Abstract
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.
Highlights
Introduction published maps and institutional affilThe global illicit drug market has changed remarkably over the last few years, and more than 400 new psychoactive substances (NPS) have been detected annually in Europe since 2015 [1], leading to an increase of the chemical diversity of NPS at an unprecedented rate
The corresponding IC50 values and hDAT/hSERT inhibition ratios are summarized in Table 1, and concentration-response curves are depicted in Figure 2A,B. 3-F-α-PVP, 4-F-α-PVP, 3-Br-α-PVP, and 4-Br-α-PVP
Regarding hSERT inhibition, the cathinones substituted with F, along with α-PVP, were the ones with a lower inhibition potency
Summary
Introduction published maps and institutional affilThe global illicit drug market has changed remarkably over the last few years, and more than 400 new psychoactive substances (NPS) have been detected annually in Europe since 2015 [1], leading to an increase of the chemical diversity of NPS at an unprecedented rate. NPS are defined as substances of abuse, either in a pure form or a preparation, that are designed in order to mimic the effect of already considered illicit compounds. Among NPS, one of the most rapidly arising groups of compounds are synthetic cathinones [2]. The effects that they produce are characterized by stimulant, empathogenic, and euphoric properties, similar to those of methamphetamine and cocaine [3]. Mephedrone (4-methyl-methcathinone) was one of the most commonly found cathinones in the illicit drug market in the early 2000s [4] and was shortly after banned in some iations
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