Anandamide

Last updated

Contents

Anandamide
Anandamide skeletal.svg
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
KEGG
MeSH Anandamide
PubChem CID
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- Yes check.svgY
    Key: LGEQQWMQCRIYKG-DOFZRALJSA-N Yes check.svgY
  • 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).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

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 (आनन्द), 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 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

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

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

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

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

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

Biosynthesis

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] with other key enzymes yet to be identified. [23]

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. [24]

Metabolism

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. [25] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis. [26] 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. [27] 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. [28] [29]

Black pepper contains the alkaloid guineesine, which is an anandamide reuptake inhibitor. It may therefore increase anandamide's physiological effects. [30]

Transport

Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs). [31] [32]

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. [33]

See also

References

  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.
  3. ↑ di Tomaso E, Beltramo M, Piomelli D (August 1996). "Brain cannabinoids in chocolate". Nature. 382 (6593): 677–678. Bibcode:1996Natur.382..677D. doi:10.1038/382677a0. PMID   8751435.
  4. 1 2 Wang J, Ueda N (September 2009). "Biology of endocannabinoid synthesis system". secondary. Prostaglandins & Other Lipid Mediators. 89 (3–4): 112–119. doi:10.1016/j.prostaglandins.2008.12.002. PMID   19126434.
  5. ↑ Gaetani S, Dipasquale P, Romano A, Righetti L, Cassano T, Piomelli D, et al. (2009). The Endocannabinoid System as a Target for Novel Anxiolytic and Antidepressant Drugs. International Review of Neurobiology. Vol. 85. pp. 57–72. doi:10.1016/S0074-7742(09)85005-8. ISBN   978-0-12-374893-5. PMID   19607961.
  6. ↑ Fazio D, Criscuolo E, Piccoli A, Barboni B, Fezza F, Maccarrone M (July 2020). "Advances in the discovery of fatty acid amide hydrolase inhibitors: what does the future hold?". Expert Opinion on Drug Discovery. 15 (7): 765–778. doi:10.1080/17460441.2020.1751118. PMID   32292082.
  7. ↑ 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.
  8. ↑ Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G (March 2019). "Brain activity of anandamide: a rewarding bliss?". Acta Pharmacologica Sinica. 40 (3): 309–323. doi:10.1038/s41401-018-0075-x. PMC   6460372 . PMID   30050084.
  9. ↑ Pacher P, Bátkai S, Kunos G (September 2006). "The endocannabinoid system as an emerging target of pharmacotherapy". Pharmacological Reviews. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC   2241751 . PMID   16968947.
  10. ↑ Piomelli D (January 2004). "THC: moderation during implantation". Nature Medicine. 10 (1): 19–20. doi:10.1038/nm0104-19. PMID   14702623. S2CID   29207064.
  11. ↑ El-Talatini MR, Taylor AH, Konje JC (April 2010). "The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle". Fertility and Sterility. 93 (6): 1989–1996. doi: 10.1016/j.fertnstert.2008.12.033 . PMID   19200965.
  12. ↑ Rapino C, Battista N, Bari M, Maccarrone M (2014). "Endocannabinoids as biomarkers of human reproduction". Human Reproduction Update. 20 (4): 501–516. doi: 10.1093/humupd/dmu004 . PMID   24516083.
  13. ↑ Crane NA, Schuster RM, Fusar-Poli P, Gonzalez R (June 2013). "Effects of cannabis on neurocognitive functioning: recent advances, neurodevelopmental influences, and sex differences". Neuropsychology Review. 23 (2): 117–137. doi:10.1007/s11065-012-9222-1. PMC   3593817 . PMID   23129391.
  14. ↑ Fantegrossi WE, Wilson CD, Berquist MD (February 2018). "Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin, and glutamate systems". Drug Metabolism Reviews. 50 (1): 65–73. doi:10.1080/03602532.2018.1428343. PMC   6419500 . PMID   29385930.
  15. ↑ Schulz P, Hryhorowicz S, Rychter AM, Zawada A, Słomski R, Dobrowolska A, et al. (January 2021). "What Role Does the Endocannabinoid System Play in the Pathogenesis of Obesity?". Nutrients. 13 (2): 373. doi: 10.3390/nu13020373 . PMC   7911032 . PMID   33530406.
  16. ↑ Kamprath K, Plendl W, Marsicano G, Deussing JM, Wurst W, Lutz B, et al. (March 2009). "Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin-releasing hormone signaling". Genes, Brain and Behavior. 8 (2): 203–211. doi: 10.1111/j.1601-183X.2008.00463.x . PMID   19077175. S2CID   21922344.
  17. ↑ Gruden G, Barutta F, Kunos G, Pacher P (April 2016). "Role of the endocannabinoid system in diabetes and diabetic complications". British Journal of Pharmacology. 173 (7): 1116–1127. doi:10.1111/bph.13226. PMC   4941127 . PMID   26076890.
  18. ↑ Kimberly WT, O'Sullivan JF, Nath AK, Keyes M, Shi X, Larson MG, et al. (May 2017). "Metabolite profiling identifies anandamide as a biomarker of nonalcoholic steatohepatitis". JCI Insight. 2 (9): e92989. doi:10.1172/jci.insight.92989. PMC   5414569 . PMID   28469090.
  19. ↑ McCormick E, Nussbaum D, Draganski A, Garcia S, Desai S, Friedman J, et al. (2023). "43357 Encapsulated anandamide: A promising therapy for cutaneous lupus erythematosus". Journal of the American Academy of Dermatology. 89 (3): AB1. doi:10.1016/j.jaad.2023.07.014.
  20. ↑ "A New Treatment in a New Package for Cutaneous Lupus Erythematosus". 19 March 2023.
  21. ↑ Natarajan V, Reddy PV, Schmid PC, Schmid HH (August 1982). "N-Acylation of ethanolamine phospholipids in canine myocardium". Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism. 712 (2): 342–355. doi:10.1016/0005-2760(82)90352-6. PMID   7126608.
  22. ↑ Cadas H, di Tomaso E, Piomelli D (February 1997). "Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain". The Journal of Neuroscience. 17 (4): 1226–1242. doi: 10.1523/JNEUROSCI.17-04-01226.1997 . PMC   6793739 . PMID   9006968.
  23. ↑ Maccarrone M (2017-05-29). "Metabolism of the Endocannabinoid Anandamide: Open Questions after 25 Years". Frontiers in Molecular Neuroscience. 10. doi: 10.3389/fnmol.2017.00166 . ISSN   1662-5099. PMC   5447297 . PMID   28611591.
  24. ↑ Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, et al. (March 2015). "Structure of human N-acylphosphatidylethanolamine-hydrolyzing phospholipase D: regulation of fatty acid ethanolamide biosynthesis by bile acids". Structure. 23 (3): 598–604. doi:10.1016/j.str.2014.12.018. PMC   4351732 . PMID   25684574.
  25. ↑ 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.
  26. ↑ Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. (May 2005). "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". The Journal of Clinical Investigation. 115 (5): 1298–1305. doi:10.1172/JCI23057. PMC   1087161 . PMID   15864349.
  27. ↑ 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.
  28. ↑ Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S (September 2006). "Paracetamol: new vistas of an old drug". CNS Drug Reviews. 12 (3–4): 250–275. doi:10.1111/j.1527-3458.2006.00250.x. PMC   6506194 . PMID   17227290.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.