Since the beginning of the phenomenon of new psychoactive substances (NPS), synthetic cannabinoid receptor agonists (SCRAs) have been the largest and most prevalent subclass of these drugs in Europe. Many countries implemented specific legislation scheduling classes of substances defined on the basis of their chemical structure to reduce supply. We describe the identification and analytical characterization within the EU project ADEBAR plus of 1-(cyclobutylmethyl)-N-(2-phenylpropan-2-yl)-1Hindole-3-carboxamide which resulted in the formal notification through the Early Warning System of the European Monitoring Centre for Drug and Drug Addiction (EMCDDA). This is the first identification of this new SCRA worldwide and the analytical data was distributed (inter-)nationally right after identification in 2019. First, the substance was isolated from the herbal material using preparative high-performance liquid chromatography (HPLC). Structure elucidation and analytical characterization were performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatographyelectrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS), Raman spectroscopy, and nuclear magnetic resonance (NMR) spectroscopy. The new compound contains a cyclobutyl methyl group as a side chain and has not been described in any patent to our knowledge. Based on the semisystematic nomenclature of SCRAs, we propose Cumyl-CBMICA as a short name for the compound.
The number of new psychoactive substances (NPS) that have emerged on the European market has been rapidly growing in recent years, with a particularly high number of new compounds from the group of synthetic cannabinoid receptor agonists. There have been various political efforts to control the trade and the use of NPS worldwide. In Germany, the Act to control the distribution of new psychoactive substances (NpSG) came into force in November 2016. In this new act, two groups of substances were defined, the group "cannabimimetics/synthetic cannabinoids" covering indole, indazole, and benzimidazole core structures, and a second group named "compounds derived from 2-phenethylamine." Shortly after, the first retailers of "herbal blends" promoted new products allegedly not violating the German NpSG. We describe the identification and structural elucidation of one of the first synthetic cannabinoids not being covered by the NpSG, 5-pentyl-2-(2-phenylpropan-2-yl)-2,5-dihydro-1H-pyrido[4,3-b]indol-1-one. For isolation of the substance a flash chromatography separation was applied. The structure elucidation was performed using gas chromatography-mass spectrometry (GC-MS), gas chromatography-solid state infrared spectroscopy (GC-sIR), liquid chromatography-electrospray ionization-quadrupole time of flight-mass spectrometry (LC-ESI-qToF-MS) and nuclear magnetic resonance (NMR) analysis. Additionally, binding affinity towards the cannabinoid receptors CB and CB and efficacy in a cAMP accumulation assay were measured, showing full agonistic activity and high potency at both receptors. The new compound bears a γ-carboline core structure circumventing the German NpSG and the generic definitions in other national laws. As a semi-systematic name for 2-cumyl-5-pentyl-gamma-carbolin-1-one CUMYL-PEGACLONE is suggested.
In 2016, several synthetic cathinones were seized by the State Bureau of Criminal Investigation Bavaria in Germany. Due to their previous appearances in other countries their metabolism was already investigated in human urine as well as different in vitro models. These investigations were conducted using ordinary metabolism studies for drugs of abuse by using general knowledge about drug metabolism and visual comparison of mass spectra. The present study aimed to use untargeted metabolomics to support and improve those methods that highly depend on the investigators experience. Incubations were conducted using pooled human liver microsomes (pHLM) and the two cathinones 1-phenyl-2-(1-pyrrolidinyl)-1-butanone and 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone. Samples were analyzed by LC-HRMS/MS using a metabolomics workflow consisting of a reversed phase or normal phase separation followed by electrospray ionization and full scan in positive or negative mode. LC-MS data was afterwards statistically evaluated using principal component analysis, t-distributed stochastic neighborhood embedding, and hierarchical clustering. Significant features were then identified using MS/MS. The workflow revealed 24 significant features after 1-phenyl-2-(1-pyrrolidinyl)-1-butanone and 39 after 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone incubation, consisting of adducts, artifacts, isomers, and metabolites. The applied untargeted metabolomics strategy was able to find almost all of the metabolites that were previously described for 1-phenyl-2-(1-pyrrolidinyl)-1-butanone in literature as well as three additional metabolites. Concerning 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone biotransformation in pHLM, merely four metabolites described in primary human hepatocytes and human urine were not found. This study revealed that untargeted metabolomics workflows are well suited to support biotransformation studies at least of the investigated compounds in pHLM.
