DOPAMINE TRANSPORTER--STRUCTURE/FUNCTION STUDIES OF TRANSPORTER AND LIGANDS

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The dopamine transporter (DAT) has been identified as a principal brain receptor site correlated with the rewarding and euphoric properties of cocaine. Analyses of DAT structure-function relationships continued during this FY with further characterization of the roles of specific nonpolar aromatic amino acids in transporter function. These studies were supplemented by identification of selective structure-function features of lead candidate small molecule compounds possibly active in vivo as cocaine antagonists. These analyses revealed candidate compounds with significant selectivity for cocaine analog recognition compared with dopamine uptake and reduced cross-reactivity with other sites. One of these compounds can serve as an apparent partial cocaine antagonist in vivo, blocking cocaine-induced locomotion in mice and reducing the breakpoint of a non-human primate=s response for cocaine self-administration.