Editing Cannabinoid (section)

=== Types of endocannabinoid ligands ===

==== Arachidonoylethanolamine (Anandamide or AEA) ====
{{Main|Arachidonoylethanolamine}}
[[Anandamide]] was the first such compound identified as [[arachidonic acid|arachidonoyl]] ethanolamine. The name is derived from ''ananda'', the [[Sanskrit]] word for bliss. It has a pharmacology similar to [[Tetrahydrocannabinol|THC]], although its structure is quite different. Anandamide binds to the central (CB<sub>1</sub>) and, to a lesser extent, peripheral (CB<sub>2</sub>) cannabinoid receptors, where it acts as a partial agonist. Anandamide is about as potent as THC at the CB<sub>1</sub> receptor.<ref name="grotenhermen 2005">{{cite journal | vauthors = Grotenhermen F | title = Cannabinoids | journal = Current Drug Targets. CNS and Neurological Disorders | volume = 4 | issue = 5 | pages = 507–530 | date = October 2005 | pmid = 16266285 | doi = 10.2174/156800705774322111 }}</ref> Anandamide is found in nearly all tissues in a wide range of animals.<ref name="pmid10462059">{{cite journal | vauthors = Martin BR, Mechoulam R, Razdan RK | title = Discovery and characterization of endogenous cannabinoids | journal = Life Sciences | volume = 65 | issue = 6–7 | pages = 573–595 | year = 1999 | pmid = 10462059 | doi = 10.1016/S0024-3205(99)00281-7 }}</ref> Anandamide has also been found in plants, including small amounts in chocolate.<ref name="pmid8751435">{{cite journal | vauthors = di Tomaso E, Beltramo M, Piomelli D | title = Brain cannabinoids in chocolate | journal = Nature | volume = 382 | issue = 6593 | pages = 677–678 | date = August 1996 | pmid = 8751435 | doi = 10.1038/382677a0 | type = Submitted manuscript | s2cid = 4325706 | bibcode = 1996Natur.382..677D | url = https://escholarship.org/uc/item/2kk1604c | access-date = 2022-10-02 | archive-date = 2022-10-02 | archive-url = https://web.archive.org/web/20221002083834/https://escholarship.org/uc/item/2kk1604c | url-status = live }}</ref>

Two analogs of anandamide, [[docosatetraenoylethanolamide|7,10,13,16-docosatetraenoylethanolamide]] and ''homo''-γ-linolenoylethanolamine, have similar [[pharmacology]]. All of these compounds are members of a family of signalling lipids called [[N-acylethanolamine|''N''-acylethanolamines]], which also includes the noncannabimimetic [[palmitoylethanolamide]] and [[oleoylethanolamide]], which possess [[anti-inflammatory]] and [[anorexigenic]] effects, respectively. Many ''N''-acylethanolamines have also been identified in plant seeds<ref>{{cite journal | vauthors = Chapman KD, Venables B, Markovic R, Bettinger C | title = N-Acylethanolamines in seeds. Quantification Of molecular species and their degradation upon imbibition | journal = Plant Physiology | volume = 120 | issue = 4 | pages = 1157–1164 | date = August 1999 | pmid = 10444099 | pmc = 59349 | doi = 10.1104/pp.120.4.1157 }}</ref> and in molluscs.<ref>{{cite journal | vauthors = Sepe N, De Petrocellis L, Montanaro F, Cimino G, Di Marzo V | title = Bioactive long chain N-acylethanolamines in five species of edible bivalve molluscs. Possible implications for mollusc physiology and sea food industry | journal = Biochimica et Biophysica Acta | volume = 1389 | issue = 2 | pages = 101–111 | date = January 1998 | pmid = 9461251 | doi = 10.1016/S0005-2760(97)00132-X }}</ref>

==== 2-Arachidonoylglycerol (2-AG) ====
{{Main|2-Arachidonoylglycerol}}
Another endocannabinoid, 2-arachidonoylglycerol, binds to both the CB<sub>1</sub> and CB<sub>2</sub> receptors with similar affinity, acting as a full agonist at both.<ref name="grotenhermen 2005" /> 2-AG is present at significantly higher concentrations in the brain than anandamide,<ref name="stella 1997">{{cite journal | vauthors = Stella N, Schweitzer P, Piomelli D | title = A second endogenous cannabinoid that modulates long-term potentiation | journal = Nature | volume = 388 | issue = 6644 | pages = 773–778 | date = August 1997 | pmid = 9285589 | doi = 10.1038/42015 | type = Submitted manuscript | s2cid = 4422311 | doi-access = free | bibcode = 1997Natur.388..773S }}</ref> and there is some controversy over whether 2-AG rather than anandamide is chiefly responsible for endocannabinoid signalling ''[[in vivo]]''.<ref name="pmid16968947" /> In particular, one ''[[in vitro]]'' study suggests that 2-AG is capable of stimulating higher [[G-protein]] activation than anandamide, although the physiological implications of this finding are not yet known.<ref>{{cite journal | vauthors = Savinainen JR, Järvinen T, Laine K, Laitinen JT | title = Despite substantial degradation, 2-arachidonoylglycerol is a potent full efficacy agonist mediating CB(1) receptor-dependent G-protein activation in rat cerebellar membranes | journal = British Journal of Pharmacology | volume = 134 | issue = 3 | pages = 664–672 | date = October 2001 | pmid = 11588122 | pmc = 1572991 | doi = 10.1038/sj.bjp.0704297 }}</ref>

