Novel Pharmacotherapies for Psychostimulant Addiction

治疗精神兴奋剂成瘾的新型药物疗法

• 批准号: 8391623
• 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/8391623
• 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.

描述（由申请人提供）： 兰德公司最近的一项研究表明，甲基安非他明滥用每年使美国损失200多亿美元。大约有1000万美国人至少使用过一次MA。长期使用MA具有深远的健康后果和巨大的社会影响。在退伍军人管理局。医疗中心，滥用MA与其他设施资源的使用增加和有害后果的退伍军人与其他精神疾病。然而，目前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是多巴胺（DA）神经元质膜上的多巴胺转运蛋白（DAT）的底物，并在细胞内囊泡单胺转运蛋白（VMAT2），并干扰生理的吸收和释放DA.The总体目标的建议是确定临床前的候选人，从一个新的和新的一类芳基哌啶quinazolinones（APQs）。本文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母体化合物的四个区域的顺序分子修饰和优化来实现，这些区域涉及VMAT 2的抑制和相对于竞争性生物靶标的选择性，这些生物靶标是使用特定目标2中的体外试验鉴定的。体外试验包括分析药物与VMAT2上多个结合位点的相互作用、VMAT2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蛋白的相互作用。将对化合物进行修饰以优化电子、空间和亲脂因子对VMAT 2的功能和抑制效力的影响。将引入拓扑变化以探索VMAT2抑制的三维要求。VMAT 2结合位点的生物对映体选择性将通过设计和评价对映体纯化合物来利用。 在特定目标3中，将对选定的先导化合物进行行为药理学评价，包括我们实验室开发的MA效应的新型测定，以及MA诱导活性的常规测定。该项目有可能使用全新的MA药物疗法加速关键突破。其独特之处在于其功能作用不依赖于通常的VMAT 2结合位点，因此提供了构建在结合和药理学特征方面与已经作为抗MA药物疗法探索的分子不同的分子的机会。