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

多巴胺转运蛋白（DAT）已被确定为主要的大脑 受体部位与奖赏和欣快特性最相关 可卡因。DAT结构-功能关系分析（续） 在本财政年度，进一步描述了特定 极性氨基酸在转运蛋白功能中的重要作用 可能参与分子内二硫键的半胱氨酸，和 开始识别重要的芳香残基。这些研究 辅以选择性结构-功能特征鉴定 可能具有可卡因活性的小分子化合物 对手。 这些分析揭示了候选化合物， 可卡因类似物识别的显著选择性， 多巴胺摄取，减少与其他部位的交叉反应，并提供 选择性可卡因拮抗作用的初步体内证据。

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.