Yuri Yu. Morzherin

Identification and analytical characteristics of synthetic cannabinoids with an indazole-3-carboxamide structure bearing a N-1-methoxycarbonylalkyl group

Illicit new psychoactive substances (NPS) are a serious threat to health throughout the world. Such NPS do not usually pass preliminary pharmacological trials. In 2014, we identified a series of five new synthetic cannabinoids with an indazole-3-carboxamide structure bearing an N-1-methoxycarbonylalkyl group. The compounds have very high cannabimimetic activity which has caused mass severe intoxication and deaths. The compounds were identified by means of gas chromatography–mass spectrometry (GC–MS), including high-resolution mass spectrometry (GC–HRMS), ultra-high-performance liquid chromatography–high-resolution tandem mass spectrometry (UHPLC–HRMS2), and 1H and 13C nuclear magnetic resonance spectroscopy (NMR). The peculiarities of mass-spectral fragmentation of the compounds after electron ionization (EI) ionization and collision-induced dissociation (CID) were studied. The analytical characteristics reported for the compounds will enable their identification in a variety of materials seized from criminals.Graphical Abstract

3-Naphthoylindazoles and 2-naphthoylbenzoimidazoles as novel chemical groups of synthetic cannabinoids: Chemical structure elucidation, analytical characteristics and identification of the first representatives in smoke mixtures

By means of gas chromatography with mass spectrometry detection (GC-MS), including high resolution mass spectrometry (GC-HRMS) together with ultra-high performance liquid chromatography in combination with high resolution tandem mass spectrometry (UHPLC-HRMS), nuclear magnetic resonance spectroscopy (NMR) and Fourier transform infrared spectroscopy (FT-IR), structure of novel synthetic cannabinoids, namely, 1-(5-fluoropentyl)-1H-indazol-3-yl(naphthalen-1-yl)methanone, naphthalen-1-yl(1-pentyl-1H-benzo[d]imidazol-2-yl)methanone and 1-(5-fluoropentyl)-1H-benzo[d]imidazol-2-yl(naphthalen-1-yl)methanone was established. Analytical data obtained in the paper enable reliable identification of these compounds during qualitative analysis of seizures, including smoke mixtures.

Synthetic cannabinoid 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]-1,2,4-oxadiazole. The first detection in illicit market of new psychoactive substances

We were the first to detect 3-benzyl-5-[1-(2-pyrrolidin-1-ylethyl)-1H-indol-3-yl]-1,2,4-oxadiazole (given name BzODZ-EPyr) as a new synthetic cannabinoid, in illegal market of new psychoactive compounds (NPS). The compound was known only from pharmaceutical literature so far. BzODZ-EPyr was identified by means of gas chromatography/mass spectrometry (GC/MS) including high resolution mass spectrometry (GC/HRMS), ultra-high performance liquid chromatography/high resolution tandem mass spectrometry (UHPLC/HRMS(2)), Fourier-transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectroscopy (NMR) (1)H and (13)C. The peculiarities of mass-spectral fragmentation in experiments in electronic ionization (EI) and collision-induced dissociation (CID) modes were studied. Herewith we report analytical characteristics of BzODZ-EPyr enabling its (and possible analogues thereof) determination in criminal seizures.

Effects of a non-competitive N-methyl-d-aspartate (NMDA) antagonist, tiletamine, in adult zebrafish

Tiletamine is a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist chemically related to ketamine and phencyclidine. A common veterinary anesthetic drug, tiletamine is currently a Schedule III controlled substance in USA. This compound exerts sedative effects in humans and animals, also having an abuse potential, toxicity and dissociative hallucinogenic properties clinically. However, the neurotropic profile of tiletamine remains poorly understood, necessitating novel models and in-vivo screens, including non-mammalian species. Zebrafish (Danio rerio) are rapidly becoming a popular model organism for screening various CNS drugs, including those acting at NMDA receptors. Here, we investigated acute behavioral effects of 1, 5 and 10mg/L of tiletamine on adult zebrafish. In the standard novel tank test, a 20-min immersion in 1mg/L of tiletamine produced no overt differences from control zebrafish (receiving 0.1% DMSO vehicle), except for reduced top entries. In contrast, tiletamine at 5 and 10mg/L exerted robust dose-dependent sedative effects in zebrafish (also darkening their skin coloration, similar to ketamine and PCP). Gas chromatography/mass spectrometry (GC/MS) analyses revealed no tiletamine peaks in control and 1mg/L groups, but detected tiletamine peaks in zebrafish brain samples at 5 and 10mg/L. Together, these findings demonstrate potent neurotropic effects of tiletamine in zebrafish, and their high sensitivity to this drug. Our findings also support the growing utility of fish-based aquatic screens for studying neuroactive properties of NMDA antagonists in-vivo.

Mass spectrometric properties of N-(2-methoxybenzyl)-2-(2,4,6-trimethoxyphenyl)ethanamine (2,4,6-TMPEA-NBOMe), a new representative of designer drugs of NBOMe series and derivatives thereof.

