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Anandamide
Anandamide skeletal.svg
IUPAC name
Other names N-arachidonoylethanolamine
arachidonoylethanolamide
Identifiers
CAS number 94421-68-8
PubChem 5281969
MeSH Anandamide
SMILES
InChI
InChI key LGEQQWMQCRIYKG-DOFZRALJBA
ChemSpider ID 4445241
Properties
Molecular formula C22H37NO2
Molar mass 347.53 g/mol
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Anandamide, also known as N-arachidonoylethanolamine or AEA, is an endogenous cannabinoid neurotransmitter found in animal and human organs, especially in the brain. It was isolated and its structure was first described by Czech analytical chemist Lumír Ondřej Hanuš and American molecular pharmacologist William Anthony Devane in the Laboratory of Raphael Mechoulam, at the Hebrew University in Jerusalem, Israel in 1992. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoylphosphatidylethanolamine by multiple pathways.[3] It is degraded primarily by the fatty acid amide hydrolase (FAAH) enzyme which converts anandamide into ethanolamine and arachidonic acid. As such, inhibitors of FAAH lead to elevated anandamide levels and are being pursued for therapeutic use.[4][5]

Contents

Physiological functions

Anandamide's effects can be either central, in the brain, or peripheral, in other parts of the body. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery. The latter are mainly involved in functions of the immune system.

Cannabinoid receptors are part of the largest known family of receptors, the G protein-coupled receptors, which span the cell membrane seven times. The CB1 receptor is one of the most abundant G protein-coupled receptors in the nervous system.

Cannabinoid receptors were originally discovered as being sensitive to Δ9-tetrahydrocannabinol9-THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis. The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors.

Anandamide has been shown to be involved in working memory.[6] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief.

Anandamide is also important for implantation of the early stage embryo in its blastocyst form into the uterus. Therefore cannabinoids such as Δ9-THC might interfere with the earliest stages of human pregnancy.[7]

Anandamide also is important in the regulation of feeding behavior, and the neural generation of motivation and pleasure. Both anandamide and exogenous cannabinoids like THC enhance food intake in animals and humans, an effect that is commonly known as "the munchies". In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[8]

Moreover, anandamide is thought to be an endogenous ligand for vanilloid receptors (which are involved in the transduction of acute and inflammatory pain signals), activating the receptor in a PKC-dependent (protein kinase C-dependent) manner.

A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[9]

Raphael Mechoulam (right), discoverer of psychoactive compound, (-)-trans-delta-9-tetrahydrocannabinol, from Cannabis sativa L. (1964) and Lumír Ondřej Hanuš (left), discoverer of endogenous ligand, anandamide, from brain (1992). Both compounds bind to the cannabinoid receptors in the brain.

Endogenous and dietary sources

Anandamide occurs in minute quantities in sea urchin roe.[10] Anandamide was reported to be present in chocolate[11] in small quantities that were assumed not to have pharmacological or psychoactive effects.[12] However, a later study failed to repeat these findings and did not detect anandamide in chocolate.[13]

Synthesis and degradation

The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NarPE)), which is itself made by transferring arachidonic acid from phosphatidylcholine (PC) to the free amine of phosphatidylethanolamine (PE) through an N-acyltransferase enzyme.[14][15] Anandamide synthesis from NarPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD. [3]

Endogenous anandamide is present at very low levels and has a very short half-life due to the action of the enzyme fatty acid amide hydrolase (FAAH) which breaks it down into free arachidonic acid and ethanolamine. Studies of piglets show that dietary levels of arachidonic acid and other essential fatty acids affect the levels of anandamide and other endocannabinoids in the brain.[16] High fat diet feeding in mice increases levels of Anandamide in the liver and increases lipogenesis.[17] This suggests that anandamide may play a role in the development of obesity, at least in rodents.

Paracetamol (or acetaminophen in the U.S.A.) is metabolically combined with arachidonic acid by FAAH to form AM404.[18] This metabolite of paracetamol is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. Subsequently, anandamide levels in the body and brain are elevated. In this fashion, paracetamol acts as a pro-drug for a cannabimimetic metabolite. This action may be partially or fully responsible for the analgesic effects of paracetamol.[19][20]

