title: A major glucuronidated metabolite of JWH-018 is a neutral antagonist at CB1 receptors.
abstract: Recently, hydroxylated metabolites of JWH-018, a synthetic cannabinoid found in many K2/Spice preparations, have been shown to retain affinity and activity for cannabinoid type 1 receptors (CB1Rs). The activity of glucuronidated metabolites of JWH-018 is not known; hence, this study investigated the affinity and activity of a major metabolite, JWH-018-N-(5-hydroxypentyl) β-D-glucuronide (018-gluc), for CB1Rs. The 018-gluc binds CB1Rs (K(i) = 922 nM), has no effect on G-protein activity, but antagonizes JWH-018 activity at CB1Rs. The data suggests that hydroxylation by cytochrome P450s and subsequent glucuronidation by UDP-glucuronosyltransferases produces a metabolite, 018-gluc, which possesses antagonistic activity at CB1Rs.
authors.affiliation: Public Health Laboratory, Arkansas Department of Health , Little Rock, Arkansas 72205, USA. katie.seely@arkansas.gov
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Seely
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Brents
authors.forename: Anna
authors.initials: A
authors.lastname: Radominska-Pandya
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Endres
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Keyes
authors.forename: Jeffery H
authors.initials: JH
authors.lastname: Moran
authors.forename: Paul L
authors.initials: PL
authors.lastname: Prather
mesh_terms: D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D020719:Glucuronides / Q000737:chemistry; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009281:Naphthalenes / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020719:Glucuronides; D007211:Indoles; D009281:Naphthalenes; D043884:Receptor, Cannabinoid, CB1; D003577:Cytochrome P-450 Enzyme System; D014453:Glucuronosyltransferase; C552597:1-pentyl-3-(1-naphthoyl)indole