N-arachidonoyl(2-methyl-2-amino-1-propanol)

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: N-arachidonoyl(2-methyl-2-amino-1-propanol)
• 英文别名: AM 359；N-(1,1-dimethyl-2-hydroxy-ethyl) arachidonoyl amine；(5Z,8Z,11Z,14Z)-N-(1-hydroxy-2-methylpropan-2-yl)icosa-5,8,11,14-tetraenamide
• 化学式: C₂₄H₄₁NO₂
• 分子量: 375.595
• InChiKey: BJEGAFQVEFFEEW-GKFVBPDJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  27
• 可旋转键数：
  16
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  花生四烯酸 在 草酰氯 、 N,N-二甲基甲酰胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.25h， 生成 N-arachidonoyl(2-methyl-2-amino-1-propanol)
  参考文献：
  名称：

  Anandamide型化合物与脑大麻素受体结合的结构要求。

  摘要：

  为了建立与脑大麻素受体（CB1）结合的结构要求，我们合成了许多脂肪酸酰胺，乙醇酰胺和一些相关的简单衍生物，并确定了它们的Ki值。还检查了一些α-甲基或α，α-二甲基花生四烯酰基烷基酰胺。在20：4，n-6系列中，未取代的酰胺是惰性的；N-单烷基化，至少直至分支的戊基，导致显着的结合。N，N-二烷基化，在一个烷基上具有或不具有羟基化，导致活性的消除。在ω碳原子上的N-单烷基的羟基化保持活性。在20x，n-6序列中，x必须为3或4；否则，x为3。只有两个双键的存在会导致失活。在n-3系列中 报告的有限数据表明，衍生的乙醇酰胺比n-6系列中的同类化合物无活性或活性较低。对于邻氨基苯甲酰胺（化合物48、49），与羰基相邻的α碳的烷基化或二烷基化保持结合水平。但是，N-丙基衍生物（50-53）的α-单甲基化或α，α-二甲基化可增强结合并导致本研究中活性最高的化合物（Ki值为6.9 +/- 0.7至8

  DOI：

  10.1021/jm960752x

文献信息

• Structural Requirements for Binding of Anandamide-Type Compounds to the Brain Cannabinoid Receptor
  作者：Tzviel Sheskin、Lumir Hanuš、Joram Slager、Zvi Vogel、Raphael Mechoulam

  DOI：10.1021/jm960752x

  日期：1997.2.1

  inactive or less active than comparable compounds in the n-6 series. Alkylation or dialkylation of the alpha carbon adjacent to the carbonyl group retains the level of binding in the case of anandamide (compounds 48, 49); however, alpha-monomethylation or alpha,alpha-dimethylation of N-propyl derivatives (50-53) potentiates binding and leads to the most active compounds seen in the present work (Ki values

  为了建立与脑大麻素受体（CB1）结合的结构要求，我们合成了许多脂肪酸酰胺，乙醇酰胺和一些相关的简单衍生物，并确定了它们的Ki值。还检查了一些α-甲基或α，α-二甲基花生四烯酰基烷基酰胺。在20：4，n-6系列中，未取代的酰胺是惰性的；N-单烷基化，至少直至分支的戊基，导致显着的结合。N，N-二烷基化，在一个烷基上具有或不具有羟基化，导致活性的消除。在ω碳原子上的N-单烷基的羟基化保持活性。在20x，n-6序列中，x必须为3或4；否则，x为3。只有两个双键的存在会导致失活。在n-3系列中 报告的有限数据表明，衍生的乙醇酰胺比n-6系列中的同类化合物无活性或活性较低。对于邻氨基苯甲酰胺（化合物48、49），与羰基相邻的α碳的烷基化或二烷基化保持结合水平。但是，N-丙基衍生物（50-53）的α-单甲基化或α，α-二甲基化可增强结合并导致本研究中活性最高的化合物（Ki值为6.9 +/- 0.7至8
• Novel Analogues of Arachidonylethanolamide (Anandamide):  Affinities for the CB1 and CB2 Cannabinoid Receptors and Metabolic Stability
  作者：Sonyuan Lin、Atmaram D. Khanolkar、Pusheng Fan、Andreas Goutopoulos、Ce Qin、Demetris Papahadjis、Alexandros Makriyannis

