Novel Pharmacotherapies for Psychostimulant Addiction

描述(由申请人提供)： 兰德公司最近的一项研究表明，甲基安非他明(MA)的滥用每年给美国造成超过200亿美元的损失。大约有1000万美国人至少使用过MA一次。长期使用MA具有深远的健康后果和巨大的社会影响。在退伍军人医疗中心，滥用MA与增加对其他设施资源的使用以及对患有额外精神障碍的退伍军人的有害后果有关。然而，目前还没有被批准的治疗MA成瘾的药物，因此迫切需要发现MA的药物疗法。MA是多巴胺(DA)神经元质膜和胞内囊泡单胺转运体(VMAT2)转运体(DAT)的底物，干扰DA的生理摄取和释放。这项建议的首要目标是从一类新的和新的芳基胡椒基不平等唑烷酮(APQs)中确定临床前候选药物。本文提出的新化合物旨在抑制VMAT2的摄取，并可能利用一种新的作用机制。在具体目标1中，临床前候选药物的鉴定将涉及先导化合物APQs的顺序分子修饰。通过连续的分子修饰和优化母体化合物的四个区域对VMAT2的抑制和相对于竞争生物靶标的选择性的优化，体外分析包括药物与VMAT2上多个结合位点的相互作用分析，VMAT2的功能，对MA诱导的VAMT2调节变化的影响，以及药物与其他神经递质受体和转运体的相互作用。化合物将进行修饰，以优化电子、空间和亲脂因子在VMAT2上的功能和抑制效力。将引入拓扑变化来探索VMAT2抑制的三维要求。VMAT2结合部位的生物对映体选择性将通过设计和评价对映体化合物来开发。在具体目标3中，将对选定的先导化合物进行行为药理学评估，包括我们实验室开发的MA效应的新分析，以及MA诱导活性的常规分析。该项目有可能利用一种全新的MA药物疗法加速关键突破。它的独特之处在于，它不依赖于通常的VMAT2结合部位来发挥其功能作用，因此提供了一个机会，构建在结合和药理学特征上不同于那些已经在探索的抗MA药物治疗的分子。 公共卫生相关性： 甲基苯丙胺滥用和成瘾是退伍军人管理局患者群体中的重大问题，并干扰其他精神疾病的诊断和治疗。此外，滥用甲基苯丙胺的退伍军人管理局患者使用退伍军人管理局资源的水平不成比例。目前，还没有被批准的针对甲基苯丙胺滥用症状的药物治疗方法。这项申请将描述一类可能包含治疗甲基苯丙胺滥用症状的药物与一种新的神经化学靶点的相互作用，并检查新药阻止甲基苯丙胺诱导行为的能力。

DESCRIPTION (provided by applicant): A recent study by the Rand Corporation indicated that methamphetamine (MA) abuse costs the United States over $20 billion/year. About 10 million Americans have used MA at least once. Chronic MA use has far reaching health consequences and a tremendous societal impact. At V.A. Medical Centers, abuse of MA is associated with increased use of other facility resources and deleterious consequences for veterans with additional psychiatric disorders. However, there are currently no approved medications for treatment of MA addiction, and consequently there is an urgent need to discover MA pharmacotherapies. MA is a substrate for the dopamine (DA) transporter (DAT) on DA neuron plasma membranes, and at intracellular vesicular monoamine transporters (VMAT2), and interferes with the physiological uptake and release of DA. The overarching goal of this proposal is to identify preclinical candidates, from a new and novel class of aryl piperidinequinazolinones (APQs). The novel compounds proposed here are designed to inhibit VMAT2 uptake and may utilize a new mechanism of action. In Specific Aim 1, identification of preclinical candidates will involve the sequential molecular modification of the lead compound APQs. Lead optimization will be achieved by sequential molecular modification and optimization of four regions of the parent compound with respect to inhibition of VMAT2 and selectivity versus competing biological targets that are identified using in vitro assays in Specific Aim 2. The in vitro assays include analysis of drug interactions with multiple binding sites on the VMAT2, VMAT2 function, effects on MA-induced changes in VAMT2 regulation, and drug interaction with other neurotransmitter receptors and transporters. Compounds will be modified to optimize electronic, steric and lipophilic factors on functional and inhibitory potency at VMAT2. Topological changes will be introduced to explore the three- dimensional requirement of VMAT2 inhibition. Bioenantioselectivity of the VMAT2 binding site will be exploited by design and evaluation of enantiopure compounds. In Specific Aim 3, selected lead compounds will be undergo behavioral pharmacological evaluation, including novel assays of MA effects developed in our laboratories, in addition to conventional assays of MA induced activity. This project has the potential to accelerate critical breakthroughs using an entirely new class of MA pharmacotherapies. It is unique in that it does not rely on the usual VMAT2 binding site for its functional effects and therefore affords an opportunity to construct molecules that differ in binding and pharmacological profiles from those already in exploration as anti-MA pharmacotherapies. PUBLIC HEALTH RELEVANCE: Methamphetamine abuse and addiction are significant problems in the VA patient population and interfere with diagnosis and treatment of other psychiatric disorders. Additionally, VA patients who abuse methamphetamine use VA resources at disproportionate levels. Currently, there are no approved pharmacological treatments for symptoms of methamphetamine abuse. This application will characterize the interactions of a new class of drugs that could contain pharmacotherapies for symptoms of methamphetamine abuse, with a novel neurochemical target, and examines the ability of the new drugs to block methamphetamine-induced behaviors.