(Z)-(R)-十八酰胺-9-烯,N-((2-羟基-1-甲基)乙基) | 213182-22-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: (Z)-(R)-十八酰胺-9-烯,N-((2-羟基-1-甲基)乙基)
• 中文别名: (Z)-(R)-N-((2-羟基-1-甲基)乙基)-9-烯十八酰胺
• 英文名称: AM 3102
• 英文别名: (Z)-N-[(1R)-2-hydroxy-1-methylethyl]-octadec-9-enamide；N-(1R)-2-hydroxy-1-methylethyl-9Z-octadecenamide；9-Octadecenamide, N-((1R)-2-hydroxy-1-methylethyl)-, (9Z)-；(Z)-N-[(2R)-1-hydroxypropan-2-yl]octadec-9-enamide
• CAS: 213182-22-0
• 化学式: C₂₁H₄₁NO₂
• 分子量: 339.562
• InChiKey: IPVYNYWIRWMRHH-JPMGXVIASA-N

物化性质

• 熔点：
  39-40 °C
• 沸点：
  503.6±43.0 °C(Predicted)
• 密度：
  0.911
• 溶解度：
  DMF：25mg/mL； DMSO：20mg/mL；乙醇：5mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  24
• 可旋转键数：
  17
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

安全信息

• 储存条件：
  -20°C，密闭保存，干燥存放

制备方法与用途

AM3102是一种油酰乙醇酰胺(OEA)类似物，也是一种内源性高亲和力的PPARα激动剂。此外，AM3102能够抵抗酶水解，在体外能高效激活PPARα，并在肠外或口服给药时持续减少食物摄入量。

反应信息

• 作为产物：
  描述：

  油酰氯 、 D-氨基丙醇 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以96%的产率得到(Z)-(R)-十八酰胺-9-烯,N-((2-羟基-1-甲基)乙基)
  参考文献：
  名称：

  Pharmacological Characterization of Hydrolysis-Resistant Analogs of Oleoylethanolamide with Potent Anorexiant Properties

  摘要：

  油酰乙醇酰胺（OEA）是一种内源性脂质介质，可通过激活过氧化物酶体增殖激活受体-α（PPAR-α）来降低啮齿动物的食物摄入量、促进脂肪分解并减少体重增加。OEA 的生物效应由两种细胞内脂质水解酶（脂肪酸酰胺水解酶和 N -酰基乙醇胺水解酸酰胺酶）终止。在本研究中，我们描述了能抵抗酶水解的 OEA 类似物，它们能在体外高效力地激活 PPAR-α，并在体内经肠道或口服给药后持续减少摄食。这些化合物中效力最强的是 ( Z )-( R )-9- 十八烯酰胺，N -（2-羟乙基，1-甲基）（KDS-5104），它能刺激 PPAR-α 的转录活性，其半最大有效浓度（EC50）为 100 ± 21 nM（n = 11）。与 OEA 相比，KDS-5104 给大鼠肠外给药会产生持续的剂量依赖性进食潜伏期和餐后间隔延长（半数最大有效剂量，ED50 = 2.4 ± 1.8 mg kg-1 i.p.；n = 18），以及组织暴露增加和延长。在自由采食的大鼠中，口服该化合物也会导致显著的组织暴露和食物摄入量减少。这些结果表明，内源性高亲和力 PPAR-α 激动剂 OEA 可为发现新型口服活性 PPAR-α 配体提供支架。

  DOI：

  10.1124/jpet.106.105221

文献信息

• Compounds, compositions and treatment of oleoylethanolamide-like modulators of PPARalpha
  申请人：Fu Jin

  公开号：US20050054730A1

  公开（公告）日：2005-03-10

  The present invention provides compounds, compositions, and methods for the treatment of disorders and conditions mediated by PPARα. The invention relates to the surprising discovery that oleoylethanolamide (OEA) is an endogenous high affinity and selective ligand of PPARα. The compounds of the invention include, but are not limited to, specific PPARα agonists sharing the receptor binding properties of OEA and fatty acid alkanolamides and their homologs which also are PPARα agonists. Such OEA-like compounds include, but are not limited to, compounds of the following formula: in which n is from 0 to 5, the sum of a and b can be from 0 to 4; Z is a member selected from the group consisting of —C(O)N(R o )—; —(R o )NC(O)—; —OC(O)—; —(O)CO—; O; NR o ; and S; and wherein R o and R 2 are members independently selected from the group consisting of unsubstituted or unsubstituted alkyl, hydrogen, C 1 -C 6 alkyl, and lower (C 1 -C 6 ) acyl, and wherein up to eight hydrogen atoms are optionally substituted by methyl or a double bond, and the bond between carbons c and d may be unsaturated or saturated, or a pharmaceutically acceptable salt thereof.

