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The omega and omega‐1 monohydroxyl metabolites of the abused K2/Spice synthetic cannabinoids JWH‐018 and JWH‐ 073 bind with high affinity and act as agonists at human cannabinoid 2 receptors (hCB2s)
Author(s) -
Brents Lisa K,
Rajasekaran Maheswari,
Franks Lirit,
Moran Jeffery H,
Prather Paul L
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.660.8
Subject(s) - synthetic cannabinoids , cannabinoid , pharmacology , chemistry , cannabinoid receptor type 2 , partial agonist , agonist , cannabinoid receptor , receptor , biochemistry , biology
JWH‐018 and JWH‐073 are synthetic cannabinoids present in K2 or Spice, drugs of abuse marketed as incense. These compounds produce psychoactive effects similar to marijuana, but can also result in death and severe adverse effects including hypertension, tachycardia, agitation, anxiety and hallucinations. Recently, we reported that mono‐hydroxylated metabolites of JWH‐018 and JWH‐073 retain high affinity and exhibit a range of activity at cannabinoid 1 receptors (CB1Rs), potentially contributing to the toxicological consequence of K2 use. Since toxicity of these compounds could also result from action at CB2Rs, this study examined the affinity and intrinsic activity of JWH‐018, JWH‐073 and several phase I monohydroxylated metabolites for hCB2Rs stably transfected in CHO cells. Competition binding experiments and functional studies examining CB2R‐mediated G‐protein activation and inhibition of adenylyl cyclase activity indicated that several metabolites retain nanomolar affinity for hCB2Rs and exhibit partial to full CB2R‐agonist activity. Importantly, this included the omega and omega‐1 monohydroxylated metabolites of JWH‐018 and JWH‐073, which are major metabolites excreted in human urine as glucuronide conjugates. Retention of high CB2R affinity and activity post‐metabolism may prolong CB2R activation, resulting in immune system dysregulation. APHL Award (JHM); 1UL1RR029884 (JHM, PLP)