Anandamide

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Anandamide
Anandamide skeletal.svg
Anandamide.gif
Names
IUPAC name
(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
Other names
N-arachidonoylethanolamine
arachidonoylethanolamide
Identifiers
94421-68-8 N
ChEBI CHEBI:2700 YesY
ChEMBL ChEMBL15848 YesY
ChemSpider 4445241 YesY
2364
Jmol 3D model Interactive image
Interactive image
MeSH Anandamide
PubChem 5281969
UNII UR5G69TJKH YesY
Properties
C22H37NO2
Molar mass 347.53 g/mol
Vapor pressure {{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Anandamide, also known as N-arachidonoylethanolamine or AEA, is an essential fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid) an essential ω-6 polyunsaturated fatty acid. The name is taken from the Sanskrit word ananda, which means "joy, bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoyl phosphatidylethanolamine 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]

History

Anandamide was isolated and its structure first described in 1992 by W. A. Devane, Lumír Hanuš et al. who were working in a team led by Raphael Mechoulam at the Hebrew University of Jerusalem.[1]

Physiological functions

Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[6] The latter are mainly involved in functions of the immune 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 impair working memory in rats.[7] 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 influence processes during the earliest stages of human pregnancy.[8] Peak plasma anandamide occurs at ovulation and positively correlates with peak estradiol and gonadotrophin levels, suggesting that these may be involved in the regulation of AEA (anandamide) levels.[9] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[10]

Anandamide plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. 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.[6][11]

A study published in 1998 shows that anandamide inhibits human breast cancer cell proliferation.[12] Some studies have linked anandamide release as a mechanism of analgesic effects induced by exercise, particularly by running.[13]

In 1996, researchers discovered anandamide in chocolate. They also detected the presence of two substances that might mimic the effects of anandamide, N-oleoylethanolamine and N-linoleoylethanolamine.[14]

Additionally, in 2014 researchers had shown the presence of anandamide and other endocannabinoids in the model organism Drosophila melanogaster (fruit fly), which had previously been unknown, as earlier research had suggested that insects would be incapable of producing these molecules due to a lack of the requisite biochemistry.[15][16]

Synthesis and degradation

The human body synthesizes anandamide from N-arachidonoyl phosphatidylethanolamine (NAPE), which is itself made by transferring arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[17][18] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.[3]

The crystal structure of NAPE-PLD in complex with phosphatidylethanolamine and deoxycholate shows how the cannabinoid anandamide is generated from membrane N-Acylphosphatidylethanolamines (NAPEs), and reveals that bile acids - which are mainly involved in the adsorption of lipids in the small intestine - modulate its biogenesis.[19] These results demonstrate how the production of the endocannabinoid anandamide and other lipid amides, is directly associated with fat digestion.[19]

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.[20] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[21] 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.[22] 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. As a result, 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.[23][24]

There have been identified transport proteins for anandamide and its sister molecule 2-arachidonoylglycerol. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[25][26]

Medical benefits

The Royal Society of Chemistry have stated that research indicates that AM1172 could potentially be developed into a drug that would increase the brain's anandamide levels to help treat anxiety and depression.[27]

See also

References

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  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.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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  13. http://www.harford.de/arne/articles/NeuroReport.pdf
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  18. Cadas H, di Tomaso E, Piomelli D; Di Tomaso; Piomelli (February 1997). "Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain". J. Neurosci. 17 (4): 1226–42. PMID 9006968. <templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>
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  27. Evans, Jon (July 2004). "Easing anxiety with anandamide". Chemistry World.<templatestyles src="Module:Citation/CS1/styles.css"></templatestyles>

External links