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Anandamide, also known as N-arachidonoylethanolamine or AEA, is a fatty acid neurotransmitter derived from the non-oxidative metabolism of eicosatetraenoic acid (arachidonic acid) an essential ω-6 polyunsaturated fatty acid. The name is taken from the Sanskrit
Sanskrit
& Pāli
Pāli
word ananda, which means "joy, bliss, delight", and amide.[1][2] It is synthesized from N-arachidonoyl phosphatidylethanolamine by multiple pathways.[3] 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.[4][5]

Contents

1 Physiological functions 2 Synthesis and degradation 3 Medical benefits 4 See also 5 References 6 External links

Physiological functions[edit] See also: Neurobiological effects of physical exercise § Anandamide Anandamide
Anandamide
was first described (and named) in 1992 by Raphael Mechoulam and his lab members W. A. Devane and Lumír Hanuš.[1] Anandamide's effects can occur in either the central or peripheral nervous system. These distinct effects are mediated primarily by CB1 cannabinoid receptors in the central nervous system, and CB2 cannabinoid receptors in the periphery.[6] The latter are mainly involved in functions of the immune system. Cannabinoid
Cannabinoid
receptors were originally discovered as being 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
Anandamide
has been shown to impair working memory in rats.[7] Studies are under way to explore what role anandamide plays in human behavior, such as eating and sleep patterns, and pain relief. Anandamide
Anandamide
is also important for 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.[8] 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 AEA (anandamide) levels.[9] Subsequently, anandamide has been proposed as a biomarker of infertility, but so far lacks any predictive values in order to be used clinically.[10] Anandamide
Anandamide
plays a role in the regulation of feeding behavior, and the neural generation of motivation and pleasure. In addition, anandamide injected directly into the forebrain reward-related brain structure nucleus accumbens enhances the pleasurable responses of rats to a rewarding sucrose taste, and enhances food intake as well.[6][11] Moreover, the acute beneficial effects of exercise (termed as runner's high) seem to be mediated by anandamide in mice.[12] Anandamide
Anandamide
is the precursor of a class of physiologically active substances, the prostamides.[13] Anandamide
Anandamide
inhibits human breast cancer cell proliferation.[14] Anandamide
Anandamide
is found in chocolate together with two substances that might mimic the effects of anandamide, N-oleoylethanolamine and N-linoleoylethanolamine.[15] Additionally, anandamide and other endocannabinoids are found in the model organism Drosophila melanogaster (fruit fly). Although no CB receptors have been found in any insects. [16][17] Synthesis and degradation[edit] 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
N-acyltransferase
enzyme.[18][19] Anandamide
Anandamide
synthesis from NAPE occurs via multiple pathways and includes enzymes such as phospholipase A2, phospholipase C and NAPE-PLD.[3] 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 adsorption of lipids in the small intestine - modulate its biogenesis.[20] 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.[21] High fat diet feeding in mice increases levels of anandamide in the liver and increases lipogenesis.[22] This suggests that anandamide may play a role in the development of obesity, at least in rodents. Paracetamol
Paracetamol
(or acetaminophen in the U.S.A. and Canada) is metabolically combined with arachidonic acid by FAAH to form AM404.[23] This metabolite of paracetamol is a potent agonist at the TRPV1
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.[24][25] Endocannabinoid transporters for anandamide and 2-arachidonoylglycerol include the heat shock proteins (Hsp70s) and fatty acid binding proteins (FABPs).[26][27] Medical benefits[edit] It has been suggested that AM1172 could potentially be developed into a drug that would increase the brain's anandamide levels to help treat anxiety and depression.[28] Black pepper
Black pepper
contains an alkaloid, Guineensine, which appears to be a relatively potent Anandamide reuptake inhibitor, thus increasing its physiological effects.[citation needed] Low dose intake has an anxiolytic effect. High dose intake in mice shows evident hippocampus death[citation needed]. It is not possible to train[clarification needed] tolerable maximum high dosage for mice.[29] Expired patents from 2004 exist that describe anandamide as a vitalising additive for alcoholic and non-alcoholic beverages, including combining it with another additive, Oleoylethanolamide, recited as an invention from Nestle, to increase the "stimulus" effect.[30] The amount of anandamide in cacao is 0.5 μg per gram.[31] According to associate statistics world cacao production in 2013 had a value of around five million metric tons annually with a rising tendency, but since the patent expired anyone is allowed to synthetically produce it and add it to food.[32] See also[edit]

Cannabinoids Virodhamine Tetrahydrocannabinol
Tetrahydrocannabinol
(THC) 2-Arachidonoylglycerol Fatty acid
Fatty acid
amide hydrolase Endocannabinoid transporters Raphael Mechoulam NAPE-PLD

References[edit]

