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Chiral Psychoactive Substances: Identification, Toxicity, and Enantioselective Studies

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (28 February 2023) | Viewed by 12137

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Special Issue Editors

Dr. Carla Fernandes

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Guest Editor

1. Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal
2. Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR/CIMAR), Universidade do Porto, Edifício do Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4050-208 Matosinhos, Portugal
Interests: medicinal chemistry; organic chemistry; chiral bioactive substances; enantioselective studies; chirality; chromatography
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Cláudia Maria Rosa Ribeiro

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TOXRUN – Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
Interests: emerging contaminants; psychoactive drugs; ecotoxicity; chromatography

Prof. Dr. Maria Elizabeth Tiritan

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Guest Editor

1. Laboratory of Organic and Pharmaceutical Chemistry, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto, Porto, Portugal
2. TOXRUN–Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, 4585-116 Gandra, Portugal
Interests: organic and pharmaceutical chemistry; chromatography; chirality; organic environmental pollutants
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The abuse of new psychoactive substances and the use of pharmaceuticals to reach psychoactive effects have dramatically increased in recent years. New psychoactive substances represent a public health threat since they are easily accessible online and are sold as a legal alternative to illicit drugs. To circumvent the law, new derivatives are clandestinely synthesized and, consequently, new psychoactive substances keep emerging on the drug market with unknown properties. Most of the psychoactive substances (legal or illicit) are chiral, meaning that they can exist as enantiomeric pairs with different biological and toxicological activities. Thus, enantioselective studies are required, including analysis, metabolism, (eco) toxicological and biodegradation.

The main aims of the present Special Issue include both fundamental studies and applications in a multidisciplinary research field that enrolls chiral psychoactive substances. Contributions to this issue, both in the form of original research or review articles, have the broad scope to illustrate recent and future trends in the identification of new chiral psychoactive substances, methodologies to obtain and analyze the enantiomers in diverse matrices such as biological or environmental, and enantioselective studies in metabolism, biodegradation and (eco)toxicity. Studies that consider enantiomeric profile as a tool for consumption estimation by wastewater-based epidemiology (WBE) are also welcome.

Key aspects such as enantioselective synthesis, enantiomeric resolution, chiral analyses by chromatographic methods, chiral recognition studies—both in enantioseparation and in biological systems—and enantioselectivity in toxicodynamic, toxicokinetic, ecotoxicity studies and enantiomeric profile in WBE will be considered in this Special Issue.

Prof. Dr. Carla Sofia Garcia Fernandes
Prof. Dr. Cláudia Maria Rosa Ribeiro
Prof. Dr. Maria Elizabeth Tiritan
Guest Editors

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Keywords

new psychoactive substances
enantioselective studies
enantioresolution
chiral recognition

Published Papers (4 papers)

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Research

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24 pages, 2936 KiB

Open AccessArticle

Integrated Approach for Synthetic Cathinone Drug Prioritization and Risk Assessment: In Silico Approach and Sub-Chronic Studies in Daphnia magna and Tetrahymena thermophila

by Ariana Pérez-Pereira, Ana Rita Carvalho, João Soares Carrola, Maria Elizabeth Tiritan and Cláudia Ribeiro

Molecules 2023, 28(7), 2899; https://doi.org/10.3390/molecules28072899 - 23 Mar 2023

Cited by 1 | Viewed by 1739

Abstract

Synthetic cathinones (SC) are drugs of abuse that have been reported in wastewaters and rivers raising concern about potential hazards to non-target organisms. In this work, 44 SC were selected for in silico studies, and a group of five emerging SC was prioritized for further in vivo ecotoxicity studies: buphedrone (BPD), 3,4-dimethylmethcathinone (3,4-DMMC), butylone (BTL), 3-methylmethcathinone (3-MMC), and 3,4-methylenedioxypyrovalerone (MDPV). In vivo short-term exposures were performed with the protozoan Tetrahymena thermophila (28 h growth inhibition assay) and the microcrustacean Daphnia magna by checking different indicators of toxicity across life stage (8 days sublethal assay at 10.00 µg L⁻¹). The in silico approaches predicted a higher toxic potential of MDPV and lower toxicity of BTL to the model organisms (green algae, protozoan, daphnia, and fish), regarding the selected SC for the in vivo experiments. The in vivo assays showed protozoan growth inhibition with MDPV > BPD > 3,4-DMMC, whereas no effects were observed for BTL and stimulation of growth was observed for 3-MMC. For daphnia, the responses were dependent on the substance and life stage. Briefly, all five SC interfered with the morphophysiological parameters of juveniles and/or adults. Changes in swimming behavior were observed for BPD and 3,4-DMMC, and reproductive parameters were affected by MDPV. Oxidative stress and changes in enzymatic activities were noted except for 3-MMC. Overall, the in silico data agreed with the in vivo protozoan experiments except for 3-MMC, whereas daphnia in vivo experiments showed that at sublethal concentrations, all selected SC interfered with different endpoints. This study shows the importance to assess SC ecotoxicity as it can distress aquatic species and interfere with food web ecology and ecosystem balance. Full article

