Para-Halogenation of Amphetamine and Methcathinone Increases the Mitochondrial Toxicity in Undifferentiated and Differentiated SH-SY5Y Cells.

Xun Zhou,Jamal Bouitbir,Matthias E Liechti,Stephan KrähenbüHl,Riccardo V Mancuso

doi:10.3390/ijms21082841

Abstract

Halogenation of amphetamines and methcathinones has become a common method to obtain novel psychoactive substances (NPS) also called “legal highs”. The para-halogenated derivatives of amphetamine and methcathinone are available over the internet and have entered the illicit drug market but studies on their potential neurotoxic effects are rare. The primary aim of this study was to explore the neurotoxicity of amphetamine, methcathinone and their para-halogenated derivatives 4-fluoroamphetamine (4-FA), 4-chloroamphetamine (PCA), 4-fluoromethcathinone (4-FMC), and 4-chloromethcathinone (4-CMC) in undifferentiated and differentiated SH-SY5Y cells. We found that 4-FA, PCA, and 4-CMC were cytotoxic (decrease in cellular ATP and plasma membrane damage) for both cell types, whereby differentiated cells were less sensitive. IC50 values for cellular ATP depletion were in the range of 1.4 mM for 4-FA, 0.4 mM for PCA and 1.4 mM for 4-CMC. The rank of cytotoxicity observed for the para-substituents was chloride > fluoride > hydrogen for both amphetamines and cathinones. Each of 4-FA, PCA and 4-CMC decreased the mitochondrial membrane potential in both cell types, and PCA and 4-CMC impaired the function of the electron transport chain of mitochondria in SH-SY5Y cells. 4-FA, PCA, and 4-CMC increased the ROS level and PCA and 4-CMC induced apoptosis by the endogenous pathway. In conclusion, para-halogenation of amphetamine and methcathinone increases their neurotoxic properties due to the impairment of mitochondrial function and induction of apoptosis. Although the cytotoxic concentrations were higher than those needed for pharmacological activity, the current findings may be important regarding the uncontrolled recreational use of these compounds.

Highlights

Amphetamine is a potent central nervous system (CNS) stimulant, which is or has been used for the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and body weight control under restricted medical prescription [1]
Since amphetamine and methcathinone are illicit for recreational use in most countries, many derivatives of these compounds were synthesized as novel psychoactive substances (NPS) and labeled “legal highs” [5]
These findings are consistent with the observations of Chen et al, who investigated the toxicity of amphetamines in a pulmonary artery model [18,38] and of Luethi et al, who studied the mechanisms with the observations of Chen et al, who investigated the toxicity of amphetamines in a pulmonary artery model [18,38] and of Luethi et al, who studied the mechanisms of hepatocellular toxicity associated with new synthetic cathinones [18,38]

Summary

Introduction

Amphetamine is a potent central nervous system (CNS) stimulant, which is or has been used for the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and body weight control under restricted medical prescription [1]. A series of structurally similar psychoactive substances were derived from amphetamine after 1877 when it was first synthesized. Methcathinone, an amphetamine derivative, is currently used widely as a recreational drug [4]. Since amphetamine and methcathinone are illicit for recreational use in most countries, many derivatives of these compounds were synthesized as novel psychoactive substances (NPS) and labeled “legal highs” [5]. Halogenation has been recognized as a possible method to create “legal highs” form amphetamine and derivatives [6], and as a method to enhance their membrane binding and permeation characteristics [7]. Many reports have documented how halogenated amphetamine derivatives such as 4-chloroamphetamine (PCA, called para-chloroamphetamine; 4-CA), 4-fluoroamphetamine (4-FA), and methcathinone derivatives such as 4-chloromethcathinone (4-CMC) and 4-fluoromethcathinone (4-FMC) have lately reached the market (Figure S1) [8,9,10,11,12]

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Conclusion