"TITLE","AUTHORS","SUBJECT","SUBJECT_RELATED","DESCRIPTION","PUBLISHER","AVAILABILITY","RESEARCH_ORG","SPONSORING_ORG","PUBLICATION_COUNTRY","PUBLICATION_DATE","CONTRIBUTING_ORGS","LANGUAGE","RESOURCE_TYPE","TYPE_QUALIFIER","JOURNAL_ISSUE","JOURNAL_VOLUME","RELATION","COVERAGE","FORMAT","IDENTIFIER","REPORT_NUMBER","DOE_CONTRACT_NUMBER","OTHER_IDENTIFIER","DOI","RIGHTS","ENTRY_DATE","OSTI_IDENTIFIER","PURL_URL" "Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors","Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)]; Moran, Jeffery H. [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)]; Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)]; Prather, Paul L., E-mail: pratherpaull@uams.edu [Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)]","60 APPLIED LIFE SCIENCES; ALBUMINS; CATTLE; CHO CELLS; DRUG ABUSE; DRUGS; GTP-ASES; GUANOSINE; MARIHUANA; METABOLISM; METABOLITES; RECEPTORS; TOXICITY","","K2 or Spice is an emerging drug of abuse that contains synthetic cannabinoids, including JWH-018 and JWH-073. Recent reports indicate that monohydroxylated metabolites of JWH-018 and JWH-073 retain high affinity and activity at cannabinoid type-1 receptors (CB{sub 1}Rs), potentially contributing to the enhanced toxicity of K2 compared to marijuana. Since the parent compounds also bind to cannabinoid type-2 receptors (CB{sub 2}Rs), this study investigated the affinity and intrinsic activity of JWH-018, JWH-073 and several monohydroxylated metabolites at human CB{sub 2}Rs (hCB{sub 2}Rs). The affinity of cannabinoids for hCB{sub 2}Rs was determined by competition binding studies employing CHO-hCB{sub 2} membranes. Intrinsic activity of compounds was assessed by G-protein activation and adenylyl cyclase (AC)-inhibition in CHO-hCB{sub 2} cells. JWH-073, JWH-018 and several of their human metabolites exhibit nanomolar affinity and act as potent agonists at hCB{sub 2}Rs. Furthermore, a major omega hydroxyl metabolite of JWH-073 (JWH-073-M5) binds to CB{sub 2}Rs with 10-fold less affinity than the parent molecule, but unexpectedly, is equipotent in regulating AC-activity when compared to the parent molecule. Finally, when compared to CP-55,940 and Δ{sup 9}-tetrahydrocannabinol (Δ{sup 9}-THC), JWH-018, JWH-018-M5 and JWH-073-M5 require significantly less CB{sub 2}R occupancy to produce similar levels of AC-inhibition, indicating that these compounds may more efficiently couple CB{sub 2}Rs to AC than the well characterized cannabinoid agonists examined. These results indicate that JWH-018, JWH-073 and several major human metabolites of these compounds exhibit high affinity and demonstrate distinctive signaling properties at CB{sub 2}Rs. Therefore, future studies examining pharmacological and toxicological properties of synthetic cannabinoids present in K2 products should consider potential actions of these drugs at both CB{sub 1} and CB{sub 2}Rs. - Highlights: • JWH-018 and JWH-073 are synthetic cannabinoids present in abused K2 products. • JWH-018, JWH-073 and their human metabolites have high affinity for CB{sub 2} receptors. • JWH-018, JWH-073 and their human metabolites are potent agonists at CB{sub 2} receptors. • JWH-018, JWH-073 and their metabolites exhibit distinct CB{sub 2} signaling properties. • Studies of JWH-018 and JWH-073 should consider actions at CB{sub 1} and CB{sub 2} receptors.","","Available from http://dx.doi.org/10.1016/j.taap.2013.03.012","","","United States","2013-06-01","","English","Journal Article","","2","269","Journal Name: Toxicology and Applied Pharmacology; Journal Volume: 269; Journal Issue: 2; Other Information: Copyright (c) 2013 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA)","","Medium: X; Size: page(s) 100-108","PII: S0041-008X(13)00108-7","","","Journal ID: ISSN 0041-008X; CODEN: TXAPA9; Other: PII: S0041-008X(13)00108-7; TRN: US14R2934106728","https://doi.org/10.1016/J.TAAP.2013.03.012","","2014-12-11","22285301",""