Dataset Information

Human phase I metabolism of the novel synthetic cannabinoid 5F-CUMYL-PEGACLONE.

ABSTRACT:

Purpose

5F-CUMYL-PEGACLONE is a recently emerged ?-carbolinone derived synthetic cannabinoid. The present study aimed to identify phase I metabolites to reliably prove consumption of the substance by urine analysis and to differentiate from the uptake of the non-fluorinated analog CUMYL-PEGACLONE.

Methods

For metabolite characterization, phase I metabolites were analyzed by liquid chromatography-high resolution mass spectrometry after incubation with pooled human liver microsomes. Reliability of the biomarkers was evaluated by analysis of human urine samples (n?=?20) by liquid chromatography-triple quadrupole tandem mass spectrometry. Sample preparation included ?-glucuronidase treatment followed by liquid-liquid extraction.

Results

In total, 15 metabolites were detected in vivo and characterized. Metabolic reactions were primarily observed at the ?-carbolinone core and the 5-fluoropentyl chain, and included N-dealkylation, hydroxylation, hydrolytic defluorination, formation of a dihydrodiol, oxidation to the pentanoic acid metabolite and formation of the propionic acid metabolite. Six of these metabolites were identical with phase I metabolites of CUMYL-PEGACLONE, which must be considered for interpretation of analytical findings in urine samples.

Conclusions

5F-CUMYL-PEGACLONE was subject to extensive metabolism in humans. The propionic acid metabolite was the most abundant metabolite in all urine samples and should be targeted when maximum sensitivity is needed (e.g., drug abstinence control). However, this metabolite also occurs in the biotransformation of the non-fluorinated analog and is, therefore, not a compound-specific marker. For differentiation, a metabolite hydroxylated at the ?-carbolinone core showed to be the most reliable marker and should be used as an additional target analyte.

SUBMITTER: Mogler L

PROVIDER: S-EPMC6315001 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Human phase I metabolism of the novel synthetic cannabinoid 5F-CUMYL-PEGACLONE.

Mogler Lukas L Halter Sebastian S Wilde Maurice M Franz Florian F Auwärter Volker V

Forensic toxicology 20181005 1

<h4>Purpose</h4>5F-CUMYL-PEGACLONE is a recently emerged <i>γ</i>-carbolinone derived synthetic cannabinoid. The present study aimed to identify phase I metabolites to reliably prove consumption of the substance by urine analysis and to differentiate from the uptake of the non-fluorinated analog CUMYL-PEGACLONE.<h4>Methods</h4>For metabolite characterization, phase I metabolites were analyzed by liquid chromatography-high resolution mass spectrometry after incubation with pooled human liver micr ...[more]

PMID: 30636984

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Project description:IntroductionSynthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances that have been associated with multiple instances and types of toxicity. Some SCRAs appear to carry a greater toxicological burden than others, or compared to the prototypical cannabis-derived agonist Δ9-tetrahydrocannabinol (Δ9-THC), despite a common primary mechanism of action via cannabinoid 1 (CB1) receptors. "Off-target" (i.e., non-CB1 receptor) effects could underpin this differential toxicity, although there are limited data around the activity of SCRAs at such targets.MethodsA selection of 7 SCRAs (AMB-FUBINACA, XLR11, PB-22, AKB-48, AB-CHMINICA, CUMYL-PINACA, and 4F-MDMB-BUTINACA), representing several distinct chemotypes and toxicological profiles, underwent a 30 μM single-point screen against 241 G protein-coupled receptor (GPCR) targets in antagonist and agonist mode using a cellular β-arrestin recruitment assay. Strong screening "hits" at specific GPCRs were followed up in detail using concentration-response assays with AMB-FUBINACA, a SCRA with a particularly notable history of toxicological liability.ResultsThe single-point screen yielded few hits in agonist mode for any compound aside from CB1 and CB2 receptors, but many hits in antagonist mode, including a range of chemokine receptors, the oxytocin receptor, and histamine receptors. Concentration-response experiments showed that AMB-FUBINACA inhibited most off-targets only at the highest 30 μM concentration, with inhibition of only a small subset of targets, including H1 histamine and α2B adrenergic receptors, at lower concentrations (≥1 μM). AMB-FUBINACA also produced concentration-dependent CB1 receptor signaling disruption at concentrations higher than 1 μM, but did not produce overt cytotoxicity beyond CP55,940 or Δ9-THC in CB1 expressing cells.DiscussionThese results suggest that while some "off-targets" could possibly contribute to the SCRA toxidrome, particularly at high concentrations, CB1-mediated cellular dysfunction provides support for hypotheses concerning on-target, rather than off-target, toxicity. Further investigation of non-GPCR off-targets is warranted.

Dataset Information

Human phase I metabolism of the novel synthetic cannabinoid 5F-CUMYL-PEGACLONE.

Purpose

Methods

Results

Conclusions

Publications

Human phase I metabolism of the novel synthetic cannabinoid 5F-CUMYL-PEGACLONE.

Similar Datasets

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