Development of peptidic dopamine transporter inhibitors via aromatic modification-mediated conformational restriction

The dopamine transporter plays an important role in the molecular mechanism of cocaine dependence. It is suggested that inhibitors of the dopamine transporter would have strong therapeutic potential. Here we report that aromatic modification can constrain a linear peptide into the beta-turn conformation, which is preferred by the dopamine transporter. On the basis of this finding, a novel selective and competitive peptidic inhibitor of the dopamine transporter was developed. The peptide binds to the dopamine- and cocaine-binding site of the dopamine transporter and has behavioral effects different from those of cocaine in mice.