N-(2-acetoxyacetyl)arachidonylamine

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-(2-acetoxyacetyl)arachidonylamine
• 英文别名: Acetic acid ((5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenyl)carbamoylmethyl ester；[2-[[(5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenyl]amino]-2-oxoethyl] acetate
• 化学式: C₂₄H₃₉NO₃
• 分子量: 389.579
• InChiKey: DWXJVUKDOLXSRK-ZKWNWVNESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  28
• 可旋转键数：
  18
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  55.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  arachidonyl mesylate 在 lithium aluminium tetrahydride 、 sodium azide 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 28.0h， 生成 N-(2-acetoxyacetyl)arachidonylamine
  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

• Cannabimimetic lipid amides as useful medications
  申请人：University of Connecticut

  公开号：US07161016B1

  公开（公告）日：2007-01-09

  Novel analogs of arachidonylethanolamide are presented which have higher affinities for the cannabinoid CB1 and/or CB2 receptor sites. Further, most of the analogs exhibit greater metabolic stability than arachidonylethanolamide. The improved receptor affinity and selectivity and/or greater metabolic stability make these analogs therapeutically useful as medications for relief of pain caused by cancer and nausea caused by chemotherapy, as well as for peripheral pain. The compounds may also be useful as oral and topical contraceptives, in suppression of the immune system, enhancement of appetite and in treatment of psychomotor disorders, multiple sclerosis and hypertension.

  新型的花生四烯酰乙醇胺类似物具有更高的亲和力，适用于大麻素CB1和/或CB2受体位点。此外，大多数类似物表现出比花生四烯酰乙醇胺更高的代谢稳定性。改善的受体亲和力和选择性和/或更高的代谢稳定性使这些类似物在作为药物用于缓解癌症引起的疼痛和化疗引起的恶心，以及外周疼痛方面具有治疗用途。这些化合物也可能用于口服和局部避孕药、免疫系统抑制、增强食欲以及治疗精神运动障碍、多发性硬化和高血压。
• US7161016B1
  申请人：——

  公开号：US7161016B1

  公开（公告）日：2007-01-09
• 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.