^ a b Devane, W.; Hanus, L; Breuer, A; Pertwee, R.; Stevenson, L.; Griffin, G; Gibson, D; Mandelbaum, A; Etinger, A; Mechoulam, R (18 December 1992). "Isolation and structure of a brain constituent that binds to the cannabinoid receptor". Science. 258 (5090): 1946–1949. Bibcode:1992Sci...258.1946D. doi:10.1126/science.1470919. PMID 1470919.  ^ Mechoulam R, Fride E (1995). "The unpaved road to the endogenous brain cannabinoid ligands, the anandamides". In Pertwee RG. Cannabinoid
Cannabinoid
receptors. Boston: Academic Press. pp. 233–258. ISBN 0-12-551460-3.  ^ a b Wang, J.; Ueda, N. (2009). "Biology of endocannabinoid synthesis system". Prostaglandins & Other Lipid
Lipid
Mediators. 89 (3–4): 112–119. doi:10.1016/j.prostaglandins.2008.12.002. PMID 19126434.  ^ Gaetani, Silvana; Dipasquale, Pasqua; Romano, Adele; Righetti, Laura; Cassano, Tommaso; Piomelli, Daniele; Cuomo, Vincenzo (2009). "The endocannabinoid system as a target for novel anxiolytic and antidepressant drugs". International review of neurobiology. International Review of Neurobiology. 85: 57–72. doi:10.1016/S0074-7742(09)85005-8. ISBN 9780123748935. PMID 19607961.  ^ Hwang, Jeannie; Adamson, Crista; Butler, David; Janero, David R.; Makriyannis, Alexandros; Bahr, Ben A. (April 2010). "Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: A neuroprotective therapeutic modality". Life Sciences. 86 (15–16): 615–623. doi:10.1016/j.lfs.2009.06.003. PMC 2848893 . PMID 19527737.  ^ a b Pacher P, Batkai S, Kunos G (2006). "The Endocannabinoid System as an Emerging Target of Pharmacotherapy". Pharmacol. Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751 . PMID 16968947.  ^ Mallet PE, Beninger RJ (1996). "The endogenous cannabinoid receptor agonist anandamide impairs memory in rats". Behavioural Pharmacology. 7 (3): 276–284. doi:10.1097/00008877-199605000-00008.  ^ Piomelli D (January 2004). "THC: moderation during implantation". Nat. Med. 10 (1): 19–20. doi:10.1038/nm0104-19. PMID 14702623.  ^ El-Talatini MR, Taylor AH, Konje JC (April 2010). "The relationship between plasma levels of the endocannabinoid, anandamide, sex steroids, and gonadotrophins during the menstrual cycle". Fertil. Steril. 93 (6): 1989–96. doi:10.1016/j.fertnstert.2008.12.033. PMID 19200965.  ^ Rapino, C.; Battista, N.; Bari, M.; Maccarrone, M. (2014). "Endocannabinoids as biomarkers of human reproduction". Human Reproduction Update. 20 (4): 501–516. doi:10.1093/humupd/dmu004. ISSN 1355-4786. PMID 24516083.  ^ Mahler SV, Smith KS, Berridge KC (November 2007). "Endocannabinoid hedonic hotspot for sensory pleasure: anandamide in nucleus accumbens shell enhances 'liking' of a sweet reward". Neuropsychopharmacology. 32 (11): 2267–78. doi:10.1038/sj.npp.1301376. PMID 17406653.  ^ Fuss J, Steinle J, Bindila L, Auer MK, Kirchherr H, Lutz B, and Gass P (2015). "A runner's high depends on cannabinoid receptors in mice". PNAS. 112 (42): 13105–13108. Bibcode:2015PNAS..11213105F. doi:10.1073/pnas.1514996112. PMC 4620874 . PMID 26438875.  ^ Woodward, D. F.; Liang, Y; Krauss, A. H. (2007). "Prostamides (prostaglandin-ethanolamides) and their pharmacology". British Journal of Pharmacology. 153 (3): 410–419. doi:10.1038/sj.bjp.0707434. PMC 2241799 . PMID 17721551.  ^ De Petrocellis, Luciano; Melck, Dominique; Palmisano, Antonella; Bisogno, Tiziana; Laezza, Chiara; Bifulco, Maurizio; Di Marzo, Vincenzo (7 July 1998). "The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation". Proceedings of the National Academy of Sciences. 95 (14): 8375–8380. Bibcode:1998PNAS...95.8375D. doi:10.1073/pnas.95.14.8375. PMC 20983 . PMID 9653194.  ^ di Tomaso E, Beltramo M, Piomelli D (Aug 1996). "Brain cannabinoids in chocolate". Nature. 382 (6593): 677–8. Bibcode:1996Natur.382..677D. doi:10.1038/382677a0. PMID 8751435.  ^ Jeffries K, Dempsey D, Behari A, Anderson R, Merkler D (Nov 2014). "Drosophila melanogaster as a model system to study long-chain fatty acid amide metabolism". FEBS Letters. 588 (9): 1596–1602. doi:10.1016/j.febslet.2014.02.051. PMC 4023565 . PMID 24650760. CS1 maint: Uses authors parameter (link) ^ McPartland J, Di Marzo V, De Petrocellis L, Mercer A, Glass M. (Aug 2001). " Cannabinoid
