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Role of amino terminal substitutions in the pharmacological, rewarding and psychostimulant profiles of novel synthetic cathinones
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  • Leticia Duart-Castells,
  • Magdalena Muralter,
  • Nuria Nadal-Gratacos,
  • Brigitte Puster,
  • Xavier Berzosa,
  • Roger Estrada,
  • Marco Niello,
  • Shreyas Bhat,
  • David Pubill,
  • Jorge Camarasa,
  • Harald Sitte,
  • Elena Escubedo,
  • Raúl López-Arnau
Leticia Duart-Castells
Universitat de Barcelona
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Magdalena Muralter
Universitat de Barcelona
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Nuria Nadal-Gratacos
Universitat Ramon Llull Institut Químic de Sarrià
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Brigitte Puster
Universitat de Barcelona
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Xavier Berzosa
Universitat Ramon Llull Institut Químic de Sarrià
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Roger Estrada
Universitat Ramon Llull Institut Químic de Sarrià
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Marco Niello
Medical University of Vienna
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Shreyas Bhat
Medical University of Vienna
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David Pubill
Universitat de Barcelona
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Jorge Camarasa
Universitat de Barcelona
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Harald Sitte
Medical University of Vienna
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Elena Escubedo
Universitat de Barcelona
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Raúl López-Arnau
Universitat de Barcelona
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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.