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

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journal contribution
posted on 16.04.2012, 00:00 by Kathryn A. Seely, Lisa K. Brents, Anna Radominska-Pandya, Gregory W. Endres, Gregory S. Keyes, Jeffery H. Moran, Paul L. Prather
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 (Ki = 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.