Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones

Abstract

Background and Purpose: The emergence of new synthetic cathinones continues to be a matter of public health concern. In fact, they are quickly replaced by new structurally related alternatives. The main goal of the present study was to characterize the pharmacological profile, the psychostimulant and rewarding properties of novel synthetic cathinones differing in its amino terminal substitution. Experimental Approach: Rat brain synaptosomes were used for [3H]dopamine uptake experiments. HEK293 transfected cells (hDAT, hSERT, hOCT; human dopamine, serotonin and organic cation transporter, respectively) were also used for [3H]monoamine uptake and transporter binding assays. Molecular docking allowed to investigate the effect of the amino substitutions on the biological activity. Locomotor activity experiments and conditioned place preference paradigm were used in order to study the psychostimulant and rewarding effects in mice. Key Results: All compounds tested are potent inhibitors of DAT with very low affinity for SERT, hOCT-2 and -3, and their potency inhibiting DAT increased when the aminosubstituent expanded from a methyl-to either an ethyl-, a pyrrolidine-or a piperidine-ring. Regarding the in vivo results, all the compounds induced an increase in locomotor activity and possess rewarding properties. Results also showed a significant correlation between predicted binding affinities by molecular docking and affinity constants (Ki) for hDAT. Conclusions and Implications: Our study demonstrated the role of the amino-substituent in the pharmacological profile of novel synthetic cathinones and provides the first evidence that some of them are potent DAT inhibitors and able to induce psychostimulant and rewarding effects in mice.

Psychoactive Drugs—From Chemical Structure to Oxidative Stress Related to Dopaminergic Neurotransmission. A Review

“…), but above all to avoid the introduction of compounds on the prohibited list. As a result, most of the new compounds, later classified into generations, were designer molecules of the old compounds, the list having to be constantly updated by the legislator [ 57 , 58 , 59 , 60 , 61 , 62 , 63 ]. The DAT vs SERT ratios of synthetic cathinones are presented in Table 1 .…”