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Anandamide

(Redirected from Arachidonoylethanolamide)

Anandamide (ANA), also referred to as N-arachidonoylethanolamine (AEA) is a fatty acid neurotransmitter belonging to the fatty acid derivative group known as N-Acylethanolamine (NAE). Anandamide takes its name from the Sanskrit word ananda, meaning "joy, bliss, delight," plus amide. Anandamide, the first discovered endocannabinoid, engages with the body's endocannabinoid system by binding to the same cannabinoid receptors that THC found in cannabis acts on. Anandamide can be found within tissues in a wide range of animals.[1][2] It has also been found in plants, such as the cacao tree.[3]

Anandamide
Names
Preferred IUPAC name
(5Z,8Z,11Z,14Z)-N-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide
Other names
N-arachidonoylethanolamine
arachidonoylethanolamide
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
MeSH Anandamide
UNII
  • InChI=1S/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- checkY
    Key: LGEQQWMQCRIYKG-DOFZRALJSA-N checkY
  • 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-
    Key: LGEQQWMQCRIYKG-DOFZRALJBA
  • O=C(NCCO)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
  • CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)NCCO
Properties
C22H37NO2
Molar mass 347.53 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Anandamide is derived from the non-oxidative metabolism of arachidonic acid, an essential omega-6 fatty acid. It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[4] 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 possible therapeutic use.[5][6]

Discovery

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Anandamide was discovered by Raphael Mechoulam and fellow coworkers in 1992. This was the first marijuana-like substance produced by the human body to be observed. By examining a pig brain and canine gut, they were able to isolate ANA using mass spectrometry and nuclear magnetic resonance spectroscopy.[7] ANA works within the system of the brain associated with the feeling of reward, and as such, has been the topic of many research studies.[8] Since the 1992 findings, many studies have been completed to examine ANA further, including research on behavioral and molecular effects.

Research

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According to in vitro research, anandamide effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[9] The latter appear to be involved in functions of the immune system. Cannabinoid receptors were originally discovered as sensitive to Δ9-tetrahydrocannabinol (Δ9-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 is under research for its potential involvement in the 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.[10] 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 anandamide levels.[11] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[12]

Behavior

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Both the CB1 and CB2 receptors (the binding site of anandamide) are under research for a possible role in positive and negative interpretation of environment and setting.[13] The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.[14]

Endocannabinoids may disturb homeostasis in several ways: by enhancing hunger sensations, encouraging increased food intake, and shifting energy balance towards energy storage. A resultant decrease in energy expenditure is observed.[15]

Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear habituation.[16]

Obesity and liver disease

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Blockade of CB1 receptors was found to improve lipid resistance and lipid profile in obese subjects with type 2 diabetes.[17] Elevated anandamide levels are found in people with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis.[18]

Topical effects

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The American Academy of Dermatology has named topical anandamide a promising therapy for cutaneous lupus erythematosus.[19][20]

Biosynthesis

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In humans, anandamide is biosynthesized from N-arachidonoyl phosphatidylethanolamine (NAPE). In turn, NAPE arises by transfer of arachidonic acid from lecithin to the free amine of cephalin through an N-acyltransferase enzyme.[21][22] Anandamide synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and N-acetylphosphatidylethanolamine-hydrolysing phospholipase D (NAPE-PLD).[4]

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 absorption of lipids in the small intestine – modulate its biogenesis.[23]

Metabolism

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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.[24] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[25] Anandamide may be relevant to the development of obesity, at least in rodents.

Paracetamol (known as acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404.[26] This metabolite is a potent agonist at the TRPV1 vanilloid receptor, a weak agonist at both CB1 and CB2 receptors, and an inhibitor of anandamide reuptake. Consequently, anandamide levels in the body and brain are elevated. Thus, paracetamol acts as a pro-drug for a cannabimimetic metabolite, which may be partially or fully responsible for its analgesic effects.[27][28]

Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects.[29]

Transport

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Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[30][31]

Anandamide shows a preference for binding to cholesterol and ceramide over other membrane lipids. Cholesterol acts as a binding partner for anandamide. Initially, a hydrogen bond facilitates their interaction. Following this, anandamide is drawn towards the membrane interior, where it forms a molecular complex with cholesterol. This process involves a conformational adaptation of anandamide to the apolar membrane environment. Subsequently, the anandamide-cholesterol complex is directed to the cannabinoid receptor (CB1) and then exits.[32]

See also

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References

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  1. ^ Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. (December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science. 258 (5090): 1946–1949. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919.
  2. ^ Martin BR, Mechoulam R, Razdan RK (July 1999). "Discovery and characterization of endogenous cannabinoids". Life Sciences. 65 (6–7): 573–595. doi:10.1016/S0024-3205(99)00281-7. PMID 10462059.
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  24. ^ 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". Proceedings of the National Academy of Sciences of the United States of America. 98 (11): 6402–6406. Bibcode:2001PNAS...98.6402B. doi:10.1073/pnas.101119098. PMC 33480. PMID 11353819.
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  26. ^ Högestätt ED, Jönsson BA, Ermund A, Andersson DA, Björk H, Alexander JP, et al. (September 2005). "Conversion of acetaminophen to the bioactive N-acylphenolamine AM404 via fatty acid amide hydrolase-dependent arachidonic acid conjugation in the nervous system". The Journal of Biological Chemistry. 280 (36): 31405–31412. doi:10.1074/jbc.M501489200. PMID 15987694.
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  28. ^ Sinning C, Watzer B, Coste O, Nüsing RM, Ott I, Ligresti A, et al. (December 2008). "New analgesics synthetically derived from the paracetamol metabolite N-(4-hydroxyphenyl)-(5Z,8Z,11Z,14Z)-icosatetra-5,8,11,14-enamide". Journal of Medicinal Chemistry. 51 (24): 7800–7805. doi:10.1021/jm800807k. PMID 19053765.
  29. ^ Nicolussi S, Viveros-Paredes JM, Gachet MS, Rau M, Flores-Soto ME, Blunder M, et al. (February 2014). "Guineensine is a novel inhibitor of endocannabinoid uptake showing cannabimimetic behavioral effects in BALB/c mice". Pharmacological Research. 80: 52–65. doi:10.1016/j.phrs.2013.12.010. PMID 24412246.
  30. ^ Kaczocha M, Glaser ST, Deutsch DG (April 2009). "Identification of intracellular carriers for the endocannabinoid anandamide". Proceedings of the National Academy of Sciences of the United States of America. 106 (15): 6375–6380. Bibcode:2009PNAS..106.6375K. doi:10.1073/pnas.0901515106. PMC 2669397. PMID 19307565.
  31. ^ Oddi S, Fezza F, Pasquariello N, D'Agostino A, Catanzaro G, De Simone C, et al. (June 2009). "Molecular identification of albumin and Hsp70 as cytosolic anandamide-binding proteins". Chemistry & Biology. 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.
  32. ^ Di Scala C, Fantini J, Yahi N, Barrantes FJ, Chahinian H (May 2018). "Anandamide Revisited: How Cholesterol and Ceramides Control Receptor-Dependent and Receptor-Independent Signal Transmission Pathways of a Lipid Neurotransmitter". Biomolecules. 8 (2): 31. doi:10.3390/biom8020031. PMC 6022874. PMID 29789479.
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