Novel Pharmacotherapies for Psychostimulant Addiction

治疗精神兴奋剂成瘾的新型药物疗法

• 批准号: 8597401
• 负责人: Aaron J. Janowsky
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597401
• 关键词: Address; Affinity; Alkaloids; American; Antihypertensive Agents; Behavior; Behavioral; Binding; Binding Sites; Biological; Biological Assay; Cell membrane; Chronic; Clinical; Development; Diagnosis; Dopamine; Drug Interactions; Electronics; Evaluation; Goals; Health; Laboratories; Lead; Medical center; Mental disorders; Methamphetamine; Methamphetamine dependence; Modification; Molecular; Neurotransmitter Receptor; Neurotransmitters; Parents; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Physiological; Property; Psychostimulant dependence; Regulation; Research; Reserpine; Resources; Rodent; Series; Site; Symptoms; Synapses; Testing; Tetrabenazine; United States; Vesicle; Veterans; analog; animal breeding; cost; design; dopamine transporter; dopaminergic neuron; in vitro Assay; interest; methamphetamine abuse; monoamine; neurochemistry; neurotransmitter uptake; novel; patient population; pre-clinical; psychostimulant; public health relevance; research study; stimulant abuse; tool; uptake; vesicular monoamine transporter

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.

描述（由申请人提供）： 兰德公司最近的一项研究表明，甲基苯丙胺 (MA) 滥用每年给美国造成超过 200 亿美元的损失。大约 1000 万美国人至少使用过一次 MA。长期使用 MA 会产生深远的健康后果和巨大的社会影响。在弗吉尼亚州在医疗中心，滥用 MA 与其他设施资源的使用增加以及对患有其他精神疾病的退伍军人造成有害后果有关。然而，目前还没有批准的药物用于治疗MA成瘾，因此迫切需要发现MA药物疗法。 MA 是 DA 神经元质膜上和细胞内囊泡单胺转运蛋白 (VMAT2) 上多巴胺 (DA) 转运蛋白 (DAT) 的底物，并干扰 DA 的生理摄取和释放。该提案的总体目标是从一类新型芳基哌啶喹唑啉酮 (APQ) 中识别临床前候选药物。这里提出的新化合物旨在抑制 VMAT2 摄取，并可能利用新的作用机制。 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 APQ 的连续分子修饰。先导化合物优化将通过连续分子修饰和母体化合物四个区域的优化来实现，这些区域涉及 VMAT2 的抑制以及相对于特定目标 2 中使用体外测定确定的竞争性生物靶标的选择性。体外测定包括药物分析与 VMAT2 上多个结合位点的相互作用、VMAT2 功能、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蛋白的相互作用。化合物将被修改以优化电子、空间和亲脂性因素对 VMAT2 的功能和抑制效力。将引入拓扑变化来探索 VMAT2 抑制的三维需求。 VMAT2 结合位点的生物对映选择性将通过对映纯化合物的设计和评估来利用。 在具体目标 3 中，选定的先导化合物将接受行为药理学评估，除了 MA 诱导活性的常规测定之外，还包括我们实验室开发的 MA 效应的新测定。该项目有潜力利用全新的 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 结合位点来发挥其功能作用，因此提供了构建与已经在探索的抗 MA 药物疗法中的分子结合和药理学特征不同的分子的机会。 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事务部患者以不成比例的水平使用退伍军人事务部资源。目前，还没有批准的药物治疗甲基苯丙胺滥用的症状。该应用将描述一类新型药物与新的神经化学靶标的相互作用，这些药物可能包含针对甲基苯丙胺滥用症状的药物疗法，并检查新药阻止甲基苯丙胺诱导的行为的能力。