(Z,Z)-N-[(1R)-2-hydroxy-1-methylethyl]-octadeca-9,12-dienamide

• 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: (Z,Z)-N-[(1R)-2-hydroxy-1-methylethyl]-octadeca-9,12-dienamide
• 英文别名: (9Z,12Z)-N-[(2R)-1-hydroxypropan-2-yl]octadeca-9,12-dienamide
• 化学式: C₂₁H₃₉NO₂
• 分子量: 337.546
• InChiKey: ADRRUPVKLINJKD-FNUGXZCYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  24
• 可旋转键数：
  16
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.76
• 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：

  (Z,Z)-9,12-十八烷二烯酸二聚物 在 草酰氯 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 1.25h， 生成 (Z,Z)-N-[(1R)-2-hydroxy-1-methylethyl]-octadeca-9,12-dienamide
  参考文献：
  名称：

  Novel Analogues of Arachidonylethanolamide (Anandamide):  Affinities for the CB1 and CB2 Cannabinoid Receptors and Metabolic Stability

  摘要：

  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.

  DOI：

  10.1021/jm970257g

文献信息

• Evaluation of endogenous fatty acid amides and their synthetic analogues as potential anti-inflammatory leads
  作者：Hung The Dang、Gyeoung Jin Kang、Eun Sook Yoo、Jongki Hong、Jae Sue Choi、Hyung Sik Kim、Hae Young Chung、Jee H. Jung

  DOI：10.1016/j.bmc.2010.12.046

  日期：2011.2

  A series of endogenous fatty acid amides and their analogues (1-78) were prepared, and their inhibitory effects on pro-inflammatory mediators (NO, IL-1 beta, IL-6, and TNF-alpha) in LPS-activated RAW264.7 cells were evaluated. Their inhibitory activity on the pro-inflammatory chemokine MDC in IFN-gamma-activated HaCaT cells was also examined. The results showed that the activity is strongly dependent on the nature of the fatty acid part of the molecules. As expected, the amides derived from enone fatty acids showed significant activity and were more active than those derived from other types of fatty acids. A variation of the amine headgroup also altered bioactivity profile remarkably, possibly by modulating cell permeability. Regarding the amine part of the molecules, N-acyl dopamines exhibited the most potent activity (IC50 similar to 2 mu M). This is the first report of the inhibitory activity of endogenous fatty acid amides and their analogues on the production of nitric oxide, cytokines (IL-1 beta, IL-6, and TNF-alpha) and the chemokine MDC. This study suggests that the enone fatty acid-derived amides (such as N-acyl ethanolamines and N-acyl amino acids) and N-acyl dopamines may be potential anti-inflammatory leads. (C) 2010 Elsevier Ltd. All rights reserved.
• 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.