Cannabinoid
receptors are absent in insects". Journal of Comparative Neurology. 436 (4): 423–429. doi:10.1002/cne.1078. PMID 11447587. CS1 maint: Uses authors parameter (link) ^ Natarajan V, Reddy PV, Schmid PC, Schmid HH (August 1982). "N-Acylation of ethanolamine phospholipids in canine myocardium". Biochim. Biophys. Acta. 712 (2): 342–55. doi:10.1016/0005-2760(82)90352-6. PMID 7126608.  ^ Cadas H, di Tomaso E, Piomelli D (February 1997). "Occurrence and biosynthesis of endogenous cannabinoid precursor, N-arachidonoyl phosphatidylethanolamine, in rat brain". J. Neurosci. 17 (4): 1226–42. PMID 9006968.  ^ Magotti P, Bauer I, Igarashi M, Babagoli M, Marotta R, Piomelli D, Garau G (Dec 2014). "Structure of Human N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D: Regulation of Fatty Acid Ethanolamide Biosynthesis by Bile Acids". Structure. 23 (3): 598–604. doi:10.1016/j.str.2014.12.018. PMC 4351732 . PMID 25684574.  ^ Berger, Alvin; Crozier, Gayle; Bisogno, Tiziana; Cavaliere, Paolo; Innis, Sheila; Di Marzo, Vincenzo (15 May 2001). " Anandamide
Anandamide
and diet: Inclusion of dietary arachidonate and docosahexaenoate leads to increased brain levels of the corresponding N-acylethanolamines in piglets". Proceedings of the National Academy of Sciences. 98 (11): 6402–6406. Bibcode:2001PNAS...98.6402B. doi:10.1073/pnas.101119098. PMC 33480 . PMID 11353819.  ^ Osei-Hyiaman, Douglas; DePetrillo, Michael; Pacher, Pál; Liu, Jie; Radaeva, Svetlana; Bátkai, Sándor; Harvey-White, Judith; Mackie, Ken; Offertáler, László; Wang, Lei; Kunos, George (2 May 2005). " Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". Journal of Clinical Investigation. 115 (5): 1298–1305. doi:10.1172/JCI23057. PMC 1087161 . PMID 15864349.  ^ Högestätt, E. D.; Jönsson, B. A.; Ermund, A.; Andersson, D. A.; Björk, H.; Alexander, J. P.; Cravatt, B. F.; Basbaum, A. I.; Zygmunt, P. M. (2005). "Conversion of Acetaminophen
Acetaminophen
to the Bioactive N-Acylphenolamine AM404
AM404
via Fatty Acid Amide
Amide
Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System" (pdf). Journal of Biological Chemistry. 280 (36): 31405–31412. doi:10.1074/jbc.M501489200. PMID 15987694.  ^ Bertolini, Alfio; Ferrari, Anna; Ottani, Alessandra; Guerzoni, Simona; Tacchi, Raffaella; Leone, Sheila (September 2006). "Paracetamol: New Vistas of an Old Drug". CNS Drug Reviews. 12 (3–4): 250–275. doi:10.1111/j.1527-3458.2006.00250.x. PMID 17227290.  ^ Sinning, Christian; Watzer, Bernhard; Coste, Ovidiu; Nüsing, Rolf M.; Ott, Ingo; Ligresti, Alessia; Marzo, Vincenzo Di; Imming, Peter (25 December 2008). "New Analgesics Synthetically Derived from the Paracetamol Metabolite-(4-Hydroxyphenyl)-(5,8,11,14)-icosatetra-5,8,11,14-enamide". Journal of Medicinal Chemistry. 51 (24): 7800–7805. doi:10.1021/jm800807k. PMID 19053765.  ^ 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-Agro, A.; Maccarrone, M. (2009). "Molecular identification of albumin and Hsp70
Hsp70
as cytosolic anandamide-binding proteins". Chemistry & Biology. 16 (6): 624–632. doi:10.1016/j.chembiol.2009.05.004. PMID 19481477.  ^ Evans, Jon (July 2004). "Easing anxiety with anandamide". Chemistry World.  ^ Ameri, A; Wilhelm, A; Simmet, T (1999). "Effects of the endogeneous cannabinoid, anandamide, on neuronal activity in rat hippocampal slices". British Journal of Pharmacology. 126 (8): 1831–1839. doi:10.1038/sj.bjp.0702478. PMC 1565956 . PMID 10372827.  ^ http://google.com/patents/DE202004013386U1?cl=da ^ Nehlig, A (2013). "The neuroprotective effects of cocoa flavanol and its influence on cognitive performance". British Journal of Clinical Pharmacology. 75 (3): 716–727. doi:10.1111/j.1365-2125.2012.04378.x. PMC 3575938 . PMID 22775434.  ^ http://www.worldcocoafoundation.org/wp-content/uploads/Cocoa-Market-Update-as-of-4-1-2014.pdf

