N-(3-methoxybenzyl)icosa-5Z,8Z,11Z,14Z-tetraenamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(3-methoxybenzyl)icosa-5Z,8Z,11Z,14Z-tetraenamide
• 英文别名: O 1986；(5Z,8Z,11Z,14Z)-N-[(3-methoxyphenyl)methyl]icosa-5,8,11,14-tetraenamide
• 化学式: C₂₈H₄₁NO₂
• 分子量: 423.639
• InChiKey: UTIZQJLALOGMDO-ZKWNWVNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  31
• 可旋转键数：
  17
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  38.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  3-甲氧基苄胺 、 花生四烯酸 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 0.25h， 以90%的产率得到N-(3-methoxybenzyl)icosa-5Z,8Z,11Z,14Z-tetraenamide
  参考文献：
  名称：

  N-Benzyl-linoleamide, a Constituent of Lepidium meyenii (Maca), Is an Orally Bioavailable Soluble Epoxide Hydrolase Inhibitor That Alleviates Inflammatory Pain

  摘要：

  Lepidium meyenii (maca), a plant indigenous to the Peruvian Andes, recently has been utilized globally for claimed health or recreational benefits. The search for natural products that inhibit soluble epoxide hydrolase (sEH), with therapeutically relevant potencies and concentrations, led to the present study on bioactive amide secondary metabolites found in L. meyenii, the macamides. Based on known and suspected macamides, 19 possible macamides were synthesized and characterized. The majority of these amides displayed excellent inhibitory potency (IC₅₀ ≈ 20-300 nM) toward the recombinant mouse, rat, and human sEH. Quantitative analysis of commercial maca products revealed that certain products contain known macamides (1-5, 8-12) at therapeutically relevant total concentrations (≥3.29 mg/g of root), while the inhibitory potency of L. meyenii extracts directly correlates with the sum of concentration/IC₅₀ ratios of macamides present. Considering both its in vitro efficacy and high abundance in commercial products, N-benzyl-linoleamide (4) was identified as a particularly relevant macamide that can be utilized for in vivo studies. Following oral administration in the rat, compound 4 not only displayed acceptable pharmacokinetic characteristics but effectively reduced lipopolysaccharide-induced inflammatory pain. Inhibition of sEH by macamides provides a plausible biological mechanism of action to account for several beneficial effects previously observed with L. meyenii treatments.

  DOI：

  10.1021/acs.jnatprod.0c00938

文献信息

• A Structure/Activity Relationship Study on Arvanil, an Endocannabinoid and Vanilloid Hybrid
  作者：Vincenzo Di Marzo、Graeme Griffin、Luciano De Petrocellis、Ines Brandi、Tiziana Bisogno、William Williams、Mark C. Grier、Sanjitha Kulasegram、Anu Mahadevan、Raj K. Razdan、Billy R. Martin

  DOI：10.1124/jpet.300.3.984

  日期：2002.3.1

  Arvanil, a structural “hybrid” between the endogenous cannabinoid CB1 receptor ligand anandamide and capsaicin, is a potent agonist for the capsaicin receptor VR1 (vanilloid receptor type 1), inhibits the anandamide membrane transporter (AMT), and induces cannabimimetic responses in mice. Novel arvanil derivatives prepared by N -methylation, replacement of the amide with urea and thiourea moieties, and manipulation of the vanillyl group were evaluated for their ability to bind/activate CB1 receptors, activate VR1 receptors, inhibit the AMT and fatty acid amide hydrolase (FAAH), and produce cannabimimetic effects in mice. The compounds did not stimulate the CB1 receptor. Methylation of the amide group decreased the activity at VR1, AMT, and FAAH. On the aromatic ring, the substitution of the 3-methoxy group with a chlorine atom or the lack of the 4-hydroxy group decreased the activity on VR1 and AMT, but not the affinity for CB1 receptors, and increased the capability to inhibit FAAH. The urea or thiourea analogs retained activity at VR1and AMT but exhibited little affinity for CB1 receptors. The urea analog was a potent FAAH inhibitor (IC50 = 2.0 μM). A water-soluble analog of arvanil, O-2142, was as active on VR1, much less active on AMT and CB1, and more potent on FAAH. All compounds induced a response in the mouse “tetrad”, particularly those with EC50 <10 nM on VR1. However, the most potent compound, N - N ′-di-(3-chloro-4-hydroxy)benzyl-arachidonamide (O-2093, ED50 ∼0.04 mg/kg), did not activate VR1 or CB1 receptors. Our findings suggest that VR1 and/or as yet uncharacterized receptors produce cannabimimetic responses in mice in vivo.

