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.; Moran, Jeffery H.; Prather, Paul L.

doi:10.1016/j.taap.2013.03.012

Cited by 80 publications

(71 citation statements)

References 41 publications

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“…Metabolite profiling data obtained from our human hepatocyte study proposes metabolites useful for identifying RCS-4 intake. Identification of RCS-4 metabolites is critical because in vitro and in vivo studies showed that Phase I and II metabolites of JWH-018 and JWH-073 retain strong binding affinity and exhibit agonist potency at CB 1 and CB 2 receptors [28–30]. These metabolites should be synthesized for use as reference standards in clinical and forensic laboratory RCS-4 urine screening and confirmation testing.…”

Section: Resultsmentioning

confidence: 99%

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Metabolite Profiling of Rcs-4, A Novel Synthetic Cannabinoid Designer Drug, Using Human Hepatocyte Metabolism And TOF-MS

Gandhi

Zhu

Pang³

et al. 2014

Bioanalysis

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Background Since 2009, scheduling legislation of synthetic cannabinoids prompted new compound emergence to circumvent legal restrictions. 2-(4-methoxyphenyl)-1-(1-pentyl-indol-3-yl)methanone (RCS-4) is a potent cannabinoid receptor agonist sold in herbal smoking blends. Absence of parent synthetic cannabinoids in urine suggests the importance of metabolite identification for detecting RCS-4 consumption in clinical and forensic investigations. Materials & methods & Results With 1 h human hepatocyte incubation and TOF high-resolution MS, we identified 18 RCS-4 metabolites, many not yet reported. Most metabolites were hydroxylated with or without demethylation, carboxylation and dealkylation followed by glucuronidation. One additional sulfated metabolite was also observed. O-demethylation was the most common biotransformation and generated the major metabolite. Conclusion For the first time, we present a metabolic scheme of RCS-4 obtained from human hepatocytes, including Phase I and II metabolites. Metabolite structural information and associated high-resolution mass spectra can be employed for developing clinical and forensic laboratory RCS-4 urine screening methods.

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Section: Resultsmentioning

confidence: 99%

“…In addition, metabolites of JWH-018 and JWH-073 were also shown to have strong binding affinity and potency at human CB 1 and CB 2 receptors [28–30]. Synthetic cannabinoids are extensively metabolized in humans [5,12].…”

Section: Introductionmentioning

confidence: 99%

Metabolite Profiling of Rcs-4, A Novel Synthetic Cannabinoid Designer Drug, Using Human Hepatocyte Metabolism And TOF-MS

Gandhi

Zhu

Pang³

et al. 2014

Bioanalysis

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“…JWH-018, JWH-073 and CP 47,497-C8-homolog bind to cannabinoid CB1 receptors, inhibit neurotransmission in hippocampal neurons and facilitate cannabinoid CB1 receptor internalization (Atwood et al, 2010, 2011; Brents et al, 2012; Showalter et al, 1996). In addition, JWH-018 and JWH-073 bind to human cannabinoid CB2 receptors and act as agonists (Rajasekaran et al, 2013). Since these compounds share their mechanism of action with Δ 9 -THC, a major active component of marijuana, it is not surprising that JWH-018 and JWH-073 fully substituted for the discriminative stimulus effects of Δ 9 -THC in rhesus monkeys (Ginsburg et al, 2012) and that monkeys developed cross-tolerance to JWH-018 and JWH-073 following repeated administration of Δ 9 -THC (Hruba et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice

Gatch

Forster

2014

Behavioural Pharmacology

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A number of cannabinoid compounds are being sold in the form of incense as “legal” alternatives to marijuana. The purpose of these experiments was to determine whether the most common of these compounds have discriminative stimulus effects similar to Δ9-tetrahydrocannabinol, the main active component in marijuana. Locomotor depressant effects of JWH-018, JWH-073, JWH-200, JWH-203, JWH-250, AM-2201 and CP 47,497-C8-homolog were tested in mice. The compounds were then tested for substitution in rats trained to discriminate Δ9-tetrahydrocannabinol (3 mg/kg, i.p.). The time course of the peak dose of each compound was also tested. Each of the synthetic cannabinoids dose-dependently decreased locomotor activity for one to two hours. Each of the compounds fully substituted for the discriminative stimulus effects of Δ9-tetrahydrocannabinol, mostly at doses that produced only marginal amounts of rate suppression. JWH-250 and CP 47,497-C8-homolog suppressed response rates at doses that fully substituted for Δ9-THC. The time courses varied markedly between compounds. Most of the compounds had a shorter onset than Δ9-THC, and three lasted substantially longer (JWH-073, JWH-250 and CP 47,497-C8-homolog). Several of the most commonly used synthetic cannabinoids produce behavioral effects comparable to those of Δ9-tetrahydrocannabinol, which suggests that these compounds may share the psychoactive effects of marijuana responsible for abuse liability. The extremely long time course of the discriminative stimulus effects and adverse effects of CP 47,497-C8-homolog suggest that CP 47,497-C8-homolog may be associated with increased hazards in humans.

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“…2016;7(10):455-458 thought to play a role in control of pain and emesis. SCs are full agonists of CB receptors with biologically active metabolites [9][10][11]. SCs are in vogue, especially among the young generation who use it for relaxation and recreation without being detected on routine toxicology screens [10,12].…”

Section: Discussionmentioning

confidence: 99%

Pneumomediastinum: A Complication of Synthetic Cannabinoid K2 Use

et al. 2016

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The use of synthetic cannabinoid K2 (SCK2) continues to rise. Products are sold in different flavors and mixed with various herbal products resulting in innumerable presenting symptoms. Common presentations are psychomotor activity, dystonia, hypertension, tachydysrhythmia, rhabdomyolysis, and renal failure. We present a 21-year-old woman who was admitted for severe nausea associated with several bouts of vomiting and upper abdominal pain. She had used SCK2 for recreation prior to the onset of her symptoms and she has been using SCK2 regularly for about a year. Chest and abdomen roentgenogram revealed pneumomediastinum. Esophagogram ruled out esophageal injury. She was managed conservatively with resolution of pneumomediastinum. We hypothesize that hyperemesis secondary to SCK2 use can increase the alveolar pressure leading to barotrauma. Although pneumomediastinum is a benign and selflimiting condition, esophagogram should be performed to exclude esophageal perforation which is a potentially life-threatening condition. Awareness of this presentation is important in order to evaluate for complications of barotrauma.

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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

Cited by 80 publications

References 41 publications

Metabolite Profiling of Rcs-4, A Novel Synthetic Cannabinoid Designer Drug, Using Human Hepatocyte Metabolism And TOF-MS

Metabolite Profiling of Rcs-4, A Novel Synthetic Cannabinoid Designer Drug, Using Human Hepatocyte Metabolism And TOF-MS

Δ9-Tetrahydrocannabinol-like discriminative stimulus effects of compounds commonly found in K2/Spice

Pneumomediastinum: A Complication of Synthetic Cannabinoid K2 Use

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