Illicit designer “bath salts” frequently contain substituted cathinones. These molecules have strong actions at monoamine transporters as both substrates and inhibitors. One compound found in these preparations is methylenedioxypyrovalerone (MDPV), which acts similarly to cocaine, and is a potent inhibitor of the human dopamine transporter (hDAT). Unlike cocaine, however, MDPV is selective for hDAT and has little affinity for the human serotonin transporter (hSERT). Using structural information from crystal structures of hSERT and the D. melanogaster dopamine transporter (dDAT), and clues from dDAT’s distinct pharmacology, we aimed to find structural features in hDAT that are critical for potent MDPV binding. A transporter-induced Ca2+ fluorescence assay was used to assess human cells stably expressing mutant transporters and transiently expressing Ca2+ channels. Critical residues for MDPV binding in hDAT were identified in helices 8 and 3 near the central binding pocket. These findings have important implications for the determination of the structural determinants of hDAT/hSERT specificity for other substituted cathinones and amphetamines, and by extension their abuse liability.

Studies of monoamine transporter interactions with MDPV, a component of illicit “bath salts”

2019 Spring National Meeting

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