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

多巴胺转运体(DAT)已被确认为主要的大脑 受体位置与奖赏和愉悦的特性最相关 可卡因。继续分析DAT结构与功能的关系 在本财年期间，将进一步描述特定的角色 极性氨基酸在转运蛋白中的作用，重要的报道 半胱氨酸可能参与分子内二硫键，以及 开始识别重要的芳香族残基。这些研究是 辅之以识别选择性结构-功能特征 可能具有可卡因活性的候选铅小分子化合物 对抗者。这些分析揭示了候选化合物具有 与可卡因类似物识别相比，可卡因类似物识别具有显著的选择性 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.