(1) and MT2 melatonin receptors. Compound 7c is a potent agonist with some selectivity (44-fold) for the MT2 receptor, while 25c is an MT2-preferring antagonist. Increasing the carbon chain length between N-1 of indole and the 2-phenyl group from n = 1 through n = 3 leads to a fairly regular decrease in the binding affinity, but, remarkably, when n = 3, it converts the methoxy compounds from melatonin agonists to antagonists. The Xenopus melatonin receptor thus cannot accommodate an N-n-alkyl chain attached to a 2-phenyl substituent with n > 2 in the required orientation to induce or stabilize the active receptor conformation.
• Spadoni, Gilberto; Balsamini, Cesarino; Bedini, Annalida, Medicinal Chemistry Research, 1998, vol. 8, # 9, p. 487 - 498
  作者：Spadoni, Gilberto、Balsamini, Cesarino、Bedini, Annalida、Carey, Aedin、Diamantini, Giuseppe、Di Giacomo, Barbara、Tontini, Andrea、Tarzia, Giorgio、Nonno, Romolo、Lucini, Valeria、Pannacci, Marilou、Michaylov Stankov, Bojidar、Fraschini, Franco

  DOI：——

  日期：——