Identification and Investigation of the Intrinsic Receptor Activation Potential and Metabolization of the New Oxo-Pyridyl Synthetic Cannabinoid Receptor Agonist CH-FUBBMPDORA.

Abstract

CH-FUBBMPDORA (CHO-4'Me-5'Br-FUBOXPYRA), a recent addition to the recreational drug market, bypasses the Chinese generic ban (2021) on synthetic cannabinoid receptor agonists (SCRAs) due to its new 5-bromo-4-methylpyridin-2(1H)-one core. Its pharmacological properties are currently undefined, and it is yet to be found in biological samples. However, it is unclear whether this is due to low prevalence or hampered detection. The aim of this study was twofold. First, we used a powder seized by customs as a case study to evaluate the utility of low-field nuclear magnetic resonance (LF-NMR) to unequivocally identify CH-FUBBMPDORA. This demonstrated the potential of this technique, which is increasingly used by customs and forensic laboratories for substance identification. High-field nuclear magnetic resonance (HF-NMR), Fourier transform infrared spectrometry (FTIR), gas chromatography-mass spectrometry (GC-MS), liquid chromatography coupled to time-of-flight mass spectrometry (LC-QTOF-MS), and Raman spectroscopy were used as complementary techniques for identification and characterization. Second, we investigated the potential to activate CB₁ and CB₂ and the metabolism of CH-FUBBMPDORA. Potencies and efficacies were assessed using βarr2 recruitment assays. Metabolite studies were conducted via human liver microsome (HLM) incubation followed by LC-QTOF-MS. CH-FUBBMPDORA showed a limited activation potential at both cannabinoid receptors. The seized powder exhibited a pronouncedly higher activity, suggesting the potential presence of contaminants with higher cannabinoid activity. Although analytical characterization revealed minor impurities, it is uncertain whether these explain the bioassay findings. Four metabolites were identified, which were all the result of hydroxylation of either the cyclohexyl head group or of the methyl group on the core.