A novel system for the introduction of liquid samples into analytical plasmas for atomic spectrometric analysis is presented in this manuscript for the first time. The proposed ''drop-on-demand'' (DOD) aerosol generator is based on the use of a modified thermal inkjet cartridge. This system employs a lab-built microcontroller, which allows accessing all parameters important for driving the dosing cartridge for the generation of pL-droplets from sample volumes in the mL range. The droplet generation frequency, thus the resulting liquid flow rate, is variable over a wide range from the generation of isolated droplets up to a theoretical flow rate of approximately 2 mL min À1 , with parallel operation of all 300 nozzles available on the employed device. The flow rate was investigated in the range from 20 nL min À1 to 6.3 mL min À1 and a new calibration strategy based on the droplet generation frequency instead of on the use of standard solutions of different concentrations is introduced. The new system is characterized and the achievable analytical figures of merit of such a DOD aerosol generator coupled to a quadrupole ICP-MS are outlined and compared to a commercially available pneumatic low-flow nebulizer, the MicroMistÔ. The new system offers a superior sensitivity by a factor of 8-18, improved limits of detection and better background equivalent concentrations for the investigated elements (Li,
One of the fastest developing fields in analytical spectrochemistry in recent years is ambient desorption/ionization mass spectrometry (ADI-MS). This burgeoning interest has been due to the demonstrated advantages of the method: simple mass spectra, little or no sample preparation, and applicability to samples in the solid, liquid, or gaseous state. One such ADI-MS source, the flowing atmospheric-pressure afterglow (FAPA), is capable of direct analysis of solids just by aiming the source at the solid surface and sampling the produced ions into a mass spectrometer. However, direct introduction of significant volumes of liquid samples into this source has not been possible, as solvent loads can quench the afterglow and, thus, the formation of reagent ions. As a result, the analysis of liquid samples is preferably carried out by analyzing dried residues or by desorbing small amounts of liquid samples directly from the liquid surface. In the former case, reproducibility of sample introduction is crucial if quantitative results are desired. In the present study, introduction of liquid samples as very small droplets helps overcome the issues of sample positioning and reduced levels of solvent intake. A recently developed “drop-on-demand” (DOD) aerosol generator is capable of reproducibly producing very small volumes of liquid (~17 pL). In this paper, the coupling of FAPA-MS and DOD is reported and applications are suggested. Analytes representing different classes of substances were tested and limits of detections were determined. Matrix tolerance was investigated for drugs of abuse and their metabolites by analyzing raw urine samples and quantification without the use of internal standards. Limits of detection below 2 µg/mL, without sample pretreatment, were obtained.
The flowing atmospheric pressure afterglow (FAPA) is a promising new source for atmospheric pressure, ambient desorption/ionization mass spectrometry. However, problems exist with reproducible sample introduction into the FAPA source. To overcome this limitation, a new FAPA geometry has been developed in which concentric tubular electrodes are utilized to form a halo-shaped discharge; this geometry has been termed the halo-FAPA or h-FAPA. With this new geometry, it is still possible to achieve direct desorption and ionization from a surface; however, sample introduction through the inner capillary is also possible and improves interaction between the sample material (solution, vapor, or aerosol) and the plasma to promote desorption and ionization. The h-FAPA operates with a helium gas flow of 0.60 L/min outer, 0.30 L/min inner, applied current of 30 mA at 200 V for 6 watts of power. In addition, separation of the discharge proper and sample material prevents perturbations to the plasma. Optical-emission characterization and gas rotational temperatures reveal that the temperature of the discharge is not significantly affected (< 3% change at 450K) by water vapor during solution-aerosol sample introduction. The primary mass-spectral background species are protonated water clusters, and the primary analyte ions are protonated molecular ions (M+H+). Flexibility of the new ambient sampling source is demonstrated by coupling it with a laser ablation unit, a concentric nebulizer and a droplet-on-demand system for sample introduction. A novel arrangement is also presented in which the central channel of the h-FAPA is used as the inlet to a mass spectrometer.
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