The Potential of Synthetic Cathinones to Block the Membrane Dopamine Transporter: A Summary of Our Molecular Docking Results and Data from In vitro and In vivo Experiments in the Literature

Introduction: The behavioral sensitization (BS) model for psychostimulants is the most developed framework for explaining the occurrence of drug-induced psychoses. However, there is limited data on the potential of synthetic cathinones (SCs) to induce BS, which restricts the model’s full application in understanding this phenomenon. Aim: This study aimed to provide theoretical evidence regarding the potential of synthetic cathinones to inhibit the dopamine membrane transporter at levels sufficient to induce behavioral sensitization. Methods: The following SCs were selected as ligands: 4-methylmethcathinone (mephedrone), 3,4- methylenedioxypyrovalerone (MDPV), and alpha-pyrrolidinovalerophenone (alpha-PVP). Amphetamine and cocaine were included for comparison. Molecular docking was performed using Auto- Dock Vina and the Attracting Cavities algorithms. The human dopamine transporter structure was obtained from the Protein Data Bank (PDB ID: 8Y2DS). Additionally, PubMed, CNKI, and eLibrary databases were searched to compare the docking results with experimental data from cell lines and animal studies; 13 publications were included in the analysis. Results: All synthetic cathinones studied showed no significant differences in binding affinity to the orthosteric site of the dopamine membrane transporter, suggesting that they may act similarly to amphetamine and cocaine. These findings were corroborated by experiments in cell lines. For mephedrone and MDPV, the potential to induce behavioral sensitization (BS) was also confirmed in animal studies. Conclusion: Theoretically, mephedrone, MDPV, and alpha-PVP can inhibit the dopamine membrane transporter, leading to increased extracellular dopamine levels and promoting the development of dopamine hypersensitivity and behavioral sensitization.