Structure-metabolism relationships of valine and tert-leucine-derived synthetic cannabinoid receptor agonists: a systematic comparison of the in vitro phase I metabolism using pooled human liver microsomes and high-resolution mass spectrometry
| Autor: | Michael Kassiou, Volker Auwärter, Verena Angerer, Mitchell Longworth, Laura M. Huppertz, Hanna Jechle, Manfred Jung, Florian Franz, Maurice Wilde |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
medicine.drug_class
Chemistry Metabolite 010401 analytical chemistry Biochemistry (medical) Cannabinoid Receptor Agonists Toxicology 01 natural sciences 0104 chemical sciences Pathology and Forensic Medicine Drug detection Designer drug Hydroxylation 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Biochemistry Valine Synthetic cannabinoids medicine 030216 legal & forensic medicine Drug metabolism medicine.drug |
| Zdroj: | Forensic Toxicology. 37:316-329 |
| ISSN: | 1860-8973 1860-8965 |
| Popis: | Synthetic cannabinoid receptor agonists, commonly referred to as ‘synthetic cannabinoids’ (SCs), gained popularity as recreational drugs due to their cannabis-like effects. The subclass of valine or tert-leucine-derived SCs has dominated the ‘designer drug’ market in recent years and has been associated with several severe intoxication cases. Most SCs are highly lipophilic compounds and are extensively metabolized prior to renal excretion. Hence, for drug detection in urine samples, the major metabolites of new compounds have to be identified first. The aim of this study was to elucidate structure-metabolism relationships (SMRs) of valine and tert-leucine-derived SCs enabling in-depth understanding of their phase I biotransformation and facilitating the prediction of suitable analytical targets for urine analysis. After incubation of 32 different valine/tert-leucine-derived SCs with pooled human liver microsomes (pHLM), the phase I metabolite profile of each compound was characterized using liquid chromatography–quadrupole time-of-flight mass spectrometry. By comparing chemical-structural analogs with the relative abundances of their metabolites, SMRs were studied. The terminal functionality (amide vs. methyl ester), the amino acid side chain (valine vs. tert-leucine), the core ring system (indole vs. indazole), and the N-alkyl side chain (cyclohexyl methyl vs. pentyl vs. 5-fluoropentyl vs. 4-fluorobenzyl) showed distinct differences of metabolic dehalogenation, dehydrogenation, formation of dihydrodiols, hydrolysis, hydroxylation, and N-dealkylation. The presented pHLM approach proved to be an effective tool for systematic investigation of SMRs. The information gained from this work may be useful for predicting potential SC metabolites for urine analysis. |
| Databáze: | OpenAIRE |
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