跳转到内容

花生四烯乙醇胺

维基百科,自由的百科全书
花生四烯乙醇胺
IUPAC名
(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
别名 N-arachidonoylethanolamine
花生四烯酰乙醇胺[1]
花生四烯酸乙醇胺[2]
识别
CAS号 94421-68-8  checkY
PubChem 5281969
ChemSpider 4445241
SMILES
 
  • O=C(NCCO)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
InChI
 
  • 1/C22H37NO2/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-22(25)23-20-21-24/h6-7,9-10,12-13,15-16,24H,2-5,8,11,14,17-21H2,1H3,(H,23,25)/b7-6-,10-9-,13-12-,16-15-
InChIKey LGEQQWMQCRIYKG-DOFZRALJBA
ChEBI 2700
MeSH Anandamide
IUPHAR配体 2364
性质
化学式 C22H37NO2
摩尔质量 347.53 g/mol g·mol⁻¹
若非注明,所有数据均出自标准状态(25 ℃,100 kPa)下。

花生四烯乙醇胺,又名N-花生四烯乙醇胺AEA,是一种内源性的大麻醇类神经传导物质。命名取自梵文(和印度半岛宗教用语)中的“阿难陀(ananda)”,意为“喜悦、极乐、欣喜”,以及酰胺[3][4]。它是由N-花生四烯酰磷脂酰乙醇胺透过多种途径合成[5]。花生四烯乙醇胺,主要是由脂肪酸酰胺水解酶(FAAH)将其降解乙醇胺花生四烯酸。如此,脂肪酸酰胺水解酶(FAAH)的抑制物导致花生四烯乙醇胺层级的提升,并被用于治疗[6][7]

历史

花生四烯乙醇胺的结构最初由W. A. Devane, Lumír Hanuš等人在1992年时提到。当时他们在耶路撒冷希伯来大学一个由Raphael Mechoulam带领的团队工作。[8]

生理功能

花生四烯乙醇胺可以作用在人体的中枢神经系统 ,例如脑部周围以及身体的其他部位。这些作用主要是由在中枢神经系统中的CB1大麻素受体,以及在周围神经系统的CB2大麻素受体调节。[9]后者主要参与免疫系统的功能作用。大麻素受体最初被发现时,其被发现对Δ9四氢大麻酚(Δ9-THC,通常称为THC)较为敏感,而其也正是大麻中的主要精神活性物质。而大麻素也因其对CB1和CB2受体不可避免的的影响而被发现。

花生四烯乙醇胺已经被证实会影响实验鼠的工作记忆。[10]而现在的研究正在探讨大麻素作用对人类行为的影响,例如:在进食和睡眠的模式,以及疼痛减轻。花生四烯乙醇胺也对早期胚胎胚囊着床在子宫时有重要影响。因此大麻素,例如:Δ9-THC,可能在人妊娠的早期阶段影响其过程。[11]花生四烯乙醇胺在血浆中的高峰期一般发生在排卵期,并与雌二醇促性腺激素呈现正相关,这表明了以上这些物质可能参与了对花生四烯乙醇胺的调节。[12]而后,花生四烯乙醇胺曾被提议用来作为不孕症的生物标志物,但迄今为止在临床上尚无任何预测值。[13]

花生四烯乙醇胺在摄食行为中扮演着调节的角色,而神经作用的行为以及产生愉悦的感受也受其影响。此外,将花生四烯乙醇胺直接注入大鼠的前脑正向强化刺激相关区域伏隔核时,会增强大鼠对于所摄取蔗糖的愉悦感,并且会增进食物的摄入量。

在一项研究中,运动的急性有益效果似乎在实验鼠中也由花生四烯乙醇胺调节。[14]花生四烯乙醇胺也是一类酰胺前体的生理活性物质的先驱。

在1998年发表的一篇研究中也曾经提到花生四烯乙醇抑制某些人类乳腺癌细胞系的增殖。[15]该现象随后在2007年的另一项研究中被再次证实。[16]

在1996年,研究人员发现巧克力中含有花生四烯乙醇胺。他们也发现,有两种物质(N-oleoylethanolamine 和 N-linoleoylethanolamine)会模仿花生四烯乙醇胺带来的影响。[17]