See also

References

  1. ^ Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science 258 (5090): 1946–9. doi:10.1126/science.1470919. PMID 1470919.  
  2. ^ Mechoulam R, Fride E (1995). "The unpaved road to the endogenous brain cannabinoid ligands, the anandamides". in Pertwee RG. Cannabinoid receptors. Boston: Academic Press. pp. 233–258. ISBN 0-12-551460-3.  
  3. ^ a b Wang, J.; Ueda, N. (2009). "Biology of endocannabinoid synthesis system". Prostaglandins & Other Lipid Mediators 89: 112. doi:10.1016/j.prostaglandins.2008.12.002.   edit
  4. ^ Gaetani, S.; Dipasquale, P.; Romano, A.; Righetti, L.; Cassano, T.; Piomelli, D.; Cuomo, V. (2009). Chapter 5 the Endocannabinoid System as a Target for Novel Anxiolytic and Antidepressant Drugs. 85. pp. 57. doi:10.1016/S0074-7742(09)85005-8.   edit
  5. ^ Hwang, J.; Adamson, C.; Butler, D.; Janero, D. R.; Makriyannis, A.; Bahr, B. A. (2009). "Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic modality". Life Sciences. doi:10.1016/j.lfs.2009.06.003.   edit
  6. ^ allet PE, Beninger RJ (1996). "The endogenous cannabinoid receptor agonist anandamide impairs memory in rats". Behavioural Pharmacology 7 (3): 276–284. http://www.behaviouralpharm.com/pt/re/bpharm/abstract.00008877-199605000-00008.htm.  
  7. ^ Piomelli D (January 2004). "THC: moderation during implantation". Nat. Med. 10 (1): 19–20. doi:10.1038/nm0104-19. PMID 14702623.  
  8. ^ Mahler SV, Smith KS, Berridge KC (November 2007). "Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet reward". Neuropsychopharmacology 32 (11): 2267–78. doi:10.1038/sj.npp.1301376. PMID 17406653.  
  9. ^ De Petrocellis L, Melck D, Palmisano A, Bisogno T, Laezza C, Bifulco M, Di Marzo V (July 1998). "The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation". Proc. Natl. Acad. Sci. U.S.A. 95 (14): 8375–80. doi:10.1073/pnas.95.14.8375. PMID 9653194.  
  10. ^ Bisogno T, Ventriglia M, Milone A, Mosca M, Cimino G, Di Marzo V (April 1997). "Occurrence and metabolism of anandamide and related acyl-ethanolamides in ovaries of the sea urchin Paracentrotus lividus". Biochim. Biophys. Acta 1345 (3): 338–48. PMID 9150253.  
  11. ^ di Tomaso E, Beltramo M, Piomelli D (August 1996). "Brain cannabinoids in chocolate". Nature 382 (6593): 677–8. doi:10.1038/382677a0. PMID 8751435.  
  12. ^ Di Marzo V, Sepe N, De Petrocellis L, et al. (1998). "Trick or treat from food endocannabinoids?". Nature 396 (6712): 636–7. doi:10.1038/25267. PMID 9872309.  
  13. ^ GC Willi, A Berger, V Di Marzo, T Bisogno, L De (2001). "Lipids in Neural Function: Modulation of Behavior by Oral Administration of Endocannabinoids Found in Foods". Nestle Nutr Workshop Ser Clin Perform Programme 5: 169–84; discussion 185–7. doi:10.1159/000061850. PMID 11510437.  
  14. ^ Natarajan V, Reddy PV, Schmid PC, Schmid HH (August 1982). "N-Acylation of ethanolamine phospholipids in canine myocardium". Biochim. Biophys. Acta 712 (2): 342–55. PMID 7126608.  
  15. ^ Cadas H, di Tomaso E, Piomelli D (February 1997). "Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain". J. Neurosci. 17 (4): 1226–42. PMID 9006968.  
  16. ^ Berger A, Crozier G, Bisogno T, Cavaliere P, Innis S, Di Marzo V (May 2001). "Anandamide and diet: inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets". Proc. Natl. Acad. Sci. U.S.A. 98 (11): 6402–6. doi:10.1073/pnas.101119098. PMID 11353819.  
  17. ^ Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, Harvey-White J, Mackie K, Offertáler L, Wang L, Kunos G (May 2005). "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". J. Clin. Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMID 15864349.  
  18. ^ Högestätt, E. D.; Jönsson, B. A. G.; Ermund, A.; Andersson, D. A.; Björk, H.; Alexander, J. P.; Cravatt, B. F.; Basbaum, A. I. et al. (2005). "Conversion of Acetaminophen to the Bioactive N-Acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System". Journal of Biological Chemistry 280 (36): 31405. doi:10.1074/jbc.M501489200. PMID 15987694.   edit
  19. ^ Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (2006). "Paracetamol: new vistas of an old drug". CNS Drug Rev 12 (3-4): 250–75. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290.  
  20. ^ Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, Di Marzo V, Imming P (December 2008). "New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide". J. Med. Chem. 51 (24): 7800–5. doi:10.1021/jm800807k. PMID 19053765.  

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