Eutylone and Its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation

Abstract

Synthetic cathinones are a class of new psychoactive substances that induce psychostimulant effects and pose risk for hospitalizations, overdose, and death. At the present time, derivatives of the synthetic cathinone, methylone, are being confiscated in nonmedical (i.e., recreational) drug markets worldwide. In particular, eutylone is a newly emerging methylone analog that possesses ethyl groups at the α-carbon and amine positions. Little information is available about the pharmacological effects of eutylone, but based on its structure, we surmised that the compound interacts with monoamine transporters in the brain. To test this hypothesis, we compared the effects of eutylone and its structural isomers, dibutylone and pentylone, using in vitro transporter assays in rat brain synaptosomes and in vivo locomotor activity assessments in mice. All drugs displayed dose-related inhibition of [3H]neurotransmitter uptake at dopamine transporters (DAT) and norepinephrine transporters (NET), but effects at DAT were 10-fold more potent (IC50 = 120 nM). Eutylone and pentylone inhibited uptake at serotonin transporters (SERT), while dibutylone did not. Additionally, eutylone and pentylone displayed weak partial releasing actions at SERT which achieved 50% of maximal response. All drugs stimulated dose-related locomotion in mice, and eutylone was most potent and efficacious in this regard (ED50 = 2 mg/kg, sc). Our results demonstrate that eutylone is a hybrid transporter compound with uptake inhibition properties at DAT and NET but substrate activity at SERT. The effects of eutylone are similar to those produced by pentylone, which suggests that eutylone will exhibit abuse liability and pose risks for psychostimulant side-effects in human users.