合成与降解

人体可以由N-花生四烯酰磷脂酰乙醇胺(NAPE)合成花生四烯乙醇胺,而N-花生四烯酰磷脂酰乙醇胺(NAPE)本身是透过N-酰基转移酶,将花生四烯酸从卵磷脂转移至脑磷脂上的游离胺上。[18][19] 花生四烯乙醇胺由NAPE的合成可以透过多种途径达成,包括酵素的参与,例如磷脂酶A2、磷脂酶C和NAPE-PLD[5]。 内源性花生四烯乙醇胺并不常存在且其半生期非常短,因为脂肪酸酰胺水解酶(FAAH)的作用,会将其分解成游离的花生四烯酸和乙醇胺。与仔猪相关的研究表明,花生四烯酸及其它必需脂肪酸的摄入量会影响其脑部花生四烯乙醇胺和其他内源性大麻素的量[20]。而被以高脂肪饮食饲养的小鼠,其肝脏中的花生四烯乙醇胺的量会增加,同时也会增进脂肪的生成[21]。这说明了至少在啮齿动物中,花生四烯乙醇胺对于肥胖的发展会产生影响。 对乙酰氨基酚(acetaminophen)在代谢上,会透过FAAH,去和花生四烯酸结合而形成AM404[22]。此对乙酰氨基酚(acetaminophen)的代谢产物,对于TRPV1香草素受体,是一种强促效剂,但对于CB1和CB2受体,为弱促效剂,而对于花生四烯乙醇胺而言,为再吸收抑制剂。因此,身体和大脑中花生四烯乙醇胺的量提升。以此方式,对乙酰氨基酚(acetaminophen)可作为仿大麻素代谢产物的前体药物。这个作用可以使得对乙酰氨基酚(acetaminophen)的镇痛作用受到部分或全部的影响[23][24] 。花生四烯乙醇胺和其姊妹分子2-花生四烯酸甘油酯的运输蛋白已经被鉴定确认了,包括热休克蛋白(Hsp70s)和脂肪酸结合蛋白(FABPs)。[25][26]

药用价值

英国皇家化学学会曾表示,有研究显示AM1172有可能被开发成药物,可以提升大脑的花生四烯乙醇胺含量,因而能够用来治疗焦虑以及忧郁。[27]

