2-Arachidonoylglycerol

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2-Arachidonoylglycerol
2-Ara-Gl.svg
2-arachidonoylglycerol 3D BS.png
Names
IUPAC name
2-O-[(5Z,8Z,11Z,14Z)-Icosa-5,8,11,14-tetraenoyl]glycerol
Systematic IUPAC name
1,3-Dihydroxypropan-2-yl (5Z,8Z,11Z,14Z)-icosa-5,8,11,14-tetraenoate
Other names
2-AG, 2-arachidonoylglycerol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C23H38O4/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-23(26)27-22(20-24)21-25/h6-7,9-10,12-13,15-16,22,24-25H,2-5,8,11,14,17-21H2,1H3/b7-6-,10-9-,13-12-,16-15- Yes check.svgY
    Key: RCRCTBLIHCHWDZ-DOFZRALJSA-N Yes check.svgY
  • InChI=1/C23H38O4/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-18-19-23(26)27-22(20-24)21-25/h6-7,9-10,12-13,15-16,22,24-25H,2-5,8,11,14,17-21H2,1H3/b7-6-,10-9-,13-12-,16-15-
    Key: RCRCTBLIHCHWDZ-DOFZRALJBN
  • O=C(OC(CO)CO)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC
Properties
C23H38O4
Molar mass 378.3 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 ?)

2-Arachidonoylglycerol (2-AG) is an endocannabinoid, an endogenous agonist of the CB1 receptor and the primary endogenous ligand for the CB2 receptor. [1] [2] It is an ester formed from the omega-6 fatty acid arachidonic acid and glycerol. It is present at relatively high levels in the central nervous system, with cannabinoid neuromodulatory effects. It has been found in maternal bovine and human milk. [3] The chemical was first described in 1994–1995, although it had been discovered some time before that. The activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL) mediate its formation. [4] 2-AG is synthesized from arachidonic acid-containing diacylglycerol (DAG).

Contents

Occurrence

2-AG, unlike anandamide (another endocannabinoid), is present at relatively high levels in the central nervous system; it is the most abundant molecular species of monoacylglycerol found in mouse and rat brain (~5–10 nmol/g tissue). [2] [5] Detection of 2-AG in brain tissue is complicated by the relative ease of its isomerization to 1-AG during standard lipid extraction conditions. It has been found in maternal bovine as well as human milk. [6] [7] [8]

Discovery

2-AG was discovered by Raphael Mechoulam and his student Shimon Ben-Shabat. [9] 2-AG was a known chemical compound but its occurrence in mammals and its affinity for the cannabinoid receptors were first described in 1994–1995. A research group at Teikyo University reported the affinity of 2-AG for the cannabinoid receptors in 1994–1995, [10] [11] but the isolation of 2-AG in the canine gut was first reported in 1995 by the research group of Raphael Mechoulam at the Hebrew University of Jerusalem, which additionally characterized its pharmacological properties in vivo. [12] 2-Arachidonoylglycerol, next with Anandamide, was the second endocannabinoid discovered. The cannabinoid established the existence of a cannabinoid neuromodulatory system in the nervous system. [13]

Pharmacology

Unlike anandamide, formation of 2-AG is calcium-dependent and is mediated by the activities of phospholipase C (PLC) and diacylglycerol lipase (DAGL). [2] 2-AG acts as a full agonist at the CB1 receptor. [14] At a concentration of 0.3 nM, 2-AG induces a rapid, transient increase in intracellular free calcium in NG108-15 neuroblastoma X glioma cells through a CB1 receptor-dependent mechanism. [2] 2-AG is hydrolyzed in vitro by monoacylglycerol lipase (MAGL), fatty acid amide hydrolase (FAAH), and the uncharacterized serine hydrolase enzymes ABHD2, [15] ABHD6 and ABHD12. [16] The exact contribution of each of these enzymes to the termination of 2-AG signaling in vivo is unknown, though it is estimated that MAGL is responsible for ~85% of this activity in the brain. [17] There have been identified transport proteins for 2-arachidonoylglycerol and anandamide. These include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs). [18] [19]

Biosynthesis

2-Arachidonoylglycerol is synthesized from arachidonic acid-containing diacylglycerol (DAG), which is derived from the increase of inositol phospholipid metabolism by the action of diacylglycerol lipase. The molecule can also be formed from pathways like the hydrolysis derived (by diglyceride) from both phosphatidylcholine (PC) and phosphatidic acid (PAs) by the action of DAG lipase and the hydrolysis of arachidonic acid-containing lysophosphatidic acid by the action of a phosphatase. [20]

See also

Related Research Articles

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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. Anandamide has also been found in plants, including small amounts in chocolate. The name 'anandamide' is taken from the Sanskrit word ananda, which means "joy, bliss, delight", plus amide.