(This article belongs to the Special Issue Chiral Psychoactive Substances: Identification, Toxicity, and Enantioselective Studies)

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20 pages, 3622 KiB

Open AccessArticle

Semi-Preparative Separation, Absolute Configuration, Stereochemical Stability and Effects on Human Neuronal Cells of MDPV Enantiomers

by Ana Sofia Almeida, Bárbara Silva, João Pedro Silva, José Augusto Pereira, Fernando Remião and Carla Fernandes

Molecules 2023, 28(5), 2121; https://doi.org/10.3390/molecules28052121 - 24 Feb 2023

Cited by 1 | Viewed by 1294

Abstract

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers’ stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins—brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)—was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed. Full article

(This article belongs to the Special Issue Chiral Psychoactive Substances: Identification, Toxicity, and Enantioselective Studies)

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Graphical abstract

8 pages, 1243 KiB

Open AccessArticle

Characterization of Three Novel 4-Methylaminorex Derivatives Applied as Designer Drugs

by Elisabeth Seibert, Olaf Kunert, Eva-Maria Pferschy-Wenzig and Martin G. Schmid

Molecules 2022, 27(18), 5770; https://doi.org/10.3390/molecules27185770 - 06 Sep 2022

Cited by 4 | Viewed by 2437

Abstract

The ongoing development of more and more new psychoactive substances continues to be a huge problem in 2022 affecting the European and international drug market. Through slight alterations in the structure of illicit drugs, a way to circumvent the law is created, as the created derivatives serve as legal alternatives with similar effects. A common way of structure modification is the induction of a halogen residue. Recently, halogenated derivatives of the well-known designer drug 4-methylaminorex appeared on the market and are available in various online shops. In this study, three novel halogenated 4-methylaminorex derivatives, namely 4′-fluoro-4-methylaminorex, 4′-chloro-4-methylaminorex, and 4′-bromo-4-methylaminorex, were purchased online and characterized using nuclear magnetic resonance (NMR) spectroscopy, liquid chromatography-high-resolution mass spectrometry (LC-HRMS), and chiral high-performance liquid chromatography with ultraviolet detection (HPLC-UV). These derivatives possess two stereogenic centers, and analyses revealed that all of them were present as a racemic mixture of the trans diastereomeric form. Full article

(This article belongs to the Special Issue Chiral Psychoactive Substances: Identification, Toxicity, and Enantioselective Studies)

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Review

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33 pages, 8093 KiB

Open AccessReview

Synthetic Cathinones: Recent Developments, Enantioselectivity Studies and Enantioseparation Methods

by Ana Sofia Almeida, Bárbara Silva, Paula Guedes de Pinho, Fernando Remião and Carla Fernandes

Molecules 2022, 27(7), 2057; https://doi.org/10.3390/molecules27072057 - 22 Mar 2022

Cited by 25 | Viewed by 5888

Abstract

New psychoactive substances represent a public health threat since they are not controlled by international conventions, are easily accessible online and are sold as a legal alternative to illicit drugs. Among them, synthetic cathinones are widely abused due to their stimulant and hallucinogenic effects. To circumvent the law, new derivatives are clandestinely synthesized and, therefore, synthetic cathinones keep emerging on the drug market, with their chemical and toxicological properties still unknown. In this review, a literature assessment about synthetic cathinones is presented focusing on the recent developments, which include more than 50 derivatives since 2014. A summary of their toxicokinetic and toxicodynamic properties are also presented. Furthermore, synthetic cathinones are chiral compounds, meaning that they can exist as two enantiomeric forms which may present different biological and toxicological activities. To analyze the enantiomers, the development of enantiomeric resolution methods for synthetic cathinones is crucial. Many methods have been reported over the years that include mostly chromatographic and electromigration techniques, with liquid chromatography using chiral stationary phases being the technique of choice. This review intended to present an overview of enantioselectivity studies and enantioseparation analysis regarding synthetic cathinones, highlighting the relevance of chirality and current trends. Full article

(This article belongs to the Special Issue Chiral Psychoactive Substances: Identification, Toxicity, and Enantioselective Studies)

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