Emergence of new psychoactive substances, hallucinogenic phenethylamines in particular, in illicit market is a serious threat to human health in global scale. We have detected and identified N-(2-methoxybenzyl)-2-(2,4,6-trimethoxyphenyl)ethanamine (2,4,6-TMPEA-NBOMe), a new compound in NBOMe series. Identification was achieved by means of gas chromatography/mass spectrometry (GC/MS), including high-resolution mass spectrometry with tandem experiments (GC/HRMS and GC/HRMS2 ), ultra-high performance liquid chromatography/high-resolution mass spectrometry with tandem experiments (UHPLC/HRMS and UHPLC/HRMS2 ), and 1 H and 13 C nuclear magnetic resonance spectroscopy. The peculiarities of fragmentation of the compound under electron ionization (EI) and collision-induced dissociation were studied. Despite of the empirical rule denying migration of the hydrogen atom in McLafferty rearrangement to the benzene ring with substituents in the both ortho-positions, it easily occurs for 2,4,6-TMPEA-NBOMe in EI conditions. We have noticed that electron-donating substituents, e.g. methoxy groups in the both ortho-positions and para-positions favor the rearrangement. For specially synthesized N-methyl and N-acyl derivatives McLafferty rearrangement is not observed. N-Acyl derivatives demonstrate McLafferty rearrangement, but the charge retains at the alternative fragment involving N-acyl carbonyl group. We have also showed that the hydrogen atoms in 2,4,6-trimethoxybenzene ring may be easily substituted for deuterium or for strong electrophiles like trifluoroacetyl. Analytical characteristics of 2,4,6-TMPEA-NBOMe and of some derivatives thereof which enable their determination in various criminal seizures are given. Copyright

Synthesis of (1,2,3-thiadiazolyl)imidazolidine-2,4-diones by microwave irradiation and characterization of their biological activity

The effects of microwave irradiation on the synthesis of (1,2,3-thiadiazol-4-yl)- and (1,2,3-thiadiazol-5-yl)imidazolidine-2,4-diones by cyclocondensation of the respective (1,2,3-thiadiazolyl)ureidoacetic acids were studied. The reactions were studied under the conditions of traditional heating at 140°C temperature and microwave irradiation at 170°C. It was shown that microwave heating of (1,2,3-thiadiazol-5-yl)ureido derivatives of carboxylic acids led to the formation of imidazolidine ring, unlike in the case of (1,2,3-thiadiazol-4-yl)ureido derivatives, for which traditional heating was more effective. The derivatives of (1,2,3-thiadiazolyl)imidazolidine-2,4-diones and (1,2,3-thiadiazolyl)ureidoacetic acids were studied with regard to their effects on pine seed germination and seedling growth.

Synthesis of spiro derivatives of 1,2,3-triazolo[5,1- b ][1,3,4]thiadiazines and biological activity thereof

3-Cyclopentylidene(cyclohexylidene)amino-3H-1,2,3-triazole-4-thiolates, formed via Dimroth rearrangement of 1,2,3-thiadiazolylhydrazones of cyclopentanone and cyclohexanone in the presence of triethylamine, reacted in situ with α-bromoacetophenones with the formation of spirocyclic 6,7-dihydro-5H-[1,2,3]triazolo[5,1-b][1,3,4]thiadiazines. The effect of the obtained compounds on the viability and proliferative activity of four lines of cell cultures was studied. The selective proliferative activity was determined.

Synthesis of 4-(4-oxo-1,3-thiazolidin-2-ylidene)-pyrrolidine-2,3,5-triones

It was shown that 2-(1,3-thiazolidin-2-ylidene)acetamides can be used as 2-enamides in cyclocondensation reactions with oxalyl chloride, leading to the formation of new heterocyclic assemblies – 4-(4-oxo-1,3-thiazolidin-2-ylidene)pyrrolidine-2,3,5-triones in 50–88% yields.

Synthesis of 5-(pyrazol-1-yl)-1,2,3-thiadiazoles

A method is proposed for the synthesis of ethyl 5-(3-aryl-4-formyl-1H-pyrazol-1-yl)-1,2,3-thiadiazole-4-carboxylates by a reaction of acetophenone (4-ethoxycarbonyl-1,2,3-thiadiazol-5-yl)hydrazones with a Vilsmeier–Haack complex. The obtained heterocyclic assemblies provide interesting substrates for further modification and study of biological activity.

Synthesis of 1,2,3-Triazolo[1,5-а]Pyridin-8-Ium-3-Olates

Alkylation of sodium 4-acetyl-1-phenyl-1,2,3-triazol-5-olate with α-bromoacetophenones was shown to occur at position 3 of the heterocycle, with the formation of 1,2,3-triazol-3-ium-5-olates. Intramolecular crotonic condensation of the latter led to the formation of 1,2,3-triazolo[1,5-а]pyridin-8-ium-3-olates.