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Allosteric modulation of dopamine transport-Functional and Biochemical Studies

多巴胺转运的变构调节-功能和生化研究

基本信息

批准号：
10179373
负责人：
Ole Valente Mortensen
金额：
$ 39.13万
依托单位：
DREXEL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179373
关键词：
Affect Alcohol abuse Allosteric Site Amphetamines Animal Model Antidepressive Agents Anxiety Attention deficit hyperactivity disorder Behavior Binding Binding Sites Biochemical Biological Assay Biotinylation Brain Diseases Cell membrane Clinical Cocaine Computer Models Data Development Disease Dopamine Drug abuse Elements Family Feedback Future Goals Knowledge Ligands Mediating Mental Depression Mental disorders Methods Modafinil Modeling Molecular Molecular Conformation Neurotransmitters Norepinephrine Orthologous Gene Pharmaceutical Preparations Pharmacology Play Process Proteins Regulation Role Schizophrenia Selective Serotonin Reuptake Inhibitor Serotonin Signal Transduction Site Structure Synapses Testing Therapeutic Transport Process analog base computer studies design dopamine transporter drug of abuse experimental study extracellular inhibitor/antagonist molecular dynamics monoamine multidisciplinary mutant nervous system disorder neurotransmission neurotransmitter transport noradrenaline transporter novel novel therapeutics pharmacophore pre-clinical psychostimulant public health relevance reuptake serotonin transporter small molecule small molecule libraries therapeutic evaluation tool virtual screening

项目摘要

Modified Project Summary/Abstract Section The plasma-membrane monoamine transporters (MATs), including the serotonin (SERT), norepinephrine (NET) and dopamine (DAT) transporters, serve a pivotal role in limiting monoamine-mediated neurotransmission through the reuptake of their respective neurotransmitters. The transporters are the main target of clinically used psychostimulants and antidepressants. The continuing need for therapeutic drugs to treat brain disorders involving aberrant monoamine signaling provides a compelling reason to further our understanding of transporter function and to identify novel ways of targeting them. In this project we will pursue the novel idea that compounds that specifically engage a novel allosteric site we have identified in DAT will provide useful mechanistic information regarding allosteric transporter modulation. Of further significance we believe these compounds could have therapeutic potential. Previous experiments in our group targeted the equivalent allosteric site in SERT in a virtual screening of chemical libraries that identified molecules that interact with this site and display remarkable transporter-modulating activities. These compounds have revealed that engaging this site modulate MAT activity in entirely novel ways, including stimulating transporter function and affecting the interaction with transporter ligands such as the selective serotonin reuptake inhibitors (SSRIs) and psychostimulants. In corresponding experiments on DAT, we have now identified compounds, KM822 among others, that modifies DAT function and its interaction with exogenous ligands and modifies psychostimulant-elicited behaviors. The overarching hypothesis of this project is that the specific engagement of the allosteric site in DAT will provide valuable information regarding mechanisms of the dopamine transport process and could provide novel therapeutic avenues for developing DAT-based medications. We propose to pursue this idea by further developing our tool compounds to study different types of allosteric modulation employing computational, functional, and biochemical assays to characterize how the compounds modulate transport mechanisms. Consequently, the successful completion of this project will result in the development of novel ligands of DAT that can be employed as experimental tools to further our understanding of this important neurotransmitter transporter and importantly, it could open new therapeutic avenues.

修改后的项目摘要/摘要部分质膜单胺转运蛋白 (MAT)，包括血清素 (SERT)、去甲肾上腺素 (NET) 和多巴胺 (DAT) 转运蛋白，通过重新摄取各自的神经递质，在限制单胺介导的神经传递中发挥关键作用。转运蛋白是临床使用的精神兴奋剂和抗抑郁药的主要靶点。对治疗涉及异常单胺信号传导的脑部疾病的治疗药物的持续需求为进一步了解转运蛋白功能并确定针对它们的新方法提供了令人信服的理由。在这个项目中，我们将追求新的想法，即专门参与我们在 DAT 中鉴定的新型变构位点的化合物将提供有关变构转运蛋白调节的有用机制信息。更重要的是，我们相信这些化合物可能具有治疗潜力。我们小组之前的实验以 SERT 中的等效变构位点为目标，对化学库进行虚拟筛选，识别出与该位点相互作用并表现出显着转运蛋白调节活性的分子。这些化合物表明，参与该位点以全新的方式调节 MAT 活性，包括刺激转运蛋白功能并影响与转运蛋白配体（如选择性血清素再摄取抑制剂 (SSRI) 和精神兴奋剂）的相互作用。在 DAT 的相应实验中，我们现已鉴定出 KM822 等化合物，它们可以改变 DAT 功能及其与外源配体的相互作用，并改变精神兴奋剂引起的行为。该项目的总体假设是，DAT 中变构位点的特定参与将提供有关多巴胺转运过程机制的有价值的信息，并可以为开发基于 DAT 的药物提供新的治疗途径。我们建议通过进一步开发我们的工具化合物来研究不同类型的变构调节，采用计算、功能和生化分析来表征化合物如何调节转运机制，从而实现这一想法。因此，该项目的成功完成将导致 DAT 新型配体的开发，这些配体可用作实验工具，以进一步了解这种重要的神经递质转运蛋白，重要的是，它可以开辟新的治疗途径。