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

Pyrovalerone derivatives (alpha-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 alpha-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 alpha-pyrrolidinophenone group, i.e., alpha-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 alpha-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 alpha-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 alpha-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.