==== 2-Arachidonyl glyceryl ether (noladin ether) ====
{{Main|2-Arachidonyl glyceryl ether}}
In 2001, a third, [[ether]]-type endocannabinoid, 2-arachidonyl glyceryl ether (noladin ether), was isolated from [[porcine]] brain.<ref>{{cite journal | vauthors = Hanus L, Abu-Lafi S, Fride E, Breuer A, Vogel Z, Shalev DE, Kustanovich I, Mechoulam R | display-authors = 6 | title = 2-arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 7 | pages = 3662–3665 | date = March 2001 | pmid = 11259648 | pmc = 31108 | doi = 10.1073/pnas.061029898 | doi-access = free | bibcode = 2001PNAS...98.3662H }}</ref> Prior to this discovery, it had been synthesized as a stable analog of 2-AG; indeed, some controversy remains over its classification as an endocannabinoid, as another group failed to detect the substance at "any appreciable amount" in the brains of several different mammalian species.<ref name="Oka 2003">{{cite journal | vauthors = Oka S, Tsuchie A, Tokumura A, Muramatsu M, Suhara Y, Takayama H, Waku K, Sugiura T | display-authors = 6 | title = Ether-linked analogue of 2-arachidonoylglycerol (noladin ether) was not detected in the brains of various mammalian species | journal = Journal of Neurochemistry | volume = 85 | issue = 6 | pages = 1374–1381 | date = June 2003 | pmid = 12787057 | doi = 10.1046/j.1471-4159.2003.01804.x | s2cid = 39905742 | doi-access = free }}</ref> It binds to the CB<sub>1</sub> cannabinoid receptor (''K''<sub>i</sub> = 21.2 [[nanomole|nmol]]/L) and causes sedation, hypothermia, intestinal immobility, and mild antinociception in mice. It binds primarily to the CB<sub>1</sub> receptor, and only weakly to the CB<sub>2</sub> receptor.<ref name="grotenhermen 2005" />

==== ''N''-Arachidonoyl dopamine (NADA) ====
{{Main|N-Arachidonoyl dopamine|l1=''N''-Arachidonoyl dopamine}}
Discovered in 2000, NADA preferentially binds to the CB<sub>1</sub> receptor.<ref>{{cite journal | vauthors = Bisogno T, Melck D, Gretskaya NM, Bezuglov VV, De Petrocellis L, Di Marzo V | title = N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo | journal = The Biochemical Journal | volume = 351 Pt 3 | issue = 3 | pages = 817–824 | date = November 2000 | pmid = 11042139 | pmc = 1221424 | doi = 10.1042/bj3510817 }}</ref> Like anandamide, NADA is also an agonist for the [[TRPV1|vanilloid receptor subtype 1]] (TRPV1), a member of the [[vanilloid]] receptor family.<ref name="Bisogno 2005">{{cite journal | vauthors = Bisogno T, Ligresti A, Di Marzo V | title = The endocannabinoid signalling system: biochemical aspects | journal = Pharmacology, Biochemistry, and Behavior | volume = 81 | issue = 2 | pages = 224–238 | date = June 2005 | pmid = 15935454 | doi = 10.1016/j.pbb.2005.01.027 | s2cid = 14186359 }}</ref><ref>{{cite journal | vauthors = Ralevic V | title = Cannabinoid modulation of peripheral autonomic and sensory neurotransmission | journal = European Journal of Pharmacology | volume = 472 | issue = 1–2 | pages = 1–21 | date = July 2003 | pmid = 12860468 | doi = 10.1016/S0014-2999(03)01813-2 }}</ref>

==== Virodhamine (OAE) ====
{{Main|Virodhamine}}
A fifth endocannabinoid, virodhamine, or ''O''-arachidonoyl-ethanolamine (OAE), was discovered in June 2002. Although it is a full [[agonist]] at CB<sub>2</sub> and a partial agonist at CB<sub>1</sub>, it behaves as a CB<sub>1</sub> antagonist ''[[in vivo]]''. In rats, virodhamine was found to be present at comparable or slightly lower concentrations than [[anandamide]] in the [[brain]], but 2- to 9-fold higher concentrations peripherally.<ref>{{cite journal | vauthors = Porter AC, Sauer JM, Knierman MD, Becker GW, Berna MJ, Bao J, Nomikos GG, Carter P, Bymaster FP, Leese AB, Felder CC | display-authors = 6 | title = Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 301 | issue = 3 | pages = 1020–1024 | date = June 2002 | pmid = 12023533 | doi = 10.1124/jpet.301.3.1020 | url = http://pdfs.semanticscholar.org/ab53/846ea9f65d5a673d2e4552933c2a26409b00.pdf | url-status = dead | s2cid = 26156181 | archive-url = https://web.archive.org/web/20190303094035/http://pdfs.semanticscholar.org/ab53/846ea9f65d5a673d2e4552933c2a26409b00.pdf | archive-date = 2019-03-03 }}</ref>

==== Lysophosphatidylinositol (LPI) ====
[[Lysophosphatidylinositol]] is the endogenous ligand to novel endocannabinoid receptor [[GPR55]], making it a strong contender as the sixth endocannabinoid.<ref>{{cite journal | vauthors = Piñeiro R, Falasca M | title = Lysophosphatidylinositol signalling: new wine from an old bottle | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1821 | issue = 4 | pages = 694–705 | date = April 2012 | pmid = 22285325 | doi = 10.1016/j.bbalip.2012.01.009 | url = https://zenodo.org/record/895487 | access-date = 2019-09-13 | archive-date = 2021-02-11 | archive-url = https://web.archive.org/web/20210211052458/https://zenodo.org/record/895487 | url-status = live }}</ref>