<span class="mw-page-title-main">Cannabinoid</span> Compounds found in cannabis

Cannabinoids are several structural classes of compounds found in the cannabis plant primarily and most animal organisms or as synthetic compounds. The most notable cannabinoid is the phytocannabinoid tetrahydrocannabinol (THC) (delta-9-THC), the primary psychoactive compound in cannabis. Cannabidiol (CBD) is also a major constituent of temperate cannabis plants and a minor constituent in tropical varieties. At least 113 distinct phytocannabinoids have been isolated from cannabis, although only four have been demonstrated to have a biogenetic origin. It was reported in 2020 that phytocannabinoids can be found in other plants such as rhododendron, licorice and liverwort, and earlier in Echinacea.

A fatty acid desaturase is an enzyme that removes two hydrogen atoms from a fatty acid, creating a carbon/carbon double bond. These desaturases are classified as:

The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors (CBRs), and cannabinoid receptor proteins that are expressed throughout the vertebrate central nervous system and peripheral nervous system. The endocannabinoid system remains under preliminary research, but may be involved in regulating physiological and cognitive processes, including fertility, pregnancy, pre- and postnatal development, various activity of immune system, appetite, pain-sensation, mood, and memory, and in mediating the pharmacological effects of cannabis. The ECS plays an important role in multiple aspects of neural functions, including the control of movement and motor coordination, learning and memory, emotion and motivation, addictive-like behavior and pain modulation, among others.

<span class="mw-page-title-main">Monoacylglycerol lipase</span> Class of enzymes

Monoacylglycerol lipase is an enzyme that, in humans, is encoded by the MGLL gene. MAGL is a 33-kDa, membrane-associated member of the serine hydrolase superfamily and contains the classical GXSXG consensus sequence common to most serine hydrolases. The catalytic triad has been identified as Ser122, His269, and Asp239.

<span class="mw-page-title-main">Diacylglycerol lipase</span> Enzyme that breaks down diacylglycerol in many organisms.

Diacylglycerol lipase, also known as DAG lipase, DAGL, or DGL, is an enzyme that catalyzes the hydrolysis of diacylglycerol, releasing a free fatty acid and monoacylglycerol:

diacylglycerol + H2O ⇌ monoacylglycerol + free fatty acid

<span class="mw-page-title-main">Fatty acid amide hydrolase</span>

Fatty acid amide hydrolase or FAAH is a member of the serine hydrolase family of enzymes. It was first shown to break down anandamide (AEA) in 1993. In humans, it is encoded by the gene FAAH. FAAH also regulate the contents of N-acylethanolamine in Dictyostelium discoideum, as they modulate their levels in vivo through the use of a semispecific FAAH inhibitor.

<span class="mw-page-title-main">AM404</span> Active metabolite of paracetamol

AM404, also known as N-arachidonoylphenolamine, is an active metabolite of paracetamol (acetaminophen), responsible for all or part of its analgesic action and anticonvulsant effects. Chemically, it is the amide formed from 4-aminophenol and arachidonic acid.

<span class="mw-page-title-main">2-Arachidonyl glyceryl ether</span> Chemical compound

2-Arachidonyl glyceryl ether is a putative endocannabinoid discovered by Lumír Hanuš and colleagues at the Hebrew University of Jerusalem, Israel. It is an ether formed from the alcohol analog of arachidonic acid and glycerol. Its isolation from porcine brain and its structural elucidation and synthesis were described in 2001.

<span class="mw-page-title-main">GPR55</span> Protein-coding gene in the species Homo sapiens

G protein-coupled receptor 55 also known as GPR55 is a G protein-coupled receptor that in humans is encoded by the GPR55 gene.

<i>N</i>-Arachidonoyl dopamine Chemical compound

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

<span class="mw-page-title-main">JZL184</span> Chemical compound

JZL184 is an irreversible inhibitor for monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading the endocannabinoid 2-arachidonoylglycerol (2-AG). It displays high selectivity for MAGL over other brain serine hydrolases, including the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH), thereby making it a useful tool for studying the effects of endogenous 2-AG signaling, in vivo. Administration of JZL184 to mice was reported to cause dramatic elevation of brain 2-AG leading to several cannabinoid-related behavioral effects.

