2-Arachidonoylglycerol
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
ChEBI
ChEMBL
ChemSpider
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-
Y Key: RCRCTBLIHCHWDZ-DOFZRALJSA-N
Y 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
C 23 H 38 O 4
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).
Chemical compound
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) .
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]
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]
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]
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]
^ 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 .
^ a b c d 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ The Endocannabinoid-CB Receptor System: Importance for development and in pediatric disease Neuroendocrinology Letters Nos.1/2, Feb-Apr Vol.25, 2004.
^ 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.
^ 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.
^ Sugiura T, Itoh K, Waku K, Hanahan DJ (1994) Proceedings of Japanese conference on the Biochemistry of Lipids, 36, 71-74 (in Japanese)
^ 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 .
^ 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 .
^ Marzo, Vincenzo Di (2004). Cannabinoids (Neuroscience Intelligence Unit) (1st ed.). Georgetown, Texas : Springer . pp. 99, 181. ISBN 978-0-306-48228-1 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
^ 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 .
Phytocannabinoids (comparison )
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Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor)
ARN-272 (FAAH-like anandamide transporter inhibitor)
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Corymine
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