A Major Glucuronidated Metabolite of JWH-018 Is a Neutral Antagonist at CB1 Receptors

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-<i>N</i>-(5-hydroxypentyl) β-d-glucuronide (018-gluc), for CB1Rs. The 018-gluc binds CB1Rs (<i>K</i>_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