Modulating P-glycoprotein to Enhance Neurodegenerative Drug Penetration of Brain

调节 P-糖蛋白增强神经退行性药物在大脑中的渗透

基本信息

  • 批准号:
    7489886
  • 负责人:
  • 金额:
    $ 18.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2007
  • 资助国家:
    美国
  • 起止时间:
    2007-09-01 至 2010-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): In this proposal, we are investigating ways to increase the brain bioavailability of agents targeted against epilepsy and Alzheimer's disease, two common and devastating neurological disorders. We are exploring ways to reversibly modulate the activity of P-glycoprotein (P-gp) at the blood brain barrier (BBB). It has been shown in vivo that pharmacological inhibition of P-gp at the blood brain barrier by valspodar (PSC833) increased the uptake of the anti-epileptic agent phenytoin, a P-gp substrate, in brains. We propose to develop novel dimeric prodrug inhibitors of P-gp based on the therapeutic agents themselves. Once into the brain, these dimeric prodrugs will revert to the known approved therapeutic agent. We hypothesize that co-administration of the dimeric prodrug inhibitor in conjunction with therapeutic doses of the monomeric drug would serve to increase the level of the therapeutic agent in the brain and potentially lower the overall patient dose level. We believe that we have assembled a team of PIs with extensive experience to address each of the Specific Aims. Specific Aim 1: We will synthesize prodrug dimers of anti-epilepsy drugs (AEDs) (phenytoin, phenobarbital and lamotrigine), an anti-Alzheimer's disease drug (galantamine) and a potential anti- Alzheimer's disease agent (Gleevec) that are tethered via traceless linkers. Specific Aim 2: We will evaluate inhibition of P-gp transport by the prodrug dimers using various cell lines that overexpress P-gp or express P-gp at endogenous in vivo levels. Specific Aim 3: We will evaluate inhibition of P-gp transport of the fluorescent substrates daunomycin, calcein-AM, Bodipy-FL-verapamil and rhodamine 123 in isolated rat brain capillaries by the prodrug dimers and will use the therapeutic monomers as controls. At the completion of the proposed funding period, we will have dimeric prodrugs with activity against P-glycoprotein in brain endothelial cell and brain capillary models. The long term goals of this research will be to monitor brain penetration of AEDs and anti-Alzheimer's drugs in combination with the active prodrugs in an epileptic mouse model. Treating brain diseases is problematic because a number of drugs are not able to enter the brain. This lack of brain penetration is caused in part by a pump at the barrier to the brain that removes drugs before brain entry. This proposal seeks to remedy this problem by blocking the pump temporarily to allow drugs to pass into the brain. Completion of these studies has the potential to improve treatment of epilepsy and Alzheimer's disease.
描述(由申请人提供):在该提案中,我们正在研究增加针对癫痫和阿尔茨海默病(两种常见的破坏性神经系统疾病)的药物的脑生物利用度的方法。我们正在探索可逆调节血脑屏障(BBB)上P-糖蛋白(P-gp)活性的方法。体内研究表明,伐司泊达(PSC833)对血脑屏障P-gp的药理学抑制作用增加了脑中抗癫痫药苯妥英钠(P-gp底物)的摄取。我们建议开发新的二聚体前体药物抑制剂的P-gp的治疗剂本身的基础上。一旦进入大脑,这些二聚体前药将恢复为已知的批准的治疗剂。我们假设,二聚体前药抑制剂与治疗剂量的单体药物联合给药将有助于增加脑中治疗剂的水平,并可能降低患者的总剂量水平。我们相信,我们已经组建了一个具有丰富经验的PI团队来解决每个特定目标。具体目标1:我们将合成抗癫痫药物(AEDs)(苯妥英、苯巴比妥和拉莫三嗪)、抗阿尔茨海默病药物(加兰他敏)和潜在的抗阿尔茨海默病药物(格列卫)的前药二聚体,它们通过无痕接头连接。具体目标二:我们将使用过表达P-gp或以内源性体内水平表达P-gp的各种细胞系评价前药二聚体对P-gp转运的抑制作用。具体目标3:我们将评估前药二聚体对荧光底物柔红霉素、钙黄绿素-AM、Bodipy-FL-维拉帕米和罗丹明123在分离的大鼠脑毛细血管中的P-gp转运的抑制作用,并将使用治疗单体作为对照。在建议的资助期结束时,我们将在脑内皮细胞和脑毛细血管模型中获得对P-糖蛋白具有活性的二聚体前药。这项研究的长期目标是监测癫痫小鼠模型中AED和抗阿尔茨海默病药物与活性前药组合的脑渗透。治疗脑部疾病是有问题的,因为许多药物无法进入大脑。这种缺乏大脑渗透的部分原因是由于大脑屏障处的泵在进入大脑之前将药物移除。这项提案试图通过暂时阻断泵来解决这个问题,让药物进入大脑。这些研究的完成有可能改善癫痫和阿尔茨海默病的治疗。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Toward eradicating HIV reservoirs in the brain: inhibiting P-glycoprotein at the blood-brain barrier with prodrug abacavir dimers.
  • DOI:
    10.1021/ja206867t
  • 发表时间:
    2012-02-15
  • 期刊:
  • 影响因子:
    15
  • 作者:
    Namanja, Hilda A.;Emmert, Dana;Davis, David A.;Campos, Christopher;Miller, David S.;Hrycyna, Christine A.;Chmielewski, Jean
  • 通讯作者:
    Chmielewski, Jean
Inhibition of human P-glycoprotein transport and substrate binding using a galantamine dimer.
  • DOI:
    10.1016/j.bbrc.2009.08.056
  • 发表时间:
    2009-10-30
  • 期刊:
  • 影响因子:
    3.1
  • 作者:
    Namanja, Hilda A.;Emmert, Dana;Pires, Marcos M.;Hrycyna, Christine A.;Chmielewski, Jean
  • 通讯作者:
    Chmielewski, Jean
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CHRISTINE A HRYCYNA其他文献

