Synthetic cannabinoid receptor agonists (SCRAs) have been the largest group of illicit psychoactive substances reported to international monitoring and early warning systems for many years. Carboxamide-type SCRAs are amongst the most prevalent and potent. Enantiospecific synthesis and characterization of four indazole-3-carboxamides, AMB-FUBINACA, AB-FUBINACA, 5F-MDMB-PINACA (5F-ADB), and AB-CHMINACA is reported. The interactions of the compounds with CB 1 and CB 2 receptors were investigated using a G-protein coupled receptor (GPCR) activation assay based on functional complementation of a split NanoLuc luciferase and EC 50 (a measure of potency) and E max (a measure of efficacy) values determined. All compounds demonstrated higher potency at the CB 2 receptor than at the CB 1 receptor and ( S )-enantiomers had an enhanced potency to both receptors over the ( R )-enantiomers. The relative potency of the enantiomers to the CB 2 receptor is affected by structural features. The difference was more pronounced for compounds with an amine moiety (AB-FUBINACA and AB-CHMINACA) than those with an ester moiety (AMB-FUBINACA and 5F-MDMB-PINACA). An HPLC method was developed to determine the prevalence of ( R )-enantiomers in seized samples. Lux® Amylose-1 [Amylose tris(3,5-dimethylphenylcarbamate)] has the greatest selectivity for the SCRAs with a terminal methyl ester moiety and a Lux® i-Cellulose-5 column for SCRAs with a terminal amide moiety. Optimized isocratic separation methods yielded enantiomer resolution values (Rs) ≥ 1.99. Achiral GC-MS analysis of seized herbal materials ( n = 16), found 5F-MDMB-PINACA (<1.0–91.5 mg/g herbal material) and AMB-FUBINACA (15.5–58.5 mg/g herbal material), respectively. EMB-FUBINACA, AMB-CHMICA, 5F-ADB-PINACA isomer 2, and ADB-CHMINACA were also tentatively identified. Analysis using chiral chromatography coupled to photodiode array and quadrupole time of flight mass spectrometry (chiral HPLC-PDA-QToF-MS/MS) confirmed that the ( S )-enantiomer predominated in all samples (93.6–99.3% (S)-enantiomer). Small but significant differences in synthesis precursor enantiopurity may provide significant differences between synthesis batches or suppliers and warrants further study. A method to compare potency between samples containing different SCRAs at varying concentrations was developed and applied in this small preliminary study. A 10-fold difference in the “intrinsic” potency of samples in the study was noted. With the known heterogeneity of SCRA infused materials, the approach provides a simplified method for assessing and communicating the risk of their use.
An automated approach to the collection of 1 H NMR (nuclear magnetic resonance) spectra using a benchtop NMR spectrometer and the subsequent analysis, processing, and elucidation of components present in seized drug samples are reported. An algorithm is developed to compare spectral data to a reference library of over 300 1 H NMR spectra, ranking matches by a correlation-based score. A threshold for identification was set at 0.838, below which identification of the component present was deemed unreliable. Using this system, 432 samples were surveyed and validated against contemporaneously acquired GC–MS (gas chromatography–mass spectrometry) data. Following removal of samples which possessed no peaks in the GC–MS trace or in both the 1 H NMR spectrum and GC–MS trace, the remaining 416 samples matched in 93% of cases. Thirteen of these samples were binary mixtures. A partial match (one component not identified) was obtained for 6% of samples surveyed whilst only 1% of samples did not match at all.
In recent years, the occurrence of synthetic opioid fentanyl and its derivatives has grown significantly in forensic casework. This study presents the synthesis and analysis of 18 fentalogs, selected based on information received from local law enforcement. This study provides colorimetric tests, thin‐layer chromatography (TLC) which can potentially be utilized for presumptive screening of the target compounds, as bulk powders or as trace‐level adulterants. The fully validated confirmatory GC–MS method (employing SIM mode) allows the identification of the 18 derivatives, five commonly encountered controlled substances and four adulterants, within 20 minutes. The cross‐validated method described herein provides a sensitive screening and quantitation method for the illicit (and potentially harmful) components at trace levels (LOD = 0.007–0.822 μg/mL and LOQ = 0.023–2.742 μg/mL respectively). Spectral data [1H‐NMR, 13C‐NMR, 19F‐NMR, FT‐IR, and HRMS] and assignments for the synthesized reference materials are also provided in the Supplementary Information for laboratories engaged in the routine analysis of fentanyl and its derivatives.
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