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Article

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

1
Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine (IBUB), Faculty of Pharmacy and Food Science, University of Barcelona, 08028 Barcelona, Spain
2
Pharmaceutical Chemistry Group (GQF), IQS School of Engineering, Universitat Ramon Llull, 08017 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Academic Editors: Matteo Marti, Liana Fattore, Carlo Locatelli and Monia Lenzi
Int. J. Mol. Sci. 2022, 23(4), 2226; https://doi.org/10.3390/ijms23042226
Received: 17 January 2022 / Revised: 8 February 2022 / Accepted: 9 February 2022 / Published: 17 February 2022
(This article belongs to the Special Issue Pharmaco-Toxicological Effects of Novel Psychoactive Substances)
Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives. View Full-Text
Keywords: synthethic cathinones; new psychoactive substances; α-PVP; psychostimulant; reward; anxiety; structure-activity relationship synthethic cathinones; new psychoactive substances; α-PVP; psychostimulant; reward; anxiety; structure-activity relationship
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MDPI and ACS Style

Nadal-Gratacós, N.; Lleixà, E.; Gibert-Serramià, M.; Estrada-Tejedor, R.; Berzosa, X.; Batllori, X.; Pubill, D.; Camarasa, J.; Escubedo, E.; López-Arnau, R. Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives. Int. J. Mol. Sci. 2022, 23, 2226. https://doi.org/10.3390/ijms23042226

AMA Style

Nadal-Gratacós N, Lleixà E, Gibert-Serramià M, Estrada-Tejedor R, Berzosa X, Batllori X, Pubill D, Camarasa J, Escubedo E, López-Arnau R. Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives. International Journal of Molecular Sciences. 2022; 23(4):2226. https://doi.org/10.3390/ijms23042226

Chicago/Turabian Style

Nadal-Gratacós, Núria, Esther Lleixà, Mónica Gibert-Serramià, Roger Estrada-Tejedor, Xavier Berzosa, Xavier Batllori, David Pubill, Jordi Camarasa, Elena Escubedo, and Raúl López-Arnau. 2022. "Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives" International Journal of Molecular Sciences 23, no. 4: 2226. https://doi.org/10.3390/ijms23042226

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