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
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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]
- Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, AR 72205 (United States)
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.
https://doi.org/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.
https://doi.org/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 = []
issue = {2}
volume = {269}
journal type = {AC}
place = {United States}
year = {2013}
month = {Jun}
}
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 = []
issue = {2}
volume = {269}
journal type = {AC}
place = {United States}
year = {2013}
month = {Jun}
}