The ADEBAR project: European and international provision of analytical data from structure elucidation and analytical characterization of NPS.

Novel substances for which none or limited analytical data are available constitute a challenge for police and customs forensic laboratories. The time-consuming process of structural elucidation and acquisition of analytical data has been centralized in the ADEBAR project in Germany, co-funded since 2017 by the EU's Internal Security Fund. The project aims to comprehensively characterize substances relevant for forensic-toxicological casework within the analytical competence network. The analytical datasets are distributed digitally through European and (inter)national channels. Additionally, pharmacological evaluation allows for estimating in vivo potency and potential harm required as scientific evidence for legislative amendments. The ADEBAR project contributes to the availability of analytical data on new substances relevant to the daily work of police and customs laboratories. Since the inception of the ADEBAR project, 549 samples have been registered, and 302 substance reports notified to the EMCDDA, including numerous spectrometric and spectroscopic data. In addition, 3,619 mass spectra have been accumulated in ADEBAR mass spectra databases. A central institution for the structure elucidation and acquisition of valid, high-quality analytical data for police and customs forensic laboratories and forensic medicine institutes is important in the future because there does not seem to be an end to the dynamic of novel NPS appearing on the drug market.

Structure elucidation of the novel synthetic cannabinoid Cumyl-Tosyl-Indazole-3-Carboxamide (Cumyl-TsINACA) found in illicit products in Germany.

New chemical moieties continue to appear in synthetic cannabimimetics (SC), the largest group of new psychoactive substances in the EU. We describe the first comprehensive characterisation of the novel SC Cumyl-Tosyl-Indazole-3-Carboxamide (Cumyl-TsINACA) (N-[2-phenylpropan-2-yl]-1-tosyl-1H-indazole-3-carboxamide) from seized case samples. Structure elucidation was performed within the EU-project ADEBAR plus to facilitate confident identification by other researchers and practitioners worldwide. Characteristic MS fragmentations include the cleavage of the sulfonamide bond (S-N), the aryl sulfone bond (C-S) and the elimination rearrangement of SO2 in the side chain. Cumyl-TsINACA is a full receptor agonist at hCB1 (Emax  = 228%) with very weak binding affinity (Ki  = 292 nm) and low functional activity (EC50  = 31 µm). Thermal degradation of Cumyl-TsINACA was observed under GC conditions. The degree to which the tosyl side chain is cleaved due to pyrolysis primarily depends on solvent, the use of glass wool in the liner and injector temperature. The determination of the constitution by NMR spectroscopy was ambiguous due to the high number of neighbouring, non-proton-bearing atoms. Therefore, other possible structures compatible with the NMR correlations were generated using the WebCocon software. The unambiguous structural evidence was finally obtained by spectra comparison after the synthesis of Cumyl-TsINACA. The low thermal stability, as well as the low affinity and potency, renders this compound unfavourable for the use as a psychoactive substance. Thus, we do not expect widespread adoption of this SC.

Synthetic cannabinoid receptor agonists: Analytical profiles and development of QMPSB, QMMSB, QMPCB, 2F-QMPSB, QMiPSB, and SGT-233.

A diverse assortment of molecules designed to explore the cannabinoid receptor system and considered new psychoactive substances (NPS) have become known as synthetic cannabinoid receptor agonists (SCRAs). One group of SCRAs that has received little attention involves those exhibiting sulfamoyl benzoate, sulfamoyl benzamide, and N-benzoylpiperidine based structures. In this study, quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB), quinolin-8-yl 4-methyl-3-(morpholine-4-sulfonyl)benzoate (QMMSB), quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11), quinolin-8-yl 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methylbenzoate (2F-QMPSB, QMDFPSB, SGT-13), quinolin-8-yl 4-methyl-3-[(propan-2-yl)sulfamoyl]benzoate (QMiPSB, SGT-46), and 3-(4,4-difluoropiperidine-1-sulfonyl)-4-methyl-N-(2-phenylpropan-2-yl)benzamide (SGT-233) were extensively characterized (including data on impurities). The analytical profiles may be useful to researchers and scientists who deal with the emergence of NPS during forensic and clinical investigations. The detection of QMPSB was first published in 2016 but it is worth noting that Stargate International, a company originally formed to develop harm reduction solutions, were involved in the investigation and development of these six compounds for potential release between 2011 and early 2014. Whilst information on the prevalence of use of these particular compounds at the present time is limited, one of the key outcomes of the research performed by Stargate International reviewed here was to set the stage for the quinolin-8-yl ester head group that ultimately led to hybridization with an N-alkyl-1H-indole core to give SGT-21 and SGT-32, which became later known as PB-22 (QMPSB/JWH-018 hybrid) and BB-22, respectively, thus, opening the door to a range of SCRAs carrying the quinolin-8-yl head group from about 2012 onwards.

Syntheses and analytical characterizations of novel (2-aminopropyl)benzo[b]thiophene (APBT) based stimulants.

Two groups of amphetamine-like drugs with psychostimulant properties that were first developed during the course of scientific studies and later emerged as new psychoactive substances (NPS) are based on the (2-aminopropyl)indole (API) and (2-aminopropyl)benzofuran (APB) structural scaffolds. However, sulfur-based analogs with a benzo[b]thiophene structure (resulting in (2-aminopropyl)benzo[b]thiophene (APBT) derivatives) have received little attention. In the present investigation, all six racemic APBT positional isomers were synthesized in an effort to understand their structure-activity relationships relative to API- and APB-based drugs. One lesson learned from the NPS phenomenon is that one cannot exclude the appearance of such substances on the market. Therefore, an in-depth analytical characterization was performed, including various single- and tandem mass spectrometry (MS) and ionization platforms coupled to gas chromatography (GC) and liquid chromatography (LC), nuclear magnetic resonance spectroscopy (NMR), and solid phase and GC condensed phase infrared spectroscopy (GC-sIR). Various derivatizations have also been explored; it was found that all six APBT isomers could be differentiated during GC analysis after derivatization with heptafluorobutyric anhydride and ethyl chloroformate (or heptafluorobutyric anhydride and acetic anhydride) under non-routine conditions. Discriminating analytical features can also be derived from NMR, GC-EI/CI- single- and tandem mass spectrometry, LC (pentafluorophenyl stationary phase), and various infrared spectroscopy approaches (including GC-sIR). Availability of detailed analytical data obtained from these novel APBT-type stimulants may be useful to researchers and scientists in cases where forensic and clinical investigations are warranted.