WIN 55,212-2

{{Short description|Chemical compound}}

{{Infobox drug

| Verifiedfields = changed

| Watchedfields = changed

| verifiedrevid = 447554700

| IUPAC_name = (11R)-2-Methyl-11-[(morpholin-4-yl)methyl]-3-(naphthalene-1-carbonyl)-9-oxa-1-azatricyclo[6.3.1.0^4,12]dodeca-2,4(12),5,7-tetraene

| image = WIN 55,212-2-2D-skeletal.svg

| width = 200px

| tradename =

| legal_CA = Schedule II {{cite web | title = Controlled Drugs and Substance Act - Schedule II | url = https://laws-lois.justice.gc.ca/eng/acts/c-38.8/page-14.html#docCont | work = Justice Laws Website | date = 18 March 2021 | publisher = Government of Canada }}

| legal_UK = Class B

| legal_US = Schedule I

| legal_status =

| routes_of_administration =

| metabolism =

| elimination_half-life =

| excretion =

| CAS_number_Ref = {{cascite|changed|??}}

| CAS_number = 131543-22-1

| PubChem = 5311501

| ChemSpiderID_Ref = {{chemspidercite|changed|chemspider}}

| ChemSpiderID = 4470978

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 73295

| IUPHAR_ligand = 733

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 188

| UNII_Ref = {{fdacite|changed|FDA}}

| UNII = 5H31GI9502

| C=27 | H=26 | N=2 | O=3

| smiles = CC1=C(C2=C3N1[C@@H](COC3=CC=C2)CN4CCOCC4)C(=O)C5=CC=CC6=CC=CC=C65

| StdInChI_Ref = {{stdinchicite|changed|chemspider}}

| StdInChI = 1S/C27H26N2O3/c1-18-25(27(30)22-9-4-7-19-6-2-3-8-21(19)22)23-10-5-11-24-26(23)29(18)20(17-32-24)16-28-12-14-31-15-13-28/h2-11,20H,12-17H2,1H3/t20-/m1/s1

| StdInChIKey_Ref = {{stdinchicite|changed|chemspider}}

| StdInChIKey = HQVHOQAKMCMIIM-HXUWFJFHSA-N

}}

File:Pancreatic stellate cell cropped.pngs. The cells in the lower frame are under the action of WIN 55,212-2. They are thought to assume a more "quiescent" phenotype. From Michalski et al., 2008.{{cite journal | vauthors = Michalski CW, Maier M, Erkan M, Sauliunaite D, Bergmann F, Pacher P, Batkai S, Giese NA, Giese T, Friess H, Kleeff J | display-authors = 6 | title = Cannabinoids reduce markers of inflammation and fibrosis in pancreatic stellate cells | journal = PLOS ONE | volume = 3 | issue = 2 | pages = e1701 | date = February 2008 | pmid = 18301776 | pmc = 2253501 | doi = 10.1371/journal.pone.0001701 | veditors = Gluud C | doi-access = free | bibcode = 2008PLoSO...3.1701M }}]]

WIN 55,212-2 is a chemical described as an aminoalkylindole derivative, which produces effects similar to those of cannabinoids such as tetrahydrocannabinol (THC) but has an entirely different chemical structure.{{cite journal | vauthors = Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR | title = Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 263 | issue = 3 | pages = 1118–1126 | date = December 1992 | pmid = 1335057 }}{{cite journal | vauthors = Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T | title = The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study | journal = Cerebral Cortex | volume = 11 | issue = 8 | pages = 728–733 | date = August 2001 | pmid = 11459762 | doi = 10.1093/cercor/11.8.728 | doi-access = free }}{{cite journal | vauthors = Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G | title = In vitro metabolism of R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo [1,2,3-de]1,4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a cannabinoid receptor agonist | journal = Drug Metabolism and Disposition | volume = 30 | issue = 10 | pages = 1077–1086 | date = October 2002 | pmid = 12228183 | doi = 10.1124/dmd.30.10.1077 | s2cid = 10848076 }}

WIN 55,212-2 is a potent cannabinoid receptor agonist{{cite journal | vauthors = Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, Lai Y, Ma AL, Mitchell RL | display-authors = 6 | title = Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors | journal = Molecular Pharmacology | volume = 48 | issue = 3 | pages = 443–450 | date = September 1995 | pmid = 7565624 }} that has been found to be a potent analgesic{{cite journal | vauthors = Meng ID, Manning BH, Martin WJ, Fields HL | title = An analgesia circuit activated by cannabinoids | journal = Nature | volume = 395 | issue = 6700 | pages = 381–383 | date = September 1998 | pmid = 9759727 | doi = 10.1038/26481 | s2cid = 1619608 | bibcode = 1998Natur.395..381M }} in a rat model of neuropathic pain.{{cite journal | vauthors = Herzberg U, Eliav E, Bennett GJ, Kopin IJ | title = The analgesic effects of R(+)-WIN 55,212-2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain | journal = Neuroscience Letters | volume = 221 | issue = 2–3 | pages = 157–160 | date = January 1997 | pmid = 9121688 | doi = 10.1016/S0304-3940(96)13308-5 | s2cid = 33643599 }} It activates p42 and p44 MAP kinase via receptor-mediated signaling.{{cite journal | vauthors = Bouaboula M, Poinot-Chazel C, Bourrié B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P | display-authors = 6 | title = Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1 | journal = The Biochemical Journal | volume = 312 ( Pt 2) | issue = Pt 2 | pages = 637–641 | date = December 1995 | pmid = 8526880 | pmc = 1136308 | doi = 10.1042/bj3120637 }}

