Structural and Mechanistic Characterization of Neurotransmitter Reuptake Inhibiti

性状（由申请人提供）：Na？-突触前质膜的依赖性神经递质转运蛋白在从突触间隙再摄取神经递质中起作用。这些蛋白质包括血清素转运体（SERT）、去甲肾上腺素转运体（NET）和多巴胺转运体（DAT）。它们通过直接降低突触间隙的神经递质浓度来调节神经传递过程。这些转运蛋白可以被各种药物抑制，因此是抗抑郁药如氟西汀（百忧解）、舍曲林（左洛复）、哌甲酯（利他林）（一种常用于治疗注意力缺陷多动障碍（ADHD）的处方药）和精神兴奋剂如可卡因的主要靶点。尽管它们具有明显的药理学和临床重要性，但这些药物在SERT、NET或DAT蛋白中的结合位点是未知的，从而阻碍了对其抑制机制和基于结构的药物设计的理解。我们的目标是确定这些不同类型的药物和精神兴奋剂的人类神经递质转运蛋白的结合位点，并了解其抑制机制，使用结构，生物化学和药理学技术相结合。具体而言，我们建议：（A）提出鉴定三种类型抗抑郁药在人SERT和NET蛋白中的结合位点;（B）鉴定可卡因在DAT中的结合位点;（C）鉴定哌醋甲酯在人DAT蛋白中的结合位点;（D）表征这些药物抑制神经递质转运蛋白的分子机制。我们的目的是了解抑制机制的5-羟色胺和去甲肾上腺素转运体的抗抑郁药和多巴胺转运体的利他林和可卡因，使用结构，生物化学和药理学的方法相结合。这些信息将有助于设计更有效的治疗抑郁症和注意力缺陷多动障碍的药物，以及治疗可卡因滥用的药物。

DESCRIPTION (provided by applicant): Na?-dependent neurotransmitter transporters of the presynaptic plasma membrane function in the reuptake of neurotransmitters from the synaptic cleft. These proteins include the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT). They regulate the neurotransmission process by directly reducing the neurotransmitter concentration at the synaptic cleft. These transporter proteins can be inhibited by various drugs and therefore are the primary targets for: antidepressants such as fluoxetine (Prozac), sertraline (Zoloft), methylphenidate (Ritalin) -a prescription drug commonly used to treat attention-deficit hyperactivity disorder (ADHD), and psychostimulants like cocaine. In spite of their obvious pharmacological and clinical importance, the binding site for these drugs in the SERT, NET or DAT proteins are unknown, thereby hindering both the understanding of their inhibition mechanism and structure-based drug design. We aim to identify the binding site in the human neurotransmitter transporters for these various types of drugs and psychostimulants, and to understand their inhibition mechanism, using a combination of structural, biochemical and pharmacological techniques. Specifically, we propose: (A) to propose to identify the binding site in the human SERT and NET proteins for three types of antidepressants; (B) to identify the binding site in DAT for cocaine; (C) to identify the binding sites in the human DAT protein for methylphenidate; (D) to characterize the molecular mechanism of inhibition of neurotransmitter transporters by these drugs. We aim to understand the inhibition mechanisms of the serotonin and norepinephrine transporters by antidepressants and of the dopamine transporters by Ritalin and cocaine, using a combination of structural, biochemical and pharmacological approaches. Such information will aid in the design of more effective drugs for depression and for attention-deficit hyperactivity disorder, and of agents for the management of cocaine abuse.