Novel Synthetic Cathinone Eutylone and its Structural Isomers Interact with Monoamine Transporters and Induce Locomotor Stimulation in Mice

Abstract

Synthetic cathinones are a class of new psychoactive substances that produce psychostimulant effects and pose public health risks. Currently, derivatives of the synthetic cathinone, methylone, are being confiscated worldwide. Eutylone is a popular emerging methylone analog with ethyl substitutions at the a-carbon and amine positions. Little information is presently available about the pharmacological effects of eutylone. Therefore, based on its structure we hypothesized that the compound interacts with monoamine transporters in the brain and produces locomotor stimulation akin to other cathinone psychostimulants. To test this hypothesis, we compared the effects of eutylone and its structural isomers, pentylone and dibutylone, using in vitro transporter assays in rat brain synaptosomes and in vivo locomotor activity assessments in mice. All drugs displayed dose-dependent inhibition of [3H]neurotransmitter uptake at dopamine transporters (DAT) and norepinephrine transporters (NET), with 10-fold more potent effects at DAT (IC50 = ~120 nM). Contrary to dibutylone, which displayed no effects at serotonin transporters (SERT), eutylone and pentylone inhibited uptake at SERT (0.69 & 1.24 μM respectively) and displayed weak partial releasing actions at SERT (both ~50% of maximal response). All drugs stimulated dose-dependent locomotion in mice, with eutylone displaying the most potent and efficacious effects (ED50 = 2.1 mg/kg, s.c.). Rank order of ED50 potency values for locomotor stimulation was eutylone ≥ pentylone > cocaine > dibutylone. Our results demonstrate that eutylone is a potent monoamine transporter inhibitor that displays preference for DAT and induces locomotor stimulation. Eutylone displayed pharmacological effects very similar to those produced by pentylone, which suggests that eutylone will exhibit similar abuse liability and pose risks for psychostimulant side-effects in human users.