20-hydroxy-5,8,11,14-eicosatetraenoic acid ethanolamide | 942069-11-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 20-hydroxy-5,8,11,14-eicosatetraenoic acid ethanolamide
• 英文别名: 20-HETE Ethanolamide；(5Z,8Z,11Z,14Z)-20-hydroxy-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
• CAS: 942069-11-6
• 化学式: C₂₂H₃₇NO₃
• 分子量: 363.541
• InChiKey: QRMZDMUHHZLRMH-DTLRTWKJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  17
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  20-羟基二十碳-5Z,8Z,11Z,14Z-四烯酸 在 2-羟基吡啶 作用下， 以 乙醚 为溶剂， 反应 1.0h， 生成 20-hydroxy-5,8,11,14-eicosatetraenoic acid ethanolamide
  参考文献：
  名称：

  Human Platelets and Polymorphonuclear Leukocytes Synthesize Oxygenated Derivatives of Arachidonylethanolamide (Anandamide): Their Affinities for Cannabinoid Receptors and Pathways of Inactivation

  摘要：

  花生四烯醇胺（AEA），即大麻素受体的假定内源性配体，已被证明是体外脂氧化酶的底物。本研究的一个目标是确定富含脂氧化酶的细胞是否代谢 AEA。[14C]AEA 被人体多形核白细胞（PMNs）转化为两种主要代谢物，它们与合成的前列腺素 E2（HAEA）共迁移。人血小板将 [14C]AEA 转化为 12(S)-HAEA。12(S)-HAEA 与 AEA 具有大致相同的亲和力，结合 CB1 和 CB2 受体。12(R)-HAEA，PMNs 不产生，对 CB1 受体的亲和力是 12(S)-HAEA 的两倍，对 CB2 受体的亲和力是 10 倍。15-HAEA 对两种受体的亲和力均低于 AEA，其 Ki 值分别为 738 和 >1000 nm，适用于 CB1 和 CB2 受体。在 AEA 的 C20 位添加羟基后，生成的配体对 CB1 受体的亲和力与 AEA 相同，但对 CB2 受体的亲和力降低了 4 倍。12(S)-HAEA 和 15-HAEA 是 AEA 酰胺水解酶的不良底物，并不与 AEA 摄取载体结合。总之，在 AEA 的花生四烯酸主链的 C12 位添加羟基不影响与 CB 受体的结合，但很可能增加其半衰期。在其他位置添加羟基会影响配体对 CB 受体的亲和力；羟基的位置和剩余双键的构型都是亲和力的决定因素。

  DOI：

  10.1124/mol.54.1.180

文献信息

• Anandamide Oxidation by Wild-Type and Polymorphically Expressed CYP2B6 and CYP2D6
  作者：Chitra Sridar、Natasha T. Snider、Paul F. Hollenberg

  DOI：10.1124/dmd.110.036707

  日期：2011.5

  20-hydroxyeicosatetraenoic acid ethanolamide (20-HETE-EA) and 14,15-epoxyeicosatetraenoic acid ethanolamide (14,15-EET-EA). Pharmacological studies showed that both 20-HETE-EA and 14,15-EET-EA bind to the rat brain cannabinoid CB1 receptor with lower affinities relative to that of anandamide. In addition, both products are degraded more rapidly than anandamide in rat brain homogenates. Their degradation

  Anandamide 是一种花生四烯酸衍生的内源性大麻素，可调节中枢神经系统和外周的正常生理功能和病理生理反应。几种细胞色素 P450 (P450) 亚型代谢 anandamide，形成羟基化和环氧化产物。人类 CYP2B6 和 CYP2D6 在整个大脑中异质表达，表现出临床上显着的多态性，并受外部因素（如酒精和吸烟）的调节。这两种 P450 对 anandamide 的氧化代谢可能对内源性大麻素系统信号传导具有重要的功能影响。在这项研究中，我们研究了野生型 CYP2B6 (2B6.1) 和 CYP2D6 (2D6.1) 及其常见的多态性突变体 2B6.4、2B6.6、2B6.9 和 2D6.34 对 anandamide 的代谢。两种亚型及其突变体在花生四烯酸代谢方面的主要差异是在体外发现 20-羟基二十碳四烯酸乙醇酰胺 (20-HETE-EA) 和 14,15-环氧二十碳四烯酸乙醇酰胺
• The Endocannabinoid Anandamide Is a Substrate for the Human Polymorphic Cytochrome P450 2D6
  作者：Natasha T. Snider、Matthew J. Sikora、Chitra Sridar、Thomas J. Feuerstein、James M. Rae、Paul F. Hollenberg

