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
amino-substituent 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.