Two 3D quantitative structure–activity relationships (3D-QSAR) models for predicting Cannabinoid receptor 1 and 2 (CB1 and CB2) ligands have been produced by way of creating a practical tool for the drug-design and optimization of CB1 and CB2 ligands. A set of 312 molecules have been used to build the model for the CB1 receptor, and a set of 187 molecules for the CB2 receptor. All of the molecules were recovered from the literature among those possessing measured Ki values, and Forge was used as software. The present model shows high and robust predictive potential, confirmed by the quality of the statistical analysis, and an adequate descriptive capability. A visual understanding of the hydrophobic, electrostatic, and shaping features highlighting the principal interactions for the CB1 and CB2 ligands was achieved with the construction of 3D maps. The predictive capabilities of the model were then used for a scaffold-hopping study of two selected compounds, with the generation of a library of new compounds with high affinity for the two receptors. Herein, we report two new 3D-QSAR models that comprehend a large number of chemically different CB1 and CB2 ligands and well account for the individual ligand affinities. These features will facilitate the recognition of new potent and selective molecules for CB1 and CB2 receptors.
Novel emerging drugs of abuse, also referred as new psychoactive substances, constitute an ever-changing mixture of chemical compounds designed to circumvent legislative controls by means of chemical modifications of previously banned recreational drugs. One such class, synthetic cathinones, namely β-keto derivatives of amphetamines, has been largely abused over the past decade. A number of new synthetic cathinones are detected each year, either in bulk powders/crystals or in biological matrices. It is therefore important to continuously monitor the supply of new synthetic derivatives and promptly report them. By using complementary analytical techniques (i.e. one- and two-dimensional NMR, FT-IR, GC-MS, HRMS and HPLC-UV), this study investigates the detection, identification and full characterization of 1-(4-methylphenyl)-2-(methylamino)pentanone (4-methylpentedrone, 4-MPD), 1-(4-fluorophenyl)-2-(pyrrolidin-1-yl)hexanone (4F-PHP) and 1-(1,3-benzodioxol-5-yl)-2-(ethylamino)-1-pentanone (bk-EPDP), three emerging cathinone derivatives.
Synthetic cannabinoids (SCs) constitute
one of the most rapidly
expanding class of new psychoactive substances. SCs pose a health
threat to the individual and to the public due to their central (psychoactive)
and peripheral effects. Their pharmacology and toxicology are poorly
understood, and the substances can be unexpectedly toxic and harmful.
The metabolism of SCs is also relevant in clinical and forensic toxicology
as SCs are excreted in urine mostly as their metabolites. Thus, SC
metabolites are widely used as markers for identifying SC intake.
Herein, we used human liver microsome systems to study the in vitro
phase I metabolic profiling of five SCs, namely AM-694, 5F-NNEI, FUB-APINACA,
MFUBINAC, and AMB-FUBINACA. The metabolites were detected and structurally
elucidated by liquid chromatography-high resolution mass spectrometry.
The main metabolic pathway of AM-694 (benzoyl-indole SC) is oxidative
defluorination; 5F-NNEI (naphthyl-indole carboxamide SC) follows amide
hydrolysis and monohydroxylation at the naphthyl moiety. However,
indazole carboxamide substituted with an adamantyl group, such as
FUB-APINACA, is likely to produce (isomeric) hydroxylation of the
adamantyl group as the main metabolite species. For the substrates
that contain ester bonds in their structure, like MFUBINAC and AMB-FUBINACA,
the ester hydrolysis metabolite is predominant.
Purpose Synthetic cannabinoids (SCs) represent a large proportion of novel psychoactive substances on the black market and have caused a number of deaths. Polydrug use including combination of SCs and ethanol could further complicate the toxicological impact. To the best of our knowledge, there have been no reports presenting evidence of transesterification between SCs and ethanol in vitro. Methods The in vitro metabolism of the four carboxylate SCs PB-22, NPB-22, 5-fluoro-PB-22 (5F-PB-22), and 5-fluoro-NPB-22 (5F-NPB-22) in the presence of ethanol using human liver microsomes with and without appropriate enzyme inhibitors was studied. Newly identified SC ethyl esters were chemically synthesised and fully characterised. The activity of these SCs and their ethanol transesterification products were assessed using cannabinoid receptor (CB 1 and CB 2) activation assays. Results SCs/ethanol transesterification products were detected and studied using liquid chromatography-high-resolution mass spectrometry. We have shown that the SC ethyl ester formation is mediated by human carboxyl esterase enzymes. The ethyl esters exhibited a reduced activity for the CB receptors compared with their parent compounds. Conclusions These novel ethyl esters may be useful additional markers of cannabinoid administration, and especially so if they prove to have longer half-lives than their parent compounds.
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