  DOI：10.1124/jpet.108.141796

  日期：2008.11

  Members of the cytochrome P450 (P450) family of drug-metabolizing enzymes are present in the human brain, and they may have important roles in the oxidation of endogenous substrates. The polymorphic CYP2D6 is one of the major brain P450 isoforms and has been implicated in neurodegeneration, psychosis, schizophrenia, and personality traits. The objective of this study was to determine whether the endocannabinoid arachidonoylethanolamide (anandamide) is a substrate for CYP2D6. Anandamide is the endogenous ligand to the cannabinoid receptor CB1, which is also activated by the main psychoactive component in marijuana. Signaling via the CB1 receptor alters sensory and motor function, cognition, and emotion. Recombinant CYP2D6 converted anandamide to 20-hydroxyeicosatetraenoic acid ethanolamide and 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EET-EAs) with low micromolar K m values. CYP2D6 further metabolized the epoxides of anandamide to form novel dioxygenated derivatives. Human brain microsomal and mitochondrial preparations metabolized anandamide to form hydroxylated and epoxygenated products, respectively. An inhibitory antibody against CYP2D6 significantly decreased the mitochondrial formation of the EET-EAs. To our knowledge, anandamide and its epoxides are the first eicosanoid-like molecules to be identified as CYP2D6 substrates. Our study suggests that anandamide may be a physiological substrate for brain mitochondrial CYP2D6, implicating this polymorphic enzyme as a potential component of the endocannabinoid system in the brain. This study also offers support to the hypothesis that neuropsychiatric phenotype differences among individuals with genetic variations in CYP2D6 could be ascribable to interactions of this enzyme with endogenous substrates.

  细胞色素P450（P450）药物代谢酶家族成员存在于人脑中，它们可能在内源性底物的氧化中发挥重要作用。多态性CYP2D6是主要的脑P450同工型之一，与神经变性、精神病、精神分裂症和人格特质有关。这项研究的目的是确定内源性大麻素花生四烯乙醇酰胺（anandamide）是否是CYP2D6的底物。Anandamide是大麻素受体CB1的内源性配体，它也可以被大麻中的主要精神活性成分激活。通过CB1受体传递的信号会改变感觉和运动功能、认知和情绪。重组CYP2D6将anandamide转化为20-羟基二十碳四烯酸乙醇酰胺和5,6-、8,9-、11,12-和14,15-环氧二十碳三烯酸乙醇酰胺（EET-EAs），其K m值较低。CYP2D6进一步代谢anandamide的环氧化物，形成新的双氧衍生物。人脑微粒体和线粒体制剂分别将anandamide代谢为羟基化和环氧化的产物。针对CYP2D6的抑制性抗体显著降低了线粒体形成的EET-EAs。据我们所知，anandamide及其环氧化物是首批被确定为CYP
• Human Platelets and Polymorphonuclear Leukocytes Synthesize Oxygenated Derivatives of Arachidonylethanolamide (Anandamide): Their Affinities for Cannabinoid Receptors and Pathways of Inactivation
  作者：William S. Edgemond、Cecilia J. Hillard、J. R. Falck、Christopher S. Kearn、William B. Campbell

  DOI：10.1124/mol.54.1.180

  日期：1998.7.1

  Arachidonylethanolamide (AEA), the putative endogenous ligand of the cannabinoid receptor, has been shown to be a substrate for lipoxygenase enzymes in vitro . One goal of this study was to determine whether lipoxygenase-rich cells metabolize AEA. [14C]AEA was converted by human polymorphonuclear leukocytes (PMNs) to two major metabolites that comigrated with synthetic 12( S )- and 15( S )-hydroxy-arachidonylethanolamide (HAEA). Human platelets convert [14C]AEA to 12( S )-HAEA. 12( S )-HAEA binds to both CB1 and CB2 receptors with approximately the same affinity as AEA. 12( R )-HAEA, which is not produced by PMNs, has 2-fold lower affinity for the CB1 receptor and 10-fold lower affinity for the CB2 receptor than 12( S )-HAEA. 15-HAEA has a lower affinity than AEA for both receptors, with K i values of 738 and >1000 nm for CB1 and CB2 receptors, respectively. The addition of a hydroxyl group at C20 of AEA resulted in a ligand with the same affinity for the CB1 receptor but a 4-fold lower affinity for the CB2 receptor than AEA. 12( S )-HAEA and 15-HAEA are poor substrates for AEA amidohydrolase and do not bind to the AEA uptake carrier. In conclusion, the addition of a hydroxyl group at C12 of the arachidonate backbone of AEA does not affect binding to CB receptors but is likely to increase its half-life. The addition of hydroxyl groups at other positions affects ligand affinity for CB receptors; both the position of the hydroxyl group and the configuration of the remaining double bonds are determinants of affinity.

  花生四烯醇胺（AEA），即大麻素受体的假定内源性配体，已被证明是体外脂氧化酶的底物。本研究的一个目标是确定富含脂氧化酶的细胞是否代谢 AEA。[14C]AEA 被人体多形核白细胞（PMNs）转化为两种主要代谢物，它们与合成的前列腺素 E2（HAEA）共迁移。人血小板将 [14C]AEA 转化为 12(S)-HAEA。12(S)-HAEA 与 AEA 具有大致相同的亲和力，结合 CB1 和 CB2 受体。12(R)-HAEA，PMNs 不产生，对 CB1 受体的亲和力是 12(S)-HAEA 的两倍，对 CB2 受体的亲和力是 10 倍。15-HAEA 对两种受体的亲和力均低于 AEA，其 Ki 值分别为 738 和 >1000 nm，适用于 CB1 和 CB2 受体。在 AEA 的 C20 位添加羟基后，生成的配体对 CB1 受体的亲和力与 AEA 相同，但对 CB2 受体的亲和力降低了 4 倍。12(S)-HAEA 和 15-HAEA 是 AEA 酰胺水解酶的不良底物，并不与 AEA 摄取载体结合。总之，在 AEA 的花生四烯酸主链的 C12 位添加羟基不影响与 CB 受体的结合，但很可能增加其半衰期。在其他位置添加羟基会影响配体对 CB 受体的亲和力；羟基的位置和剩余双键的构型都是亲和力的决定因素。