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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) .
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
References
Notes
^ 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 .
General references
Phytocannabinoids (
comparison )
Cannabibutols Cannabichromenes Cannabicyclols Cannabidiols Cannabielsoins Cannabigerols Cannabiphorols Cannabinols Cannabitriols Cannabivarins Delta-8-tetrahydrocannabinols Delta-9-tetrahydrocannabinols Delta-10-Tetrahydrocannabinols Miscellaneous cannabinoids Active metabolites
Endocannabinoids
Synthetic cannabinoid receptor agonists / neocannabinoids
Classical cannabinoids (dibenzopyrans) Non-classical cannabinoids Adamantoylindoles Benzimidazoles Benzoylindoles Cyclohexylphenols
Eicosanoids
Hydrocarbons Indazole carboxamides Indazole-3- carboxamides Indole-3-carboxamides Indole-3-carboxylates Naphthoylindazoles
Naphthoylindoles Naphthoylpyrroles Naphthylmethylindenes Naphthylmethylindoles Phenylacetylindoles Pyrazolecarboxamides Pyrrolobenzoxazines Quinolinyl esters Tetramethylcyclo- propanoylindazoles Tetramethylcyclo- propanoylindoles Tetramethylcyclo- propylindoles Others
Allosteric
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Receptor (
ligands )
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Agonists(abridged,
full list ) Inverse agonists Antagonists
CB2 Tooltip Cannabinoid receptor type 2
Agonists
2-AG
2-AGE (noladin ether)
3,3'-Diindolylmethane
4-O-Methylhonokiol
α-Amyrin · β-Amyrin
A-796,260
A-834,735
A-836,339
AM-1172
AM-1221
AM-1235
AM-1241
AM-2232
Anandamide
AZ-11713908
Cannabinol
Caryophyllene
CB-13
CBS-0550
CP 55,940
GW-405,833 (L-768,242)
GW-842,166X
HU-308
JTE 7-31
JWH-007
JWH-015
JWH-018
JWH-73
JWH-133
L-759,633
L-759,656
Lenabasum (anabasum)
Magnolol
MDA-19
Nabitan
NADA
Olorinab (APD-371)
PF-03550096
S-444,823
SER-601
Serinolamide A
UR-144
Tedalinab
THC (dronabinol)
THCV
Tetrahydromagnolol
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Antagonists
NAGly (
GPR18 )
GPR55
GPR119
Transporter (
modulators )
eCBTs Tooltip Endocannabinoid transporter
Enzyme (
modulators )
Others
Others:
2-PG (directly potentiates activity of 2-AG at CB1 receptor)
ARN-272 (FAAH-like anandamide transporter inhibitor)
Receptor (
ligands )
GlyR Tooltip Glycine receptor
Positive modulators:
Alcohols (e.g.,
brometone ,
chlorobutanol (chloretone) ,
ethanol (alcohol) ,
tert -butanol (2M2P) ,
tribromoethanol ,
trichloroethanol ,
trifluoroethanol )
Alkylbenzene sulfonate
Anandamide
Barbiturates (e.g.,
pentobarbital ,
sodium thiopental )
Chlormethiazole
D12-116
Dihydropyridines (e.g.,
nicardipine )
Etomidate
Ginseng constituents (e.g.,
ginsenosides (e.g.,
ginsenoside-Rf ))
Glutamic acid (glutamate)
Ivermectin
Ketamine
Neuroactive steroids (e.g.,
alfaxolone ,
pregnenolone (eltanolone) ,
pregnenolone acetate ,
minaxolone ,
ORG-20599 )
Nitrous oxide
Penicillin G
Propofol
Tamoxifen
Tetrahydrocannabinol
Triclofos
Tropeines (e.g.,
atropine ,
bemesetron ,
cocaine ,
LY-278584 ,
tropisetron ,
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Volatiles /
gases (e.g.,
chloral hydrate ,
chloroform ,
desflurane ,
diethyl ether (ether) ,
enflurane ,
halothane ,
isoflurane ,
methoxyflurane ,
sevoflurane ,
toluene ,
trichloroethane (methyl chloroform) ,
trichloroethylene )
Xenon
Zinc
Antagonists:
2-Aminostrychnine
2-Nitrostrychnine
4-Phenyl-4-formyl-N-methylpiperidine
αEMBTL
Bicuculline
Brucine
Cacotheline
Caffeine
Colchicine
Colubrine
Cyanotriphenylborate
Dendrobine
Diaboline
Endocannabinoids (e.g.,
2-AG ,
anandamide (AEA) )
Gaboxadol (THIP)
Gelsemine
iso-THAZ
Isobutyric acid
Isonipecotic acid
Isostrychnine
Laudanosine
N-Methylbicuculline
N-Methylstrychnine
N,N-Dimethylmuscimol
Nipecotic acid
Pitrazepin
Pseudostrychnine
Quinolines (e.g.,
4-hydroxyquinoline ,
4-hydroxyquinoline-3-carboxylic acid ,
5,7-CIQA ,
7-CIQ ,
7-TFQ ,
7-TFQA )
RU-5135
Sinomenine
Strychnine
Thiocolchicoside
Tutin
Negative modulators:
Amiloride
Benzodiazepines (e.g.,
bromazepam ,
clonazepam ,
diazepam ,
flunitrazepam ,
flurazepam )
Corymine
Cyanotriphenylborate
Daidzein
Dihydropyridines (e.g.,
nicardipine ,
nifedipine ,
nitrendipine )
Furosemide
Genistein
Ginkgo constituents (e.g.,
bilobalide ,
ginkgolides (e.g.,
ginkgolide A ,
ginkgolide B ,
ginkgolide C ,
ginkgolide J ,
ginkgolide M ))
Imipramine
NBQX
Neuroactive steroids (e.g.,
3α-androsterone sulfate ,
3β-androsterone sulfate ,
deoxycorticosterone ,
DHEA sulfate ,
pregnenolone sulfate ,
progesterone )
Opioids (e.g.,
codeine ,
dextromethorphan ,
dextrorphan ,
levomethadone ,
levorphanol ,
morphine ,
oripavine ,
pethidine ,
thebaine )
Picrotoxin (i.e.,
picrotin and
picrotoxinin )
PMBA
Riluzole
Tropeines (e.g.,
bemesetron ,
LY-278584 ,
tropisetron ,
zatosetron )
Verapamil
Zinc
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Transporter (
blockers )
GlyT1 Tooltip Glycine transporter 1
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