Distinct molecular recognition of psychostimulants by human and Drosophila serotonin transporters

In this study, human embryonic kidney (HEK)-293 cells stably expressing human, Drosophila, or a chimeric serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, dSERT, and H1–281D282–476H477–638, respectively) were used to explore the ability of two libraries of structurally distinct psychostimulants to inhibit 5-HT uptake. One library consisted of 3-phenyltro-pane analogs, whereas the second library consisted of several substituted amphetamines. hSERT exhibited a lower Ki value for all the compounds in both libraries compared with dSERT, whereas the chimeric SERT exhibited properties more closely resembling those of dSERT. This species selectivity was ex-plored using computer-generated comparative molecular field analysis to model the interactions of the cocaine analogs and substituted amphetamines at hSERT, dSERT, and the cross