  阿伐那非(Arvanil)是一种结构上的"杂交体",结合了内源性大麻素CB1受体配体大麻二酚(anandamide)和辣椒素。它是一种有效的辣椒素受体VR1(香草酸受体1型)激动剂,抑制了大麻二酚膜转运体(AMT),并在小鼠体内诱导出类似大麻的反应。通过N-甲基化、用尿素和硫脲部分替换酰胺、操作香草醛基团制备的新型阿伐那非衍生物,评估了它们结合/激活CB1受体、激活VR1受体、抑制AMT和脂肪酸酰胺水解酶(FAAH)以及在小鼠体内产生类似大麻效应的能力。这些化合物并未刺激CB1受体。酰胺基团的甲基化降低了其在VR1、AMT和FAAH上的活性。在芳香环上,用氯原子替换3-甲氧基或去除4-羟基会降低VR1和AMT上的活性,但不影响CB1受体的亲和力,并增加了抑制FAAH的能力。尿素或硫脲类似物保留了VR1和AMT上的活性,但对CB1受体亲和力较小。尿素类似物是一种有效的FAAH抑制剂(IC50 = 2.0 μM)。水溶性阿伐那非类似物O-2142在VR1上同样有效,在AMT和CB1上活性较低,在FAAH上更有效。所有化合物在小鼠"四联症"上诱导出反应,特别是那些在VR1上EC50 <10 nM的化合物。然而,最强的化合物N-N'-二-(3-氯-4-羟基)苄基-花生四烯酰胺(O-2093, ED50 ∼0.04 mg/kg)并未激活VR1或CB1受体。我们的发现表明,VR1和/或尚未表征的受体在体内诱导小鼠产生类似大麻的反应。
• <i>N</i>-Benzyl-linoleamide, a Constituent of <i>Lepidium meyenii</i> (Maca), Is an Orally Bioavailable Soluble Epoxide Hydrolase Inhibitor That Alleviates Inflammatory Pain
  作者：Nalin Singh、Bogdan Barnych、Christophe Morisseau、Karen M. Wagner、Debin Wan、Ashley Takeshita、Hoang Pham、Ting Xu、Abhaya Dandekar、Jun-Yan Liu、Bruce D. Hammock

  DOI：10.1021/acs.jnatprod.0c00938

  日期：2020.12.24

  Lepidium meyenii (maca), a plant indigenous to the Peruvian Andes, recently has been utilized globally for claimed health or recreational benefits. The search for natural products that inhibit soluble epoxide hydrolase (sEH), with therapeutically relevant potencies and concentrations, led to the present study on bioactive amide secondary metabolites found in L. meyenii, the macamides. Based on known and suspected macamides, 19 possible macamides were synthesized and characterized. The majority of these amides displayed excellent inhibitory potency (IC₅₀ ≈ 20-300 nM) toward the recombinant mouse, rat, and human sEH. Quantitative analysis of commercial maca products revealed that certain products contain known macamides (1-5, 8-12) at therapeutically relevant total concentrations (≥3.29 mg/g of root), while the inhibitory potency of L. meyenii extracts directly correlates with the sum of concentration/IC₅₀ ratios of macamides present. Considering both its in vitro efficacy and high abundance in commercial products, N-benzyl-linoleamide (4) was identified as a particularly relevant macamide that can be utilized for in vivo studies. Following oral administration in the rat, compound 4 not only displayed acceptable pharmacokinetic characteristics but effectively reduced lipopolysaccharide-induced inflammatory pain. Inhibition of sEH by macamides provides a plausible biological mechanism of action to account for several beneficial effects previously observed with L. meyenii treatments.