<span class="mw-page-title-main">Abnormal cannabidiol</span> Synthetic, cannabinoid-like compound

Abnormal cannabidiol (Abn-CBD) is a synthetic regioisomer of cannabidiol, which unlike most other cannabinoids produces vasodilator effects, lowers blood pressure, and induces cell migration, cell proliferation and mitogen-activated protein kinase activation in microglia, but without producing any psychoactive effects.

RVD-Hpα (pepcan-12) is an endogenous neuropeptide found in human and mammalian brain, which was originally proposed to act as a selective agonist for the CB1 cannabinoid receptor. It is a 12-amino acid polypeptide having the amino acid sequence Arg-Val-Asp-Pro-Val-Asn-Phe-Lys-Leu-Leu-Ser-His and is an N-terminal extended form of hemopressin, a 9-AA polypeptide derived from the α1 subunit of hemoglobin which has previously been shown to act as a CB1 inverse agonist. All three polypeptides have been isolated from various mammalian species, with RVD-Hpα being one of the more abundant neuropeptides expressed in mouse brain, and these neuropeptides represent a new avenue for cannabinoid research distinct from the previously known endogenous lipid-derived cannabinoid agonists such as anandamide. Recently it was shown that RVD-Hpα (also called Pepcan-12) is a potent negative allosteric modulator at CB1 receptors, together with other newly described N-terminally extended peptides (pepcans).

<span class="mw-page-title-main">URB602</span> Chemical compound

URB602 is a compound that has been found to inhibit hydrolysis of monoacyl glycerol compounds, such as 2-arachidonoylglycerol (2-AG) and 2-oleoylglycerol (2-OG). It was first described in 2003. A study performed in 2005 found that the compound had specificity for metabolizing 2-AG over anandamide in rat brain presumably by inhibiting the enzyme monoacylglycerol lipase (MAGL), which is the primary metabolic enzyme of 2-AG. However, subsequent studies have shown that URB602 lacks specificity for MAGL inhibition in vitro.

<span class="mw-page-title-main">2-Oleoylglycerol</span> Chemical compound

2-Oleoylglycerol (2OG) is a monoacylglycerol that is found in biologic tissues. Its synthesis is derived from diacylglycerol precursors. It is metabolized to oleic acid and glycerol primarily by the enzyme monoacylglycerol lipase (MAGL). In 2011, 2OG was found to be an endogenous ligand to GPR119. 2OG has been shown to increase glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels following administration to the small intestine.

<span class="mw-page-title-main">JZL195</span> Chemical compound

JZL195 is a potent inhibitor of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively.

IDFP is an organophosphorus compound related to the nerve agent sarin.

<span class="mw-page-title-main">ABHD6</span> Protein-coding gene in the species Homo sapiens

alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.

<span class="mw-page-title-main">ABHD12</span> Protein-coding gene in the species Homo sapiens

alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system. It is responsible for about 9% of brain 2-AG hydrolysis. Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain. ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS).

