Centro de Química Estrutural

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Metabolic stability and metabolite profiling of emerging synthetic cathinones

Publication . Lopes, Rita P.; Ferro, Raquel A.; Milhazes, Margarida; Figueira, Margarida; Caldeira, Maria João; Antunes, Alexandra M.M.; Gaspar, Helena

Synthetic cathinones constitute the second largest groups of new psychoactive substances (NPS), which are especially popular among adolescents and young adults. Due to their potential toxicity, the recreational use of these NPS constitute a serious worldwide public health problem. However, their fast appearance in the market renders the continuous updating of NPS information highly challenging for forensic authorities. The unavailability of pharmacokinetic data for emerging NPS is critical for forensic and clinical verifications. With the ultimate goal of having a proactive approach towards the NPS issue, high resolution mass spectrometry was used in the current work to assess preliminary pharmacokinetic data for 8 selected cathinones: 4 reported substances (4-CIC, 3-CMC, 4-CMC and 4-MEAP) and 4 previously unreported ones (3-CIC, 4-MDMB, 4-MNEB and 4-MDMP) for which the emergence on the NSP market is expected to be eminent, were also included in this study. Based on the calculation of pharmacokinetic parameters, half-life and intrinsic clearance, 4-CMC and 4-MDMB are low and high clearance compounds, respectively, and all the remaining cathinones included in this study are intermediate clearance compounds. This fact anticipates the key role of metabolites as suitable biomarkers to extend detection windows beyond those provided by the parent cathinones. Reduction of the keto group and hydroxylation on the alkyl chains were the common metabolic pathways identified for all cathinones. However, the relative importance of these metabolic transformations is dependent on the cathinone substituents. The glucuronic acid conjugation to metabolites stemming for keto group reduction constituted the sole Phase II transformation identified. To our knowledge, this study constitutes the first metabolite profiling of the already reported synthetic cathinones 4-CIC, 3-CMC and 4-CMC. Noteworthy is the fact that 3-CMC accounts for almost a quarter of the quantity of powders seized during 2020. The analytical methods developed, and the metabolites characterized, are now available to be included in routine screening methods to attest the consumption of the 8 cathinones studied.

2023Journal article

Open access

Synthesis of emerging cathinones and validation of a SPE GC–MS method for their simultaneous quantification in blood

Publication . Júlio, Sara; Ferro, Raquel A.; Santos, Susana; Alexandre, Andrea; Caldeira, Maria João; Franco, João; Barroso, Mário; Gaspar, Helena

Over the past 15 years, synthetic cathinones have emerged as an important class of new psychoactive substances (NPS) worldwide. The proliferation of these psychostimulants and their sought-after effects among recreational drug users pose a serious threat to public health and enormous challenges to forensic laboratories. For forensic institutions, it is essential to be one step ahead of covert laboratories, foreseeing the structural changes possible to introduce in the core skeleton of cathinones while maintaining their stimulating activity. In this manner, it is feasible to equip themselves with standards of possible new cathinones and validated analytical methods for their qualitative and quantitative detection. Therefore, the aim of the work herein described was to synthesize emerging cathinones based on the evolving patterns in the illicit drug market, and to develop an analytical method for their accurate determination in forensic situations. Five so far unreported cathinones [4′-methyl-N-dimethylbuphedrone (4-MDMB), 4′-methyl-N-ethylbuphedrone (4-MNEB), 4′-methyl-N-dimethylpentedrone (4-MDMP), 4′-methyl-N-dimethylhexedrone (4-MDMH), and 4′-methyl-N-diethylbuphedrone (4-MDEB)] and a sixth one, 4′-methyl-N-ethylpentedrone, already reported to EMCDDA and also known as 4-MEAP, were synthesized and fully characterized by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). An analytical method for the simultaneous quantification of these cathinones in blood, using solid phase extraction (SPE) combined with gas chromatography-mass spectrometry (GC–MS) was developed and validated. The results prove that this methodology is selective, linear, precise, and accurate. For all target cathinones, the extraction efficiency was higher than 73%, linearity was observed in the range of 10 (lower limit of quantification, LLOQ) to 800 ng/mL, with coefficients of determination higher than 0.99, and the limits of detection (LODs) were 5 ng/mL for all target cathinones. The stability of these cathinones in blood matrices is dependent on the storage conditions; 4-MNEB is the most stable compound and 4-MDMH is the least stable compound. The low limits obtained allow the detection of the compounds in situations where they are involved, even if present at low concentrations.

2023Journal article

Restricted access

Valorisation of Sargassum muticum through the extraction of phenolic compounds using eutectic solvents and intensification techniques

Publication . Jesus, Bárbara C.; Sáenz de Miera, Blanca; Santiago, Rubén; Martins, Alice; Pedrosa, Rui; Gonzalez-Miquel, Maria; Marrucho, Isabel M.

Seaweeds are naturally abundant and spread all over the globe. They have several biologically active secondary metabolites of great interest. In this work, Sargassum muticum was the algae employed as biomass and the aim was to extract phenolic compounds (PCs) using eutectic solvents (ESs). Several betaine-based, proline-based, and choline-based ESs were tested for the extraction of PCs. All extracts were evaluated according to the total phenolic content (TPC), total flavonoid content (TFC) and antioxidant activity (DPPH). Afterwards, the extracts were characterized using HPLC in terms of 9 target PCs (gallic acid, 3,4-dihydroxybenzoic acid, caffeic acid, syringic acid, p-coumaric acid, ferulic acid, salicylic acid, catechin and quercetin). Proline combined with propylene glycol (Pro[thin space (1/6-em)]:[thin space (1/6-em)]PPG) exhibited a higher yield according to HPLC results, followed by proline[thin space (1/6-em)]:[thin space (1/6-em)]1,2-butanediol (Pro[thin space (1/6-em)]:[thin space (1/6-em)]1,2-But) and choline[thin space (1/6-em)]:[thin space (1/6-em)]citric acid (ChCl[thin space (1/6-em)]:[thin space (1/6-em)]CA). Pro[thin space (1/6-em)]:[thin space (1/6-em)]PPG also presented high selectivity towards salicylic acid, while ChCl[thin space (1/6-em)]:[thin space (1/6-em)]CA towards gallic acid. Optimization studies of water content and temperature were performed for the three best ESs, the optimum conditions being 30% (v/v) water and 60 °C extraction temperature. Ultrasound-assisted extraction (UAE) and microwave-assisted extraction (MAE) were two intensification methods evaluated to enhance the extraction process, proving their ability to reduce the extraction time when compared with the conventional solid–liquid extraction (SLE) process. In particular, Pro[thin space (1/6-em)]:[thin space (1/6-em)]PPG-based MAE provided a significantly higher extraction yield in comparison with conventional extraction and with the other extraction solvents. In summary, the combination of ESs with intensification techniques was shown to be a valuable valorization strategy of a marine macroalgae waste, in particular Sargassum muticum.

2023Journal article

Open access