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Anandamide

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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 (ANA), also known as N-arachidonoylethanolamine (AEA), an N-acylethanolamine (NAE), is a fatty acid neurotransmitter. Anandamide was the first endocannabinoid to be discovered: it participates in the body's endocannabinoid system by binding to cannabinoid receptors, the same receptors that the psychoactive compound THC in cannabis acts on. Anandamide is found in nearly all tissues in a wide range of animals.[1][2] Anandamide has also been found in plants, including small amounts in chocolate.[3] The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.[1][4]

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.[5] 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.[6][7]

Anandamide is also being explored for its role in diabetic neuropathy/neuropathy, as cannabinoids as well as exogenous or endogenous anandamide, demonstrate broad-spectrum antinociceptive properties in a model of painful diabetic neuropathy, mediated through peripheral activation of both cannabinoid receptors, i.e. CB1 and CB2,[8][9] beside involvement of transient receptor vanilloid type-1 (TRPV1) channels in the pain modulation, as endovanilloid signalling modulates local pain,[10] as well as in reduction of inflammation associated with renal injury.[11]

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.[12] 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.[13] 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.[14] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[15]

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.[16] The binding relationship of anandamide and the CB1/CB2 may affect neurotransmission of dopamine, serotonin, GABA, and glutamate.[17]

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.[18]

Cortical glutamatergic transmission may be modulated by endocannabinoids during stress and fear habituation.[19]

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.[20] Elevated anandamide levels are found in people with nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and liver fibrosis.[21]

Synthesis and degradation

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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.[22][23] 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).[5]

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]

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 (called acetaminophen in the US and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404.[27] 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.[28][29]

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

It is found that anandamide prefers cholesterol and ceramide more than other membrane lipids, and cholesterol can behave as a binding partner for it, and following an initial interaction mediated by the establishment of a hydrogen bond, the endocannabinoid is attracted towards the membrane interior, where it forms a molecular complex with cholesterol after a functional conformation adaptation to the apolar membrane milieu, and from there, the complex is further directed to the cannabinoid receptor (CB1) and out.[32]

See also

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References

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  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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