External links[edit]

Could anandamide be the missing link to "runner's high"? Accessed 2015-10-31 https://web.archive.org/web/20131215032041/http://www.harford.de/arne/articles/NeuroReport.pdf

v t e

Cannabinoids

Phytocannabinoids

Alkylamides Caryophyllene CBC CBCV CBD CBDV CBG CBGM CBGV CBL CBDL CBN CBV Epigallocatechin gallate Gallocatechol Perrottetinene Serinolamide A THC THC-C4 THCA THCV Yangonin

Active metabolites: 8,11-DiOH-THC 11-COOH-THC 11-OH-THC

Endocannabinoids

Arachidonoyl ethanolamide (AEA; anandamide) 2-Arachidonoylglycerol
2-Arachidonoylglycerol
(2-AG) 2-Arachidonyl glyceryl ether
2-Arachidonyl glyceryl ether
(2-AGE; noladin ether) 2-Oleoylglycerol
2-Oleoylglycerol
(2-OG) N-Arachidonoyl dopamine
N-Arachidonoyl dopamine
(NADA) N-Arachidonylglycine
N-Arachidonylglycine
(NAGly) 2-Arachidonoyl lysophosphatidylinositol (2-ALPI) N- Arachidonoyl serotonin
Arachidonoyl serotonin
(AA-5-HT) Docosatetraenoylethanolamide
Docosatetraenoylethanolamide
(DEA) Lysophosphatidylinositol
Lysophosphatidylinositol
(LPI) Oleamide Oleoylethanolamide
Oleoylethanolamide
(OEA) Palmitoylethanolamide
Palmitoylethanolamide
(PEA) RVD-Hpα Stearoylethanolamide (SEA) O-Arachidonoyl ethanolamine (O-AEA; virodhamine)

Synthetic cannabinoids

Classical cannabinoids (dibenzopyrans)

A-40174 A-41988 A-42574 Ajulemic acid AM-087 AM-411 AM-855 AM-905 AM-906 AM-919 AM-926 AM-938 AM-2389 AM-4030 AMG-1 AMG-3 AMG-36 AMG-41 Dexanabinol
Dexanabinol
(HU-211) DMHP Dronabinol HHC HU-210 HU-243 JWH-051 JWH-133 JWH-139 JWH-161 JWH-229 JWH-359 KM-233 L-759,633 L-759,656 Levonantradol
Levonantradol
(CP 50,5561) Menabitan Nabazenil Nabidrox (Canbisol) Nabilone Nabitan Naboctate O-224 O-581 O-774 O-806 O-823 O-1057 O-1125 O-1191 O-1238 O-2048 O-2113 O-2365 O-2372 O-2373 O-2383 O-2426 O-2484 O-2545 O-2694 O-2715 O-2716 O-3223 O-3226 Parahexyl Pirnabine THC-O-acetate THC-O-phosphate

Non-classical cannabinoids

Cannabicyclohexanol CBD-DMH CP 47,497 (C6)-CP 47,497 (C9)-CP 47,497 CP 55,244 CP 55,940 HU-308 HU-320 HU-331 HU-336 HU-345 HU-446 HU-465 HU-910 HUF-101 Nonabine O-1376 O-1422 O-1601 O-1656 O-1657 O-1660 O-1663 O-1871 SPA-229 Tinabinol

Benzoylindoles

1-Butyl-3-(2-methoxybenzoyl)indole 1-Butyl-3-(4-methoxybenzoyl)indole 1-Pentyl-3-(2-methoxybenzoyl)indole AM-630 AM-679 AM-694 AM-1241 AM-2233 GW-405,833
GW-405,833
(L-768,242) Pravadoline RCS-4 WIN 54,461

Naphthoylindoles

AM-1220 AM-1221 AM-1235 AM-2201 AM-2232 CHM-081 EAM-2201 FUB-JWH-018 JWH-007 JWH-015 JWH-018 JWH-019 JWH-073 JWH-081 JWH-098 JWH-116 JWH-122 JWH-149 JWH-164 JWH-182 JWH-193 JWH-198 JWH-200 JWH-210 JWH-398 JWH-424 MAM-1220 MAM-2201 NE-CHMIMO

Naphthoylindazoles

THJ-018 THJ-2201

Pyrrolobenzoxazines

WIN 55,212-2

Naphthylmethylindoles

JWH-175 JWH-176 JWH-184 JWH-185 JWH-192 JWH-194 JWH-195 JWH-196 JWH-197 JWH-199

Phenylacetylindoles

Cannabipiperidiethanone JWH-167 JWH-203 JWH-249 JWH-250 JWH-251 JWH-302 RCS-8

Indole-3-carboxamides

5F-ADBICA 5F-NNE1 5F-PCN 5F-SDB-006 AB-FUBICA AB-PICA ADBICA ADB-FUBICA APICA CUMYL-BICA CUMYL-PICA CUMYL-5F-PICA FDU-NNE1 MDMB-CHMICA MMB-2201 MN-25
MN-25
(UR-12) NNE1 PX-1 Org 28312 Org 28611 SDB-006 STS-135

