Cytotoxicity of α-Pyrrolidinophenones: an Impact of α-Aliphatic Side-chain Length and Changes in the Plasma Membrane Fluidity

Abstract

Pyrovalerone derivatives (α-pyrrolidinophenones) form a branch of synthetic cathinones, a second most prominent group of novel psychoactive substances. Although the toxicity of 3,4-MDPV, a progenitor of the α-pyrrolidinophenones, is well described, little is known of the potential cytotoxicity of the new members of this group entering the recreational drug market each year. The present study assesses the cytotoxicity of members of the α-pyrrolidinophenone group, i.e., α-PVP, its longer side-chain derivatives PV8 and PV9, and their 4-fluoro- and 4-methoxy-analogs, against model cell lines for the nervous system (SH-SY5Y), liver (Hep G2) and upper airway epithelium (RPMI 2650), and cardiomyocytes (H9C2(2-1)). Additionally, an impact of pyrovalerones on the fluidity of the plasma membrane, as the potential mechanism of their cytotoxicity, was examined. The longer side-chain α-pyrrolidinophenones and their fluoro- and methoxy-analogs produce more pronounced maximal cytotoxicity, with regard to mitochondrial activity and cell membrane integrity, than the five-carbon α-PVP and its substituted derivatives. The report demonstrates, for the first time, that changes of fluidity of the interior part of plasma membrane contribute to the cytotoxicity of pyrovalerone derivatives, in addition to the previously reported mechanisms. Taking into consideration our previous findings that PV8 and PV9 produce weaker psychostimulatory effects than α-PVP, the higher cytotoxicity of the new generation of pyrovalerones can pose a serious threat to abusers, as it is possible that longer-chain compounds may be taken in higher doses to obtain similar levels of stimulation.

Synthetic Cathinones Induce Cell Death in Dopaminergic SH-SY5Y Cells via Stimulating Mitochondrial Dysfunction

“…These results were consistent with previous studies conducted, where an increasing cytotoxicity was documented for drugs with longer alkyl side-chains. Such elongation is thought to increase the lipophilicity (XLogP3-AA values, Figure 1: butylone 1.9, pentylone 2.3, and MDPV 3.3) and hence its ability to penetrate the cell membrane, in order to facilitate cell death [43,44]. Drug potency is also influenced by drug permeability of the blood-brain barrier (BBB).…”

Design, synthesis and biological evaluation of a bi-specific vaccine against α-pyrrolidinovalerophenone (α-PVP) and 3,4-methylenedioxypyrovalerone (MDPV) in rats

“…Abuse of MDPV and α-PVP can have serious medical consequences including abnormal behaviors, profound ataxia, convulsions, severe neuropsychiatric reactions and adverse cardiovascular effects [11][12][13][14]. One treatment approach is by development of a conjugate vaccine, which would function by stimulating the production of anti-drug polyclonal antibodies (pAb) that would bind the drug in the bloodstream and limit its distribution into critical tissues like the brain [15][16][17][18].…”

Methcathinone and 3-Fluoromethcathinone Stimulate Spontaneous Horizontal Locomotor Activity in Mice and Elevate Extracellular Dopamine and Serotonin Levels in the Mouse Striatum

“…During their relatively short presence on the recreational drug market, synthetic cathinones were found to be the causal factor in numerous acute intoxications, some of which resulted in fatalities (Karila et al 2015 ; Marinetti and Antonides 2013 ; Prosser and Nelson 2012 ; Zawilska and Wojcieszak 2013 , 2017 ). Additionally, many synthetic cathinones, such as 3-FMC, 4-methylethcathinone (4-MEC), 3,4-MDPV, mephedrone, methylone, naphyrone, pentedrone, and α-PVP, together with α-PVP derivatives obtained by an alkyl side chain elongation and phenyl ring substitution, were found to be cytotoxic in vitro against neuronal and liver cells (den Hollander et al 2014 , 2015 ; Luethi et al 2017 ; Matsunaga et al 2017a , b ; Siedlecka-Kroplewska et al 2014 , 2018 ; Valente et al 2016a , b , 2017a , b ; Wojcieszak et al 2016 , 2018a ). Typical intoxication with synthetic cathinones produces symptoms associated with the cardiovascular (increased heart rate, arrhythmias, elevated blood pressure, and chest pain) and central nervous systems (dizziness, disorientation, insomnia, seizures, delusions, panic attacks, aggression, memory loss, anxiety, hallucinations), while overdose of compounds endowed with strong serotomimetic activity may result in a life-threatening serotonin syndrome and hyperthermia (Karila et al 2015 ; Liechti 2015 ; Madras 2017 ; Prosser and Nelson 2012 ; Rickli et al 2015 ; Zawilska and Wojcieszak 2013 , 2017 ).…”