  本发明提供了化合物、组合物和方法，用于治疗由PPARα介导的疾病和病症。本发明涉及到一项令人惊讶的发现，即油酰乙醇胺（OEA）是PPARα的内源性高亲和力和选择性配体。本发明的化合物包括但不限于与OEA具有受体结合特性的特定PPARα激动剂，以及脂肪酸烷基醇胺及其同系物，它们也是PPARα激动剂。这样的类OEA化合物包括但不限于以下公式的化合物：其中n为0至5，a和b的总和可以为0至4；Z是从以下群组中选择的成员：—C(O)N(Ro)—；—(Ro)NC(O)—；—OC(O)—；—(O)CO—；O；NRo；和S；Ro和R2是独立选择的成员，选自未取代或未取代的烷基、氢、C1-C6烷基和较低的（C1-C6）酰基的群组，其中最多八个氢原子可以选择性地被甲基或双键取代，且碳c和d之间的键可能是不饱和或饱和的，或其药学上可接受的盐。
• Combination therapy for controlling appetites
  申请人：Piomelli Daniele

  公开号：US20050101542A1

  公开（公告）日：2005-05-12

  The invention provides methods and pharmaceutical compositions for administering a PPARα agonist (e.g., OEA-like agonist, OEA-like compound), an OEA-like appetite reducing compound, or a FAAH inhibitor and a CB1 cannabinoid receptor antagonist to a subject in order to reduce the consumption or ingestion of food, ethanol or other appetizing substances as well as in treating appetency disorders related to the excess consumption of food, ethanol, and other appetizing substances. The combination therapy can also be useful for reducing body fat or body weight and modulating lipid metabolism.

  该发明提供了一种方法和制药组合物，用于给予PPARα激动剂（例如，OEA样激动剂，OEA样化合物），OEA样食欲减少化合物，或FAAH抑制剂和CB1大麻素受体拮抗剂给予受试者，以减少食物、乙醇或其他开胃物质的摄入或摄入量，并治疗与过量摄入食物、乙醇和其他开胃物质相关的食欲紊乱。该联合治疗也可用于减少体脂肪或体重和调节脂质代谢。
• Methods, compounds, and compositions for reducing body fat and modulating fatty acid metabolism
  申请人：Regents of the University of California

  公开号：US20030018081A1

  公开（公告）日：2003-01-23

  Methods, pharmaceutical compositions, and compounds for reducing body weight, modulating body lipid metabolism, and reducing food intake in mammals are provided. The compounds of the invention include fatty acid ethanolamide compounds, homologues and analogs of which the prototype is the endogenous fatty acid ethanolamide, oleoylethanolamide.

  本发明提供了减轻哺乳动物体重、调节体内脂质代谢和减少食物摄入量的方法、药物组合物和化合物。本发明的化合物包括脂肪酸乙醇酰胺化合物、同源物和类似物，其原型是内源性脂肪酸乙醇酰胺--油酰乙醇酰胺。
• Dietary and other compositions, compounds, and methods for reducing body fat, controlling appetite, and modulating fatty acid metabolism
  申请人：Piomelli Daniele

  公开号：US20050154064A1

  公开（公告）日：2005-07-14

  Methods, pharmaceutical, dietary supplement, and nutraceutical compositions, and compounds for reducing body weight, modulating body lipid metabolism, and reducing food intake in mammals are provided. The compounds of the invention include fatty acid ethanolamide compounds, homologues and analogs of which the prototype is the endogenous fatty acid ethanolamide, oleoylethanolamide.

  本发明提供了减轻哺乳动物体重、调节体内脂质代谢和减少食物摄入量的方法、药物、膳食补充剂和营养保健品组合物及化合物。 本发明的化合物包括脂肪酸乙醇酰胺化合物、同源物和类似物，其原型是内源性脂肪酸乙醇酰胺--油酰乙醇酰胺。
• 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.