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.
Lysergic acid diethylamide (LSD) is known to induce powerful psychoactive effects in humans, which cemented its status as an important tool for clinical research. A range of analogues and derivatives has been investigated over the years, including those classified as new psychoactive substances. This study presents the characterization of the novel lysergamide N,N-diethyl-1-propanoyl-6-(prop-2-en-1-yl)-9,10-didehydroergoline-8β-carboxamide (1P-AL-LAD) using various mass spectrometric, gas-and liquid chromatographic and spectroscopic methods. In vitro metabolism studies using pooled human liver microsomes (pHLM) confirmed that 1P-AL-LAD converted to AL-LAD as the most abundant metabolite consistent with the hypothesis that 1P-AL-LAD may act as a prodrug. Fourteen metabolites were detected in total; metabolic reactions included hydroxylation of the core lysergamide ring structure or the N 6 -allyl group, formation of dihydrodiol metabolites, Ndealkylation, N 1 -deacylation, dehydrogenation, and combinations thereof. The in vivo behavioral activity of 1P-AL-LAD was evaluated using the mouse head twitch response (HTR), a 5-HT 2A -mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. 1P-AL-LAD induced a dosedependent increase in HTR counts with an inverted U-shaped dose-response function, similar to lysergic acid diethylamide (LSD), psilocybin, and other psychedelics.Following intraperitoneal injection, the median effective dose (ED 50
Synthetic cannabinoids (SCs) represent a large group of new psychoactive substances (NPS), sustaining a high prevalence on the drug market since their first detection in 2008. Cumyl-CBMICA and Cumyl-CBMINACA, the first representatives of a new subclass of SCs characterized by a cyclobutyl methyl (CBM) moiety, were identified in July 2019 and February 2020. This work aimed at evaluating basic pharmacological characteristics and human phase-I-metabolism of these compounds. Human phase-I metabolites were tentatively identified by liquid-chromatographyquadrupole-time-of-flight-mass-spectrometry (LC-QToF-MS) of urine samples and confirmed by a pooled-human-liver-microsome (pHLM) assay. The basic pharmacological evaluation was performed applying a competitive ligand binding assay and a functional activation assay (GTPγS) using cell membranes carrying the human cannabinoid receptor 1 (hCB1). Investigation of the human phase-I-metabolism resulted in the identification of specific urinary markers built by mono-or dihydroxylation. While Cumyl-CBMICA was primarily hydroxylated at the indole ring, hydroxylation of Cumyl-CBMINACA mainly occurred at the CBM moiety. Both substances acted as agonists at the hCB1 receptor, although substantial differences could be observed. Cumyl-CBMINACA showed higher binding affinity (Ki = 1.32 nM vs. 29.3 nM), potency (EC50 = 55.4 nM vs. 497 nM) and efficacy (Emax = 207% vs. 168%) than its indole counterpart Cumyl-CBMICA.This study confirms that substitution of an indole by an indazole core tends to increase in vitro potency which is potentially reflected by higher in vivo potency. The emergence and disappearance of SCs distributed via online shops carrying a CBM moiety once more demonstrates the "cat-and-mouse" game between manufacturers and legislation.
The present work is the last of a three-part study investigating a panel of 30 systematically designed synthetic cannabinoid receptor agonists (SCRAs) including features such as the 4-pentenyl tail and varying head groups including amides and esters of L-valine (MMB, AB), L-tert-leucine (ADB), and L-phenylalanine (APP), as well as adamantyl (A) and cumyl moieties (CUMYL). Here, we evaluated these SCRAs for their capacity to activate the human cannabinoid receptor 1 (CB 1 ) via indirect measurement of G protein recruitment. Furthermore, we comparatively evaluated the results obtained from three in vitro assays, based on the recruitment of β-arrestin 2 (βarr2 assay) or Gα i protein (mini-Gα i assay), or binding of [ 35 S]-GTPγS. The observed efficacies (E max ) varied depending on the conducted assay. Statistical analysis suggests that the population means of the relative intrinsic activity (RA i ) significantly differ for the [ 35 S]-GTPγS assay and the other two assays, but the population means of the βarr2 and mini-Gα i assays were not statistically different. Our data suggest that differences observed between the βarr2 and mini-Gα i assays are the best The contribution to this article by Patrick Juchli is independent from and unrelated to his function at PwC Switzerland.
The psychopharmacological properties of the psychedelic drug lysergic acid diethylamide (LSD) have attracted the interest of several generations of scientists.While further explorations involving novel LSD-type compounds are needed to assess their potential as medicinal drugs, the emergence of novel derivatives as recreational drugs has also been observed. 1-Valeroyl-LSD (also known as 1-valeryl-LSD, 1-pentanoyl-LSD, 1V-LSD, or "Valerie") is a new N 1 -acylated LSD derivative that recently appeared on the online market, and it could be viewed as a higher homolog of ALD-52, 1P-LSD, and 1B-LSD. The present study included the analytical characterization and involved various methods of mass spectrometry (MS), gas and liquid chromatography (GC and LC), nuclear magnetic resonance (NMR) spectroscopy, GC-solid-state infrared (GC-sIR) analysis, and Raman spectroscopy. The in vivo activity of 1V-LSD was assessed using the mouse head-twitch response (HTR), a 5-HT 2A -mediated head movement that serves as a behavioral proxy in rodents for human hallucinogenic effects. Similar to LSD and other psychedelic drugs, the HTR induced by 1V-LSD was dose dependent, and the median effective dose for 1V-LSD was 373 nmol/kg, which was about a third of the potency of LSD (ED 50 = 132.8 nmol/kg). Lysergamides containing the N 1 -substituent typically act as weak partial agonists at the 5-HT 2A receptor and are believed to serve as prodrugs for LSD. 1V-LSD is also likely to be hydrolyzed to LSD and serve as a prodrug, but studies to assess the biotransformation and receptor pharmacology of 1V-LSD should be performed to fully elucidate its mechanism of action.
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 Svenja Fischmann and Benedikt Pulver contributed equally to this work.
Synthetic cannabinoids (SCs), often sold as “legal” replacements for cannabis, are the largest group of new psychoactive substances monitored by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA). Currently, close to 240 structurally heterogeneous SCs are monitored through the European Union (EU) Early Warning System, and attributing consistent, informative, and user‐friendly names to SCs has been a challenge in the past. Over time, several naming conventions have been employed with the aim of making SCs more easily recognizable by non‐chemists, including regulators. To achieve this, the names assigned need to contain detailed information on the structural features present in the substance.
This work provides a theoretical framework and a practical hands‐on guideline for consistent naming of SCs, which is easy to understand and can be applied by the forensic community, researchers, clinical practitioners, and policy‐makers. The proposed framework builds on the established letter code system for molecular building blocks (core, linker, linked group, and tail) implemented by the EMCDDA in 2013 and has been expanded to incorporate additional structural features through substitution. The scope of the issue of attributing semi‐systematic code names is illustrated, and earlier approaches used for naming SCs are discussed. The concepts and rules of the EMCDDA framework are described through a flowchart that provides a basis for naming new SCs, a graphical overview of the chemical diversity of SCs, and a detailed list of the SCs identified in the EU by the Early Warning System of the EMCDDA for reference.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.