Indole-3-carboxylates

5F-PB-22 FDU-PB-22 FUB-PB-22 QUCHIC
QUCHIC
(BB-22) QUPIC
QUPIC
(PB-22) NM-2201

Tetramethylcyclo- propanoylindoles

5Br-UR-144 5Cl-UR-144 A-796,260 A-834,735 FUB-144 UR-144 XLR-11 XLR-12

Indazole-3- carboxamides

5Cl-APINACA 5F-ADB 5F-ADB-PINACA 5F-AMB 5F-APINACA 5F-CUMYL-PINACA 5F-EMB-PINACA AB-CHMINACA AB-FUBINACA AB-FUBINACA
AB-FUBINACA
2-fluorobenzyl isomer AB-PINACA ADB-CHMINACA ADB-FUBINACA ADB-PINACA ADAMANTYL-THPINACA ADSB-FUB-187 AMB-CHMINACA AMB-FUBINACA APINACA
APINACA
(AKB48) APP-FUBINACA CUMYL-4CN-BINACA CUMYL-PINACA CUMYL-THPINACA EMB-FUBINACA FUB-APINACA MDMB-FUBINACA MDMB-CHMINACA MN-18 PX-2 PX-3

Tetramethylcyclo- propanoylindazoles

FAB-144

Naphthoylpyrroles

JWH-030 JWH-147 JWH-307 JWH-369 JWH-370

Eicosanoids

AM-883 AM-1346 ACEA ACPA Methanandamide
Methanandamide
(AM-356) O-585 O-689 O-1812 O-1860 O-1861

Pyrazolecarboxamides

5F-AB-FUPPYCA AB-CHFUPYCA AB-CHMFUPPYCA

Others

4-HTMPIPO 5F-PY-PICA 5F-PY-PINACA 5F-3-pyridinoylindole A-836,339 A-955,840 Abnormal cannabidiol AB-001 BzODZ-EPyr AM-1248 AM-1714 AZ-11713908 BAY 38-7271 BAY 59-3074 BIM-018 CB-13 CB-86 CBS-0550 CUMYL-4CN-B7AICA CUMYL-5F-P7AICA CUMYL-PEGACLONE FUBIMINA GSK-554,418A GW-842,166X JTE 7-31 LASSBio-881 LBP-1 Leelamine MDA-7 MDA-19 MEPIRAPIM NESS-040C5 NMP-7 O-889 O-1269 O-1270 O-1399 O-1602 O-2220 PF-03550096 PSB-SB-1202 PTI-1 PTI-2 QMPSB S-444,823 SER-601 Tedalinab URB-447 VSN-16 WIN 56,098

Allosteric CBR ligands

Org 27569 Org 27759 Org 29647 RTI-371 Pregnenolone

Endocannabinoid enhancers (inactivation inhibitors)

4-Nonylphenylboronic acid AM-404 Arachidonoyl serotonin Arvanil BIA 10-2474 Biochanin A CAY-10401 CAY-10429 Genistein Guineesine IDFP JNJ 1661010 JNJ-42165279 JZL184 JZL195 Kaempferol LY-2183240 MK-4409 O-1624 O-2093 Oleoylethanolamide
Oleoylethanolamide
(OEA) Olvanil Palmitoylethanolamide
Palmitoylethanolamide
(PEA) PF-04457845 PF-622 PF-750 PF-3845 PHOP URB-447 URB-597 URB-602 URB-754 VDM-11

Anticannabinoids (antagonists/inverse agonists/antibodies)

AM-251 AM-281 AM-630 AM-1387 AM-4113 AM-6527 AM-6545 BML-190 Brizantin (Бризантин) CAY-10508 CB-25 CB-52 CB-86 Dietressa (Диетресса) Drinabant
Drinabant
(AVE1625) Hemopressin Ibipinabant
Ibipinabant
(SLV319) JTE-907 LH-21 LY-320,135 MDA-77 MJ-15 MK-9470 NESS-0327 NIDA-41020 O-606 O-1184 O-1248 O-1918 O-2050 O-2654 Otenabant
Otenabant
(CP-945,598) PF-514273 PipISB PSB-SB-487 Rimonabant
Rimonabant
(SR141716) Rosonabant
Rosonabant
(E-6776) SR-144,528 Surinabant
Surinabant
(SR147778) Taranabant
Taranabant
(MK-0364) TM-38837 VCHSR

See also: Cannabinoid receptor
Cannabinoid receptor
modulators (cannabinoids by pharmacology) List of: AM cannabinoids JWH cannabinoids Designer drugs § Synthetic cannabimimetics

