Probing the Selectivity of Monoamine Transporter Substrates by Means of Molecular Modeling

The structurally similar serotonin and dopamine transporter (resp. SERT and DAT) play an important role in neuronal transmission. Although the concept of their function, i.e. the re-uptake of neurotransmitters from the synaptic cleft, has been extensively studied, the exact mechanism for their substrate selectivity is still unknown. Phenylethylamines (PEAs) are ligands of SERT and DAT and many induce reverse transport (efflux) of the protein’s natural substrate (the neurotransmitters 5-hydroxytryptamine and dopamine) in varying degrees and with different kinetics. Thus, studying the interplay of bioactivity values and certain structural features of selected PEAs can lead to new insights about monoamine transporter selectivity. The broadest SAR data currently available for PEAs and their interaction with SERT and DAT has been measured in rat synaptosomes by Baumann and colleagues. Thus, we used this data set to figure out important features which contribute towards selectivity and to guide the selection of a probe compound for subsequent structure-based studies. Consequently, pEC50 values of 28 compounds for SERT and DAT (Table 1) were plotted against each other, providing a clear picture of the PEA’s selectivity profile (Figure 1). Out of this, a couple of detailed SARs can be drawn: