Medication development of agonist-type treatment agents for stimulant addiction

兴奋剂成瘾激动剂型治疗剂的药物开发

• 批准号: 9348211
• 负责人: Michael Baumann
• 金额: $ 35.24万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9348211
• 关键词: 3,4-Methylenedioxyamphetamine; Address; Adopted; Adverse effects; Advocate; Affinity; Agonist; Amines; Amphetamines; Binding; Binding Sites; Brain; Carrier Proteins; Cells; Clinical Trials; Cocaine; Complex; Data; Development; Docking; Dopamine; Elements; FDA approved; Hybrids; Journals; Lead; Ligand Binding; Ligands; Mediating; Mental disorders; Methadone; Methamphetamine; Modeling; Neurons; Nicotine; Opioid; Paper; Peer Review; Pharmaceutical Preparations; Pharmacotherapy; Proteins; Psychostimulant dependence; Public Health; Publishing; Reporting; Series; Serotonin; United States; addiction; analog; brain tissue; design; dopamine transporter; drug development; drug seeking behavior; effective therapy; inhibitor/antagonist; monoamine; novel; preclinical study; serotonin transporter; stimulant abuse; uptake; varenicline

Summary- Significant progress was made on this project, which involves the development of medications for psychiatric diseases. Four papers were published in peer-reviewed journals. In one notable article, we report that increasing the size of the N-alkyl substituent on the compound 3,4-methylenedioxyamphetamine converts the drug from a transporter releaser into a transporter blocker. These finding have ramifications for designing new medications which target transporters. Specifically, the results demonstrate that increasing steric bulk on the amine group of amphetamine-type compounds will render the drugs less apt to serve as substrate-type releasers, thereby reducing their tendency to produce adverse effects in monoaminergic cells. Determining the structural elements that define substrates and inhibitors at the monoamine transporters is critical to elucidating mechanisms underlying these disparate functions. In this study, we addressed this question directly by generating a series of N-substituted-3,4-methylenedioxyamphetamine (MDA) analogs that differ only in the number of methyl substituents on the terminal amine group. Starting with 3,4-methylenedioxy-Nmethylamphetamine (MDMA), 3,4-ethylenedioxy-N,N-dimethylamphetamine (MDDMA) and 3,4-methylenedioxy-N,N,N-trimethylamphetamine (MDTMA) were prepared. We evaluated functional activities of the compounds at all three monoamine transporters in native brain tissue and in cells expressing the transporters. In addition, we used ligand docking to generate models of the respective protein-ligand complexes, which allowed us to relate experimental findings to available structural information. Our results suggest that the 3,4-methylenedioxy amphetamine analogs bind at the monoamine transporter orthosteric binding site by adopting one of two mutually exclusive binding modes: MDA and MDMA adopt a high-affinity binding mode consistent with a transportable substrate, whereas MDDMA and MDTMA adopt a low-affinity binding mode consistent with an inhibitor, in which the ligand orientation is inverted. Importantly, MDDMA can alternate between both binding modes while MDTMA exclusively binds to the low-affinity mode. Our experimental results are consistent with the idea that the initial orientation of bound ligands is critical for subsequent interactions that lead to transporter conformational changes and substrate translocation.

摘要 - 对该项目取得了重大进展，其中涉及开发精神疾病药物。在同行评审期刊上发表了四篇论文。 在一篇值得注意的文章中，我们报告说，在化合物3,4-甲基二羟基苯丙胺上增加了N-烷基取代基的大小，将该药物从转运蛋白释放器转化为转运蛋白阻滞剂。 这些发现在设计针对转运蛋白的新药物方面产生了影响。具体而言，结果表明，苯丙胺型化合物的胺基上的空间量增加会使这些药物变得较少地作为底物型释放剂，从而降低了它们在单胺能细胞中产生不良影响的趋势。 确定将底物和抑制剂定义在单胺转运蛋白上的结构元素对于阐明这些不同功能的基础机制至关重要。在这个 研究，我们通过产生一系列N-取代的-3,4-甲基二甲基苯丙胺（MDA）类似物直接解决了这个问题，这些类似物仅在末端胺基上的甲基取代基的数量上有所不同。从3,4-甲基二氧基 - nm甲基苯丙胺（MDMA），3,4-乙二基N，N-二甲基甲基苯丙胺（MDDMA）和3,4-甲基二甲基N，N，N，N，N，N-甲基甲基苯丙胺（MDTMA）开始。我们评估了本天然脑组织和表达转运蛋白的细胞中所有三种单胺转运蛋白的功能活性。此外，我们使用配体对接来生成相应的蛋白质配体复合物的模型，这使我们能够将实验发现与可用的结构信息联系起来。我们的结果表明，通过采用两种相互排斥的结合模式之一，通过一种与可运输的基质相一致的高亲和力结合模式，将3,4-甲基二氧二苯丙胺类似物通过采用两种相互排斥的结合模式来在单胺转运蛋白转运蛋白的正骨结合位点结合：MDA和MDMA与可运输的基质相一致的高亲和力结合模式一致方向反转。重要的是，MDDMA可以在两种结合模式之间交替，而MDTMA仅与低亲和力模式结合。我们的实验结果与以下想法一致：结合配体的初始方向对于随后导致转运蛋白构象变化和底物易位的相互作用至关重要。