The serotonin, dopamine and norepinephrine transporter (SERT, DAT and NET) are transmembrane proteins that regulate the neurotransmitter concentration in the synaptic cleft. Elucidating the molecular basis for their selectivity remains a major interest for the rational design of more selective modulators against mental illnesses such as depression, addiction and Parkinson's disease.In this study we exploit transporter uptake inhibitory activities of cathinones, an amphetamine subclass with increasing recreational popularity, using ligand- and structure-based methods.A QSAR analysis of 16 cathinone analogs pointed mainly towards the importance of lipophilic para substituents for SERT affinity and selectivity. In addition, an electron-poor aromatic ring of the ligand seems to drive NET affinity, suggesting that pi-pi stacking interactions play a role. Conversely, an absence of substituents on any ligand position renders cathinones DAT/NET-over-SERT-selective.The set of cathinones was docked in the central binding site of homology models of the transporter derived from Drosophila DAT(pdb 4M48) with a topology optimized by superposition of a high affinity inhibitor from the humanized leucine transporter, i.e. paroxetine (pdb 4MM4) in SERT and mazindol (pdb 4MME) in DAT and NET. This led to a statistically significant ranking correlation between enthalpy-based scoring functions and affinity at SERT, but not at DAT and NET.These results provide strong evidence for lipophilicity driven SERT selectivity of amphetamines and indicate that differences in stacking interactions are determinants of DAT/NET-over-SERT selectivity.We acknowledge financial support provided by the Austrian Science Fund, grants F035 and W1232.

Interaction type differences as proposed determinants of monoamine transporter selectivity for amphetamines

248th National Meeting (2014)

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