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

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The dopamine transporter (DAT) has been identified as the principal brain receptor site best 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 polar amino acids in transporter function, reporting of important cysteines possibly involved in intramolecuclar disulfide bonding, and beginning to identify important aromatic residues. These studies were supplemented by identification of selective structure-function features of lead candidte small molecule compounds possibly active as cocaine antagonists. These analyses revealed candidate compounds with significant selectivity for cocaine analog recognition compared with dopamine uptake, reduced cross-reactivity with other sites, and provided preliminary in vivo evidence for selective cocaine antagonism.