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Neurotransmitters

Amino acid-derived

Major excitatory/inhibitory systems: Glutamate system: Agmatine Aspartic acid
Aspartic acid
(aspartate) Cycloserine Glutamic acid
Glutamic acid
(glutamate) Glutathione Glycine GSNO GSSG Kynurenic acid NAA NAAG Proline Serine; GABA system: GABA GABOB GHB; Glycine
Glycine
system: α-Alanine β-Alanine Glycine Hypotaurine Proline Sarcosine Serine Taurine; GHB system: GHB T-HCA (GHC)

Biogenic amines: Monoamines: 6-OHM Dopamine Epinephrine
Epinephrine
(adrenaline) NAS (normelatonin) Norepinephrine
Norepinephrine
(noradrenaline) Serotonin
Serotonin
(5-HT); Trace amines: 3-Iodothyronamine N-Methylphenethylamine N-Methyltryptamine m-Octopamine p-Octopamine Phenylethanolamine Phenethylamine Synephrine Tryptamine m-Tyramine p-Tyramine; Others: Histamine

Neuropeptides: See here instead.

Lipid-derived

Endocannabinoids: 2-AG 2-AGE (noladin ether) 2-ALPI 2-OG AA-5-HT Anandamide
Anandamide
(AEA) DEA LPI NADA NAGly OEA Oleamide PEA RVD-Hpα SEA Virodhamine
Virodhamine
(O-AEA)

Neurosteroids: See here instead.

Nucleobase-derived

Nucleosides: Adenosine
Adenosine
system: Adenosine ADP AMP ATP

Vitamin-derived

Cholinergic system: Acetylcholine

Miscellaneous

Gasotransmitters: Carbon monoxide
Carbon monoxide
(CO) Hydrogen sulfide
Hydrogen sulfide
(H2S) Nitric oxide
Nitric oxide
(NO); Candidates: Acetaldehyde Ammonia
Ammonia
(NH3) Carbonyl sulfide
Carbonyl sulfide
(COS) Nitrous oxide
Nitrous oxide
(N2O) Sulfur dioxide
Sulfur dioxide
(SO2)

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Cannabinoid receptor
Cannabinoid receptor
modulators

Receptor (ligands)

CB1

Agonists (abridged; see here for more): 2-AG 2-AGE (noladin ether) 11-Hydroxy-THC α-Amyrin β-Amyrin AB-CHMINACA AM-1172 AM-1220 AM-1221 AM-1235 AM-2201 AM-2232 Anandamide Arvanil AZ-11713908 Cannabinol CB-13 CP 47,497 CP 55,940 Dimethylheptylpyran DEA ECG EGCG Epicatechin Gallocatechol
Gallocatechol
(gallocatechin) Honokiol HU-210 JWH-007 JWH-015 JWH-018 JWH-073 Kavain L-759,633 Levonantradol Menabitan Nabilone Nabitan NADA O-1812 Oleamide Pravadoline Serinolamide A THC (dronabinol) UR-144 WIN 55,212-2 Yangonin

Antagonists: AM-251 AM-6545 Cannabidiol Cannabigerol Drinabant Falcarinol
Falcarinol
(carotatoxin) Hemopressin Ibipinabant LY-320,135 MK-9470 NESS-0327 O-2050 Otenabant PF-514273 PipISB Rimonabant Rosonabant Surinabant Taranabant THCV TM-38837 VCHSR Virodhamine

Antibodies: Brizantin (Бризантин) Dietressa (Диетресса)

Unknown/unsorted: MAFP

CB2

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
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 Magnolol MDA-19 Nabitan NADA PF-03550096 S-444,823 SER-601 Serinolamide A UR-144 Tedalinab THC (dronabinol) THCV Tetrahydromagnolol Virodhamine

Antagonists: 4-O-Methylhonokiol AM-630 BML-190 Cannabidiol Honokiol JTE-907 SR-144,528 WIN 54,461 WIN 56,098

NAGly (GPR18)

Agonists: Abnormal cannabidiol ACPA AM251 Anandamide Cannabidiol NADGly THC (dronabinol) O-1602

Antagonists: CID-85469571 O-1918

GPR55

Agonists: 2-AGE (noladin ether) 2-ALPI Abnormal cannabidiol AM-251 CID1011163 CID1252842 CID1792579 CP 55,940 GSK-494581A Lysophosphatidylinositol ML-184 ML-185 ML-186 O-1602 Oleoylethanolamide Palmitoylethanolamide THC (dronabinol)

Antagonists: Cannabidiol CID-16020046 ML-191 ML-192 ML-193 O-1918 PSB-SB-487 PSB-SB-1202 PSB-SB-1203 Tetrahydromagnolol

GPR119

Agonists: 2-Oleoylglycerol Anandamide APD668 AR-231,453 AS-1269574 MBX-2982 N-Oleoyldopamine Oleoylethanolamide Olvanil PSN-375,963 PSN-632,408