  DOI：10.1021/jm970257g

  日期：1998.12.1

  Several analogues of the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide) were synthesized and evaluated in order to study (a) the structural requirements for high-affinity binding to the CB1 and CB2 cannabinoid receptors and (b) their hydrolytic stability toward anandamide amidase. The series reported here was aimed at exploring structure-activity relationships (SAR) primarily with regard to stereoelectronic requirements of ethanolamido headgroup for interaction with the cannabinoid receptor active site. Receptor affinities, reported as K-i values, were obtained by a standard receptor binding assay using [H-3]CP-55,940 as the radioligand, while stability toward the amidase was evaluated by comparing the K-i of each analogue in the presence and absence of phenylmethanesulfonyl fluoride (PMSF), a serine protease blocker and inhibitor of anandamide amidase. Introduction of a methyl group in the 1'- and 2'-positions or substitution of the ethanolamido headgroup with a butylamido group gave analogues with vastly improved biochemical stability. This is accomplished in some cases with increased receptor affinity. Conversely, oxazolyl and methyloxazolyl headgroups led to low-affinity analogues. Substitution of the hydroxyl group with electronegative substituents such as fluoro, chloro, allyl, and propargyl groups significantly increased receptor affinity but did not influence the biochemical stability. The 2'-chloro analogue of anandamide was found to have the highest affinity for CB1. Additionally, reversing the positions of the carbonyl and NH in the amido group produces retro-anandamides possessing considerably higher metabolic stability. Replacement of the arachidonyl tail with oleyl or linoleyl results in analogues with low affinities for both receptors. All of the analogues in this study showed high selectivity for the CB1 receptor over the peripheral CB2 receptor. The most potent analogues were tested for their ability to stimulate the binding of [S-35]GTP gamma S to G-proteins and were shown to be potent cannabimimetic agonists. The results are discussed in terms of pharmacophoric features affecting receptor affinity and enzymatic stability.
• Improved Enzymatic Procedure for the Synthesis of Anandamide and<i>N</i>-Fatty Acylalkanolamine Analogues: A Combination Strategy to Antitumor Activity
  作者：Paula G. Quintana、Guadalupe García Liñares、Santiago N. Chanquia、Roxana M. Gorojod、Mónica L. Kotler、Alicia Baldessari

  DOI：10.1002/ejoc.201501263

  日期：2016.1

  (temperature, E/S ratio, alcohol and alkanolamine/fatty acid ratio, time, solvent, free-solvent system, etc.). To identify ideal enzymatic methods for generating the alkanolamides we evaluated enzyme performance in three procedures: i) aminolysis of ethyl ester, ii) direct condensation between the fatty acid and the alkanolamine, and iii) a one-pot/two-step conversion of fatty acids into alkanolamides via in

  通过南极念珠菌 B 脂肪酶催化的酯化和氨解反应，以非常好的收率和高化学选择性获得了来自亚麻酸和花生四烯酸的 20 种 N-脂肪酰胺，其中 15 种是新化合物。通过研究反应参数（温度、E/S比、醇和链烷醇胺/脂肪酸比、时间、溶剂、游离溶剂体系等）获得最佳反应条件。为了确定产生链烷醇酰胺的理想酶促方法，我们在三个程序中评估了酶的性能：i) 乙酯的氨解，ii) 脂肪酸和链烷醇胺之间的直接缩合，以及 iii) 脂肪的一锅/两步转化通过原位形成乙酯和随后由链烷醇胺氨解，将酸转化为链烷醇酰胺。酶促方法的优点，如温和的反应条件和低环境影响，强调生物催化是制备报告化合物的便捷方式。在大鼠神经胶质瘤 C6 细胞中评估了所有化合物和 anandamide 及其类似物的混合物的细胞毒活性。这些研究表明，一些 anandamide 类似物增强了 anandamide 的抗肿瘤作用，表明它们可能作为治疗工具用于癌症治疗。