References

Notes

  1. ↑ Stella N, Schweitzer P, Piomelli D (August 1997). "A second endogenous cannabinoid that modulates long-term potentiation" (PDF). Nature. 388 (6644): 773–8. Bibcode:1997Natur.388..773S. doi: 10.1038/42015 . PMID   9285589. S2CID   4422311.
  2. 1 2 3 4 Sugiura T, Kodaka T, Nakane S, et al. (January 1999). "Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds". The Journal of Biological Chemistry. 274 (5): 2794–801. doi: 10.1074/jbc.274.5.2794 . PMID   9915812.
  3. ↑ Berrendero, F.; Sepe, N.; Ramos, J. A.; Di Marzo, V.; Fernández-Ruiz, J. J. (1999-09-01). "Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period". Synapse (New York, N.Y.). 33 (3): 181–191. doi:10.1002/(SICI)1098-2396(19990901)33:3<181::AID-SYN3>3.0.CO;2-R. ISSN   0887-4476. PMID   10420166. S2CID   39220005.
  4. ↑ Witting, Anke; Walter, Lisa; Wacker, Jennifer; Möller, Thomas; Stella, Nephi (2004-03-02). "P2X7 receptors control 2-arachidonoylglycerol production by microglial cells". Proceedings of the National Academy of Sciences of the United States of America. 101 (9): 3214–3219. Bibcode:2004PNAS..101.3214W. doi: 10.1073/pnas.0306707101 . ISSN   0027-8424. PMC   365769 . PMID   14976257.
  5. ↑ Kondo S, Kondo H, Nakane S, et al. (June 1998). "2-Arachidonoylglycerol, an endogenous cannabinoid receptor agonist: identification as one of the major species of monoacylglycerols in various rat tissues, and evidence for its generation through Ca2+-dependent and -independent mechanisms". FEBS Letters. 429 (2): 152–6. doi: 10.1016/S0014-5793(98)00581-X . PMID   9650580. S2CID   10583431.
  6. ↑ Fride E, Bregman T, Kirkham TC (April 2005). "Endocannabinoids and food intake: newborn suckling and appetite regulation in adulthood" (PDF). Experimental Biology and Medicine. 230 (4): 225–234. doi:10.1177/153537020523000401. PMID   15792943. S2CID   25430588.
  7. ↑ The Endocannabinoid-CB Receptor System: Importance for development and in pediatric disease Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004.
  8. ↑ Cannabinoids and Feeding: The Role of the Endogenous Cannabinoid System as a Trigger for Newborn Suckling Archived 2020-10-01 at the Wayback Machine Women and Cannabis: Medicine, Science, and Sociology, 2002 The Haworth Press, Inc.
  9. ↑ Pizzorno, Lara; MDiv; MA; LMT. "New Developments in Cannabinoid-Based Medicine: An Interview with Dr. Raphael Mechoulam" Archived 2018-06-19 at the Wayback Machine . Longevity Medicine Review. Retrieved 2011-05-26.
  10. ↑ Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese)
  11. ↑ Sugiura T, Kondo S, Sukagawa A, et al. (October 1995). "2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain". Biochem. Biophys. Res. Commun. 215 (1): 89–97. doi:10.1006/bbrc.1995.2437. PMID   7575630.
  12. ↑ Mechoulam R, Ben-Shabat S, Hanuš L, et al. (June 1995). "Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors". Biochemical Pharmacology . 50 (1): 83–90. doi:10.1016/0006-2952(95)00109-D. PMID   7605349.
  13. ↑ Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience Intelligence Unit) (1st ed.). Georgetown, Texas: Springer. pp. 99, 181. ISBN   978-0-306-48228-1.
  14. ↑ Savinainen JR, Järvinen T, Laine K, Laitinen JT (October 2001). "Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes". British Journal of Pharmacology . 134 (3): 664–72. doi:10.1038/sj.bjp.0704297. PMC   1572991 . PMID   11588122.
  15. ↑ Miller, Melissa R.; Mannowetz, Nadja; Iavarone, Anthony T.; Safavi, Rojin; Gracheva, Elena O.; Smith, James F.; Hill, Rose Z.; Bautista, Diana M.; Kirichok, Yuriy; Lishko, Polina V. (2016-04-29). "Unconventional endocannabinoid signaling governs sperm activation via the sex hormone progesterone". Science. 352 (6285): 555–559. Bibcode:2016Sci...352..555M. doi:10.1126/science.aad6887. ISSN   0036-8075. PMC   5373689 . PMID   26989199.
  16. ↑ Blankman JL, Simon GM, Cravatt BF (December 2007). "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & Biology. 14 (12): 1347–56. doi:10.1016/j.chembiol.2007.11.006. PMC   2692834 . PMID   18096503.
  17. ↑ Savinainen, JR; Saario, SM; Laitinen, JT (2012). "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors". Acta Physiologica. 204 (2): 267–76. doi:10.1111/j.1748-1716.2011.02280.x. PMC   3320662 . PMID   21418147.
  18. ↑ Kaczocha, M.; Glaser, S.T.; Deutsch, D.G. (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.
  19. ↑ Oddi, S.; Fezza, F.; Pasquariello, N.; d'Agostino, A.; Catanzaro, G.; De Simone, C.; Rapino, C.; Finazzi-Agrò, A.; MacCarrone, M. (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.
  20. ↑ Murataeva N, Straiker A, Mackie K (Mar 2014). "Parsing the players: 2-arachidonoylglycerol synthesis and degradation in the CNS". Br J Pharmacol. 171 (6): 1379–91. doi:10.1111/bph.12411. PMC   3954479 . PMID   24102242.

General references