参见

参考文献

  1. ^ 唐双奇; 陆阳. 内源性大麻素—生物合成、信号转导及生物降解. 中国药理学通报. 2013, 29 (08): 1037–1041. 
  2. ^ 封玉玲; 陈杰; 封海涛; 董志; 李晶. 脑脊液中花生四烯酸乙醇胺浓度变化与精神分裂症的病理机制. 中国医院药学杂志. 2014, 34 (01): 8–11. doi:10.13286/j.cnki.chinhosppharmacyj.2014.01.03. 
  3. ^ Devane, W.; Hanus, L; Breuer, A; Pertwee, R.; Stevenson, L.; Griffin, G; Gibson, D; Mandelbaum, A; Etinger, A; Mechoulam, R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 18 December 1992, 258 (5090): 1946–1949. doi:10.1126/science.1470919. 
  4. ^ Mechoulam R, Fride E. The unpaved road to the endogenous brain cannabinoid ligands, the anandamides. Pertwee RG (编). Cannabinoid receptors. Boston: Academic Press. 1995: 233–258. ISBN 0-12-551460-3. 
  5. ^ 5.0 5.1 Wang, Jun; Ueda, Natsuo. Biology of endocannabinoid synthesis system. Prostaglandins & Other Lipid Mediators (Elsevier BV). 2009, 89 (3-4): 112–119. ISSN 1098-8823. doi:10.1016/j.prostaglandins.2008.12.002. 
  6. ^ Gaetani, Silvana; Dipasquale, Pasqua; Romano, Adele; Righetti, Laura; Cassano, Tommaso; Piomelli, Daniele; Cuomo, Vincenzo. The endocannabinoid system as a target for novel anxiolytic and antidepressant drugs.. International review of neurobiology. 2009, 85: 57–72. PMID 19607961. doi:10.1016/S0074-7742(09)85005-8. 
  7. ^ Hwang, Jeannie; Adamson, Crista; Butler, David; Janero, David R.; Makriyannis, Alexandros; Bahr, Ben A. Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic modality. Life Sciences. April 2010, 86 (15-16): 615–623. doi:10.1016/j.lfs.2009.06.003. 
  8. ^ Mechoulam, WA; Hanus L; Breuer A; Pertwee RG; Stevenson LA; Griffin G; Gibson D; Mandelbaum A; Etinger A; Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. December 1992, 258 (5090): 1946–9 [2015-01-18]. Bibcode:1992Sci...258.1946D. PMID 1470919. doi:10.1126/science.1470919. (原始内容存档于2014-08-10). 
  9. ^ Pacher, P. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews (American Society for Pharmacology & Experimental Therapeutics (ASPET)). 2006-09-01, 58 (3): 389–462. ISSN 0031-6997. doi:10.1124/pr.58.3.2. 
  10. ^ allet PE, Beninger RJ; Beninger. The endogenous cannabinoid receptor agonist anandamide impairs memory in rats. Behavioural Pharmacology. 1996, 7 (3): 276–284 [2015-01-18]. doi:10.1097/00008877-199605000-00008. (原始内容存档于2019-12-09). 
  11. ^ Piomelli D. THC: moderation during implantation. Nat. Med. January 2004, 10 (1): 19–20. PMID 14702623. doi:10.1038/nm0104-19. 
  12. ^ El-Talatini MR, Taylor AH, Konje JC; Taylor; Konje. The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle. Fertil. Steril. April 2010, 93 (6): 1989–96. PMID 19200965. doi:10.1016/j.fertnstert.2008.12.033. 
  13. ^ Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M. Endocannabinoids as biomarkers of human reproduction. Human Reproduction Update. 2014, 20 (4): 501–516. ISSN 1355-4786. PMID 24516083. doi:10.1093/humupd/dmu004. 
  14. ^ Fuss, Johannes; Steinle, Jörg; Bindila, Laura; Auer, Matthias K.; Kirchherr, Hartmut; Lutz, Beat; Gass, Peter. A runner’s high depends on cannabinoid receptors in mice. Proceedings of the National Academy of Sciences. 2015-10-20, 112 (42) [2024-01-26]. ISSN 0027-8424. doi:10.1073/pnas.1514996112. (原始内容存档于2023-02-19) (英语). 
  15. ^ De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences. 7 July 1998, 95 (14): 8375–8380. PMID 9653194. doi:10.1073/pnas.95.14.8375. 
  16. ^ De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo. The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation. Proceedings of the National Academy of Sciences. 1998-07-07, 95 (14) [2024-01-26]. ISSN 0027-8424. doi:10.1073/pnas.95.14.8375. (原始内容存档于2024-01-26) (英语). 
  17. ^ di Tomaso E, Beltramo M, Piomelli D.; Beltramo; Piomelli. Brain cannabinoids in chocolate. Nature. Aug 1996, 382 (6593): 677–8. PMID 8751435. doi:10.1038/382677a0. 
  18. ^ Natarajan V, Reddy PV, Schmid PC, Schmid HH; Reddy; Schmid; Schmid. N-Acylation of ethanolamine phospholipids in canine myocardium. Biochim. Biophys. Acta. August 1982, 712 (2): 342–55. PMID 7126608. doi:10.1016/0005-2760(82)90352-6. 
  19. ^ Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli. Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain. J. Neurosci. February 1997, 17 (4): 1226–42. PMID 9006968. 
  20. ^ Berger, Alvin; Crozier, Gayle; Bisogno, Tiziana; Cavaliere, Paolo; Innis, Sheila; Di Marzo, Vincenzo. Anandamide and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets. Proceedings of the National Academy of Sciences. 15 May 2001, 98 (11): 6402–6406. PMID 11353819. doi:10.1073/pnas.101119098. 
  21. ^ Osei-Hyiaman, Douglas; DePetrillo, Michael; Pacher, Pál; Liu, Jie; Radaeva, Svetlana; Bátkai, Sándor; Harvey-White, Judith; Mackie, Ken; Offertáler, László; Wang, Lei; Kunos, George. Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. Journal of Clinical Investigation. 2 May 2005, 115 (5): 1298–1305. PMID 15864349. doi:10.1172/JCI23057. 
  22. ^ Högestätt, Edward D.; Jönsson, Bo A. G.; Ermund, Anna; Andersson, David A.; Björk, Henrik; Alexander, Jessica P.; Cravatt, Benjamin F.; Basbaum, Allan I.; Zygmunt, Peter M. Conversion of Acetaminophen to the BioactiveN-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System. Journal of Biological Chemistry (American Society for Biochemistry & Molecular Biology (ASBMB)). 2005-06-29, 280 (36): 31405–31412. ISSN 0021-9258. doi:10.1074/jbc.m501489200. 
  23. ^ Bertolini, Alfio; Ferrari, Anna; Ottani, Alessandra; Guerzoni, Simona; Tacchi, Raffaella; Leone, Sheila. Paracetamol: New Vistas of an Old Drug. CNS Drug Reviews. September 2006, 12 (3-4): 250–275. PMID 17227290. doi:10.1111/j.1527-3458.2006.00250.x. 
  24. ^ Sinning, Christian; Watzer, Bernhard; Coste, Ovidiu; Nüsing, Rolf M.; Ott, Ingo; Ligresti, Alessia; Marzo, Vincenzo Di; Imming, Peter. New Analgesics Synthetically Derived from the Paracetamol Metabolite-(4-Hydroxyphenyl)-(5,8,11,14)-icosatetra-5,8,11,14-enamide. Journal of Medicinal Chemistry. 25 December 2008, 51 (24): 7800–7805. PMID 19053765. doi:10.1021/jm800807k. 
  25. ^ Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. Identification of intracellular carriers for the endocannabinoid anandamide. Proceedings of the National Academy of Sciences of the United States of America. 2009, 106 (15): 6375–6380. PMC 2669397可免费查阅. PMID 19307565. doi:10.1073/pnas.0901515106. 
  26. ^ Oddi, S.; Fezza, F.; Pasquariello, N.; D'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agro, A.; Maccarrone, M. Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins. Chemistry & Biology. 2009, 16 (6): 624–632. PMID 19481477. doi:10.1016/j.chembiol.2009.05.004. 
  27. ^ Evans, Jon. Easing anxiety with anandamide. Chemistry World. July 2004 [2015-01-18]. (原始内容存档于2014-12-24). 

外部链接