%0 Journal Article %A Peter S Hasenhuetl %A Klaus Schicker %A Xaver Koenig %A Yang Li %A Subhodeep Sarker %A Thomas Stockner %A Sonja Sucic %A Harald H Sitte %A Michael Freissmuth %A Walter Sandtner %T Ligand Selectivity among the Dopamine and the Serotonin Transporter Specified by the Forward Binding Reaction %D 2015 %R 10.1124/mol.115.099036 %J Molecular Pharmacology %P mol.115.099036 %X The membrane transporters for the monoamines serotonin (SERT) and dopamine (DAT) are prominent targets of various psychoactive substances, including competitive inhibitors such as tricyclic antidepressants, methylphenidate, and cocaine. Upon rapid application of substrate, SERT and DAT display an inwardly directed current comprised of a peak- and a steady-state component. Binding of a competitive inhibitor to the transporter leads to reduction of the peak current amplitude, because occupancy of the transporter by an inhibitor prevents the induction of the peak current by substrate. We show that the inhibitory effect on the peak current can be used to study kon, koff, and KD of chemically distinct SERT and DAT inhibitors with high temporal precision and without the need of high-affinity radioligands as surrogate. We exemplify our approach by measuring the kinetics of cocaine, methylphenidate, and desipramine binding to SERT and DAT. Our analysis revealed that the selectivity of methylphenidate and desipramine for DAT and SERT, respectively, can be accounted for by their rate of association, and not by the residence time in their respective binding sites. %U https://molpharm.aspetjournals.org/content/molpharm/early/2015/04/14/mol.115.099036.full.pdf