Transporter (modulators)

eCBTs

Inhibitors: 5'-DMH-CBD AM-404 AM-1172 Arachidonoyl serotonin Arvanil Cannabidiol Guineensine LY-2183240 O-2093 OMDM-2 Paracetamol
Paracetamol
(acetaminophen) SB-FI-26 UCM-707 URB-597 VDM-11 WOBE490 WOBE491 WOBE492

Enzyme (modulators)

FAAH

Inhibitors: 4-Nonylphenylboronic acid AACOCF3 AM-404 Arachidonoyl serotonin BIA 10-2474 Biochanin A Genistein IDFP JNJ-1661010 JNJ-42165279 JZL-195 Kaempferol LY-2183240 MAFP Palmitoylisopropylamide Paracetamol
Paracetamol
(acetaminophen) PF-3845 PF-04457845 PF-750 SA-47 SA-57 TAK 21d TC-F 2 UCM710 URB-597

Activators: PDP-EA

MAGL

Inhibitors: ABX-1431 IDFP JJKK 048 JW 642 JZL-184 JZL-195 JZP-361 KML 29 MAFP MJN110 NAM Pristimerin URB-602

ABHD6

Inhibitors: JZP-169 JZP-430 KT182 KT185 KT195 KT203 LEI-106 ML294 ML295 ML296 UCM710 WWL-70

ABHD12

Inhibitors: Betulinic acid Maslinic acid MAFP Oleanolic acid Orlistat
Orlistat
(tetrahydrolipstatin) Ursolic acid

Others

Precursors: Phosphatidylethanolamine NAPE Diacylglycerol

Others: 2-PG (directly potentiates activity of 2-AG at CB1 receptor) ARN-272 (FAAH-like anandamide transporter inhibitor)

See also Receptor/signaling modulators Cannabinoids
Cannabinoids
(cannabinoids by structure)

v t e

Glycine
Glycine
receptor modulators

Receptor (ligands)

GlyR

Agonists: β-Alanine β-ABA (BABA) β-AIBA Caesium D-Alanine D-Serine GABA Glycine Hypotaurine Ivermectin L-Alanine L-Proline L-Serine L-Threonine MDL-27531 Milacemide Picolinic acid Propofol Quisqualamine Sarcosine Taurine

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
Ginseng
constituents (e.g., ginsenosides (e.g., ginsenoside-Rf)) Glutamic acid
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, zatosetron) 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
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
Picrotoxin
(i.e., picrotin and picrotoxinin) PMBA Riluzole Tropeines (e.g., bemesetron, LY-278584, tropisetron, zatosetron) Verapamil Zinc

NMDAR

See here instead.

Transporter (blockers)

GlyT1

ACPPB ALX-1393 ALX-5407 (NFPS) AMG-747 ASP2535 Bitopertin
Bitopertin
(RG1678/RO4917838) CP-802079 Ethanol (alcohol) Glycyldodecylamide GSK1018921 LY-2365109 ORG-24598 ORG-25935
ORG-25935
(SCH-900435) PF-02545920 PF-03463275 PF-04958242 Sarcosine SSR-103,800 SSR-504,734

GlyT2

Amoxapine Ethanol (alcohol) NAGly Opiranserin (VVZ-149) ORG-25543 VVZ-368

See also Receptor/signaling modulators GABA receptor modulators GABAA receptor positive modulators Ionotropic glutamate receptor modulators

v t e

TRP channel modulators

TRPA

Activators

4-Hydroxynonenal 4-Oxo-2-nonenal 4,5-EET 12S-HpETE 15-Deoxy-Δ12,14-prostaglandin J2 α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Acrolein Allicin
Allicin
(garlic) Allyl isothiocyanate
Allyl isothiocyanate
(mustard, radish, horseradish, wasabi) AM404 Bradykinin Cannabichromene
Cannabichromene
(cannabis) Cannabidiol
Cannabidiol
(cannabis) Cannabigerol
Cannabigerol
(cannabis) Cinnamaldehyde
Cinnamaldehyde
(cinnamon) CR gas
CR gas
(dibenzoxazepine; DBO) CS gas
CS gas
(2-chlorobenzal malononitrile) Curcumin
Curcumin
(turmeric) Dehydroligustilide (celery) Diallyl disulfide Dicentrine
Dicentrine
( Lindera
Lindera
spp.) Farnesyl thiosalicylic acid Formalin Gingerols (ginger) Hepoxilin A3 Hepoxilin B3 Hydrogen peroxide Icilin Isothiocyanate Ligustilide (celery, Angelica acutiloba) Linalool
Linalool
(Sichuan pepper, thyme) Methylglyoxal Methyl salicylate
Methyl salicylate
(wintergreen) N-Methylmaleimide Nicotine
Nicotine
(tobacco) Oleocanthal
Oleocanthal
(olive oil) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) PF-4840154 Phenacyl chloride Polygodial
Polygodial
(Dorrigo pepper) Shogaols (ginger, Sichuan and melegueta peppers) Tear gases Tetrahydrocannabinol
Tetrahydrocannabinol
(cannabis) Thiopropanal S-oxide
Thiopropanal S-oxide
(onion) Umbellulone
Umbellulone
(Umbellularia californica) WIN 55,212-2

Blockers

Dehydroligustilide (celery) Nicotine
Nicotine
(tobacco) Ruthenium red

TRPC

Activators

Adhyperforin
Adhyperforin
(St John's wort) Diacyl glycerol GSK1702934A Hyperforin
Hyperforin
(St John's wort) Substance P

Blockers

DCDPC DHEA-S Flufenamic acid GSK417651A GSK2293017A Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid Niflumic acid Pregnenolone
Pregnenolone
sulfate Progesterone Pyr3 Tolfenamic acid

TRPM

Activators

ADP-ribose BCTC Calcium
Calcium
(intracellular) Cold Coolact P Cooling Agent 10 CPS-369 Eucalyptol
Eucalyptol
(eucalyptus) Frescolat MGA Frescolat ML Geraniol Hydroxycitronellal Icilin Linalool Menthol
Menthol
(mint) PMD 38 Pregnenolone
Pregnenolone
sulfate Rutamarin (Ruta graveolens) Steviol glycosides (e.g., stevioside) (Stevia rebaudiana) Sweet tastants (e.g., glucose, fructose, sucrose; indirectly) Thio-BCTC WS-3 WS-12 WS-23

Blockers

Capsazepine Clotrimazole DCDPC Flufenamic acid Meclofenamic acid Mefenamic acid N-(p-amylcinnamoyl)anthranilic acid Nicotine
Nicotine
(tobacco) Niflumic acid Ruthenium red Rutamarin (Ruta graveolens) Tolfenamic acid TPPO

TRPML

Activators

MK6-83 PI(3,5)P2 SF-22

TRPP

Activators

Triptolide
Triptolide
(Tripterygium wilfordii)

Blockers

Ruthenium red

TRPV

Activators

2-APB 5',6'-EET 9-HODE 9-oxoODE 12S-HETE 12S-HpETE 13-HODE 13-oxoODE 20-HETE α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Allicin
Allicin
(garlic) AM404 Anandamide Bisandrographolide (Andrographis paniculata) Camphor
Camphor
(camphor laurel, rosemary, camphorweed, African blue basil, camphor basil) Cannabidiol
Cannabidiol
(cannabis) Cannabidivarin
Cannabidivarin
(cannabis) Capsaicin
Capsaicin
(chili pepper) Carvacrol
Carvacrol
(oregano, thyme, pepperwort, wild bergamot, others) DHEA Diacyl glycerol Dihydrocapsaicin
Dihydrocapsaicin
(chili pepper) Estradiol Eugenol
Eugenol
(basil, clove) Evodiamine
Evodiamine
(Euodia ruticarpa) Gingerols (ginger) GSK1016790A Heat Hepoxilin A3 Hepoxilin B3 Homocapsaicin
Homocapsaicin
(chili pepper) Homodihydrocapsaicin
Homodihydrocapsaicin
(chili pepper) Incensole
Incensole
(incense) Lysophosphatidic acid Low pH (acidic conditions) Menthol
Menthol
(mint) N-Arachidonoyl dopamine N-Oleoyldopamine N-Oleoylethanolamide Nonivamide
Nonivamide
(PAVA) (PAVA spray) Nordihydrocapsaicin
Nordihydrocapsaicin
(chili pepper) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) Phorbol esters
Phorbol esters
(e.g., 4α-PDD) Piperine
Piperine
(black pepper, long pepper) Polygodial
Polygodial
(Dorrigo pepper) Probenecid Protons RhTx Rutamarin (Ruta graveolens) Resiniferatoxin
Resiniferatoxin
(RTX) (Euphorbia resinifera/pooissonii) Shogaols (ginger, Sichuan and melegueta peppers) Tetrahydrocannabivarin
Tetrahydrocannabivarin
(cannabis) Thymol
Thymol
(thyme, oregano) Tinyatoxin
Tinyatoxin
(Euphorbia resinifera/pooissonii) Tramadol Vanillin
Vanillin
(vanilla) Zucapsaicin

Blockers

α- Spinasterol
Spinasterol
( Vernonia
Vernonia
tweediana) AMG-517 Asivatrep BCTC Cannabigerol
Cannabigerol
(cannabis) Cannabigerolic acid (cannabis) Cannabigerovarin (cannabis) Cannabinol
Cannabinol
(cannabis) Capsazepine DCDPC DHEA DHEA-S Flufenamic acid GRC-6211 HC-067047 Lanthanum Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid NGD-8243 Niflumic acid Pregnenolone
Pregnenolone
sulfate RN-1734 RN-9893 Ruthenium red SB-705498 Tivanisiran Tolfenamic acid

See also: Receptor/signaling modulators • Ion

.