SYNTHESIS, BIOLOGICAL ASSESSMENT OF CANDIDATE MEDICATIONS FOR STIMULANT ABUSE

兴奋剂滥用候选药物的合成和生物学评估

• 批准号: 8358001
• 负责人: Bertha K Madras
• 金额: $ 1.38万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358001
• 关键词: Amines; Binding; Biological; Brain; Cells; Cocaine; Cocaine Dependence; Corpus striatum structure; Dopamine; Dopamine Receptor; Evaluation; Funding; Grant; Human Cloning; Inhibitory Concentration 50; Isoxazoles; National Center for Research Resources; New England; Nitrogen; Nucleus Accumbens; Octanes; Pharmaceutical Preparations; Pharmacotherapy; Positioning Attribute; Primates; Principal Investigator; Property; Research; Research Infrastructure; Resources; Series; Serotonin; Source; Tissues; United States National Institutes of Health; analog; base; cost; design; extracellular; inhibitor/antagonist; monoamine; prototype; research study; serotonin transporter; stimulant abuse

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. AIMS: The stimulant and reinforcing properties of cocaine, correlate with its ability to inhibit monoamine transporters, e.g. dopamine (DAT), and serotonin (SERT) transporters, in brain (e.g. striatum, nucleus accumbens). Cocaine blockade of monoamine transporters results in elevated extracellular concentrations of dopamine, resulting in enhanced stimulation medicated by dopamine receptor activity. The search for pharmacotherapies for cocaine addiction has focused on the design of compounds that bind selectively to the DAT but with slow onset of DAT occupancy and extended duration of action. Phenyltropane analogs of cocaine, of which CFT (WIN 35,428) is the prototype, have offered promising leads for the discovery of DAT selective inhibitors. Building on our previous studies indicating that an amine nitrogen in the 8-aza position is not a prerequisite for potent inhibition of monoamine inhibition, we discovered that 8-thiatropanes retain substantial DAT binding potency and DAT:SERT selectivity. Presently, we evaluate replacing the 2-carbomethoxy group with a 2-isoxazole. METHODS: Binding experiments initially were established using tissue homogenates from primate brain and then applied to cloned human transporters expressed in HEK-293 cells. RESULTS: This new class of 8-thiabicyclo(3.2.1)octanes displayed potent and selective DAT inhibition, with the 3b-aryl compounds particularly potent (IC50 = 743 nM). In both the 3a-aryl and 3b-aryl series, the 3-methylisoxazole manifested superior DAT inhibitory potency and selectivity compared with the 3-phenylisoxazoles. CONCLUSIONS: The results with this new class of 8-thiatropanes suggests further evaluation is warranted.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 目标：可卡因的刺激和增强特性与其抑制脑（例如纹状体、丘脑核）中的单胺转运体（例如多巴胺（DAT）和5-羟色胺（SERT）转运体）的能力相关。单胺转运蛋白的皮质醇阻断导致多巴胺的细胞外浓度升高，从而导致由多巴胺受体活性介导的增强的刺激。对可卡因成瘾药物疗法的研究集中在设计选择性结合DAT但DAT占用开始缓慢且作用持续时间延长的化合物。可卡因的苯托烷类似物，其中CFT（WIN 35，428）是原型，为发现DAT选择性抑制剂提供了有希望的线索。基于我们先前的研究表明8-氮杂位置上的胺氮不是有效抑制单胺抑制的先决条件，我们发现8-硫托烷保留了大量的DAT结合效力和DAT：SERT选择性。目前，我们评估用2-异恶唑取代2-甲氧羰基。方法：最初使用来自灵长类动物脑的组织匀浆建立结合实验，然后应用于在HEK-293细胞中表达的克隆人转运蛋白。研究结果：这类新的8-硫杂双环（3.2.1）辛烷显示出有效的和选择性的DAT抑制，其中3b-芳基化合物特别有效（IC 50 = 743 nM）。在3a-芳基和3b-芳基系列中，与3-苯基异恶唑相比，3-甲基异恶唑表现出上级DAT抑制效力和选择性。结论：这类新的8-thiatropane的结果表明，需要进一步评价。