CHRISTINE A HRYCYNA的其他文献

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{{ truncateString('CHRISTINE A HRYCYNA', 18)}}的其他基金

FASEB SRC on Protein Lipidation, Signaling and Membrane Domains.
FASEB SRC 关于蛋白质脂化、信号传导和膜结构域。
  • 批准号:
    8977960
  • 财政年份:
    2015
  • 资助金额:
    $ 18.04万
  • 项目类别:
Structure, Function and Conformational Dynamics of the Ste14p Methyltransferase
Ste14p 甲基转移酶的结构、功能和构象动力学
  • 批准号:
    8483309
  • 财政年份:
    2013
  • 资助金额:
    $ 18.04万
  • 项目类别:
Structure, Function and Conformational Dynamics of the Ste14p Methyltransferase
Ste14p 甲基转移酶的结构、功能和构象动力学
  • 批准号:
    9040994
  • 财政年份:
    2013
  • 资助金额:
    $ 18.04万
  • 项目类别:
Structure, Function and Conformational Dynamics of the Ste14p Methyltransferase
Ste14p 甲基转移酶的结构、功能和构象动力学
  • 批准号:
    8675864
  • 财政年份:
    2013
  • 资助金额:
    $ 18.04万
  • 项目类别:
FASEB SRC on Protein Lipidation, Signaling and Membrane Domains
FASEB SRC 关于蛋白质脂化、信号传导和膜结构域
  • 批准号:
    8203842
  • 财政年份:
    2011
  • 资助金额:
    $ 18.04万
  • 项目类别:
Modulating P-glycoprotein to Enhance Neurodegenerative Drug Penetration of Brain
调节 P-糖蛋白增强神经退行性药物在大脑中的渗透
  • 批准号:
    7329774
  • 财政年份:
    2007
  • 资助金额:
    $ 18.04万
  • 项目类别:

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