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Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors

Abstract

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>>
Authors:
Rajasekaran, Maheswari; Brents, Lisa K.; Franks, Lirit N.; [1]  Moran, Jeffery H.; [1]  Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)]; Prather, Paul L., E-mail: pratherpaull@uams.edu [1] 
  1. Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)
Publication Date:
Jun 01, 2013
Product Type:
Journal Article
Resource Relation:
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)
Subject:
60 APPLIED LIFE SCIENCES; ALBUMINS; CATTLE; CHO CELLS; DRUG ABUSE; DRUGS; GTP-ASES; GUANOSINE; MARIHUANA; METABOLISM; METABOLITES; RECEPTORS; TOXICITY
OSTI ID:
22285301
Country of Origin:
United States
Language:
English
Other Identifying Numbers:
Journal ID: ISSN 0041-008X; CODEN: TXAPA9; Other: PII: S0041-008X(13)00108-7; TRN: US14R2934106728
Availability:
Available from http://dx.doi.org/10.1016/j.taap.2013.03.012
Submitting Site:
USN
Size:
page(s) 100-108
Announcement Date:
Dec 11, 2014

Citation Formats

Rajasekaran, Maheswari, Brents, Lisa K., Franks, Lirit N., Moran, Jeffery H., Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)], and Prather, Paul L., E-mail: pratherpaull@uams.edu. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. United States: N. p., 2013. Web. doi:10.1016/J.TAAP.2013.03.012.
Rajasekaran, Maheswari, Brents, Lisa K., Franks, Lirit N., Moran, Jeffery H., Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)], & Prather, Paul L., E-mail: pratherpaull@uams.edu. Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors. United States. doi:10.1016/J.TAAP.2013.03.012.
Rajasekaran, Maheswari, Brents, Lisa K., Franks, Lirit N., Moran, Jeffery H., Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)], and Prather, Paul L., E-mail: pratherpaull@uams.edu. 2013. "Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors." United States. doi:10.1016/J.TAAP.2013.03.012. https://www.osti.gov/servlets/purl/10.1016/J.TAAP.2013.03.012.
@misc{etde_22285301,
title = {Human metabolites of synthetic cannabinoids JWH-018 and JWH-073 bind with high affinity and act as potent agonists at cannabinoid type-2 receptors}
author = {Rajasekaran, Maheswari, Brents, Lisa K., Franks, Lirit N., Moran, Jeffery H., Arkansas Department of Public Health, Public Health Laboratory, Little Rock, AR 72205 (United States)], and Prather, Paul L., E-mail: pratherpaull@uams.edu}
abstractNote = {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.}
doi = {10.1016/J.TAAP.2013.03.012}
journal = {Toxicology and Applied Pharmacology}
issue = {2}
volume = {269}
journal type = {AC}
place = {United States}
year = {2013}
month = {Jun}
}