At 5 μM WIN 55,212-2 inhibits ATP production in sperm in a CB₁ receptor-dependent fashion.{{cite journal | vauthors = Morgan DJ, Muller CH, Murataeva NA, Davis BJ, Mackie K | title = Δ9-Tetrahydrocannabinol (Δ9-THC) attenuates mouse sperm motility and male fecundity | journal = British Journal of Pharmacology | volume = 165 | issue = 8 | pages = 2575–2583 | date = April 2012 | pmid = 21615727 | pmc = 3423255 | doi = 10.1111/j.1476-5381.2011.01506.x }}

WIN 55,212-2, along with HU-210 and JWH-133, may prevent the inflammation caused by amyloid beta proteins involved in Alzheimer's disease, in addition to preventing cognitive impairment and loss of neuronal markers. This anti-inflammatory action is induced through agonist action at cannabinoid receptors, which prevents microglial activation that elicits the inflammation.

WIN 55,212-2 is a full agonist at the CB₁ cannabinoid receptor (K_i = 1.9 nM) and has much higher affinity than THC (K_i = 41 nM) for this receptor.{{cite journal | vauthors = Kuster JE, Stevenson JI, Ward SJ, D'Ambra TE, Haycock DA | title = Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 264 | issue = 3 | pages = 1352–1363 | date = March 1993 | pmid = 8450470 }}

WIN 55,212-2 is also an agonist of the PPARα and PPARγ nuclear receptors.{{cite journal | vauthors = O'Sullivan SE | title = An update on PPAR activation by cannabinoids | journal = British Journal of Pharmacology | volume = 173 | issue = 12 | pages = 1899–1910 | date = June 2016 | pmid = 27077495 | pmc = 4882496 | doi = 10.1111/bph.13497 }}

WIN 55,212-2 reduces voluntary wheel running in laboratory mice, but with effects that depend on both genetic background and sex.{{cite journal | vauthors = Keeney BK, Meek TH, Middleton KM, Holness LF, Garland T | title = Sex differences in cannabinoid receptor-1 (CB1) pharmacology in mice selectively bred for high voluntary wheel-running behavior | journal = Pharmacology, Biochemistry, and Behavior | volume = 101 | issue = 4 | pages = 528–537 | date = June 2012 | pmid = 22405775 | doi = 10.1016/j.pbb.2012.02.017 | s2cid = 25174208 }}

In the United States, all CB₁ receptor agonists of the 3-(1-naphthoyl)indole class such as WIN 55,212-2 are Schedule I Controlled Substances.{{UnitedStatesCode2|21|812|Schedules of controlled substances}} WIN 55,212-2 is illegal in the UK.{{cite web|url=http://www.legislation.gov.uk/uksi/2013/239/article/4/made|title=The Misuse of Drugs Act 1971 (Amendment) Order 2013 | work = legislation.gov.uk }}

WIN 55,212-2 is also a CB2 receptor agonist and thereby, like other cannabinoid CB2 agonists, found to significantly improve cardiac recovery after ischaemia/reperfusion (I/R) in the hearts of diabetic fatty rats, by restoring coronary perfusion pressure and heart rate to pre-ischaemic levels, by the restoration of the inducible nitric oxide synthase (iNOS)/endothelial nitric oxide synthase (eNOS) cardiac equilibrium.{{cite journal | vauthors = González C, Herradón E, Abalo R, Vera G, Pérez-Nievas BG, Leza JC, Martín MI, López-Miranda V | display-authors = 6 | title = Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS | journal = Diabetes/Metabolism Research and Reviews | volume = 27 | issue = 4 | pages = 331–340 | date = May 2011 | pmid = 21309057 | doi = 10.1002/dmrr.1176 | s2cid = 32450365 }}{{cite journal | vauthors = Shmist YA, Goncharov I, Eichler M, Shneyvays V, Isaac A, Vogel Z, Shainberg A | title = Delta-9-tetrahydrocannabinol protects cardiac cells from hypoxia via CB2 receptor activation and nitric oxide production | journal = Molecular and Cellular Biochemistry | volume = 283 | issue = 1–2 | pages = 75–83 | date = February 2006 | pmid = 16444588 | doi = 10.1007/s11010-006-2346-y | s2cid = 24074568 }}