Development of amodiaquine and its analogs as reactivators of organophosphate-inh
作为有机磷-inh再激活剂的阿莫地喹及其类似物的开发
基本信息
- 批准号:8551780
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-30 至 2015-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylcholinesteraseActive SitesAdverse effectsAmodiaquineAnti-Inflammatory AgentsAntidotesAntimalarialsBiochemicalBlood - brain barrier anatomyBrainCaviaChemical WarfareChemoprophylaxisChloroquineChronicComplexDevelopmentDoseDrug KineticsExposure toFamilyFoundationsFundingGenerationsGoalsHumanIn VitroKineticsLeadLifeMedicalMusOrganophosphatesOximesParaoxonPesticidesPharmaceutical ChemistryPharmaceutical PreparationsPoisoningPositioning AttributeProcessProphylactic treatmentRecoveryReportingResidual stateRodent ModelStructureTestingToxic effectadductagedanalogbasebrain tissuedesignfluorophosphateimprovedin vivoinsightlipophilicitymembernerve agentorganophosphate poisoningpreclinical studyprocess optimizationpublic health relevanceresearch studyscaffold
项目摘要
DESCRIPTION (provided by applicant): Once acetylcholinesterase (AChE) reacts with organophosphorous compounds (OPCs) developed for chemical warfare, there is very little anyone can do in case of a massive real-life crisis. Part of the issue is that broad-spectrum antidotes to reverse the effects of OPC exposure have yet to be developed. We have recently discovered that amodiaquine, a well-established anti-malarial drug, is a good candidate for such an antidote: it acts as a reactivator of acetylcholinesterase (AChE) from adducts with organophosphorous compounds (OPCs) via a yet undefined, but not oxime-based, mechanism. In this proposal we will test the hypothesis that lipophilic amodiaquine is suitable for use in viv as a post-exposure treatment of organophosphorous poisoning. We will also study the mechanism of reactivation and demonstrate that we can use amodiaquine and related compounds as scaffolds to achieve reactivation under more optimal conditions. We will pursue three aims:
In Aim 1 we will provide a detailed biochemical and mechanistic characterization of the interactions of amodiaquine and its close structural analogs with AChE and different adducts that AChE forms with organophosphorous compounds.
In Aim 2 we will obtain crystal structures of amodiaquine and its selected analogs with native and OPC inhibited AChE, in order to facilitate rational design of efficient reactivators.
In Aim 3 we will study the ability of amodiaquine to reverse the effects of organophosphorous compounds in vivo, particularly focusing on reactivation of AChE in brain. The results of our experiments will firmly establish amodiaquine as the first member of a new class of reactivators of AChE, enabling pre-clinical studies of post-OPC-exposure treatment. Our mechanistic studies will also help us to generate additional analogs suitable for chronic administration (chemoprophylaxis) as well.
描述(由申请人提供):一旦乙酰胆碱酯酶(ACHE)与为化学战开发的有机磷化合物(OPC)反应,在发生大规模现实生活危机的情况下,几乎没有人可以做。问题的一部分是,尚未开发出OPC暴露影响的广谱解毒剂。我们最近发现,一种良好的抗疟疾药物Amodiaquine是这种解毒剂的良好候选者:它可以通过有机磷酸化合物(OPC)(OPC)的乙酰胆碱酯酶(ACHE)的重新激活,但尚未确定但尚未基于氧电机,但基于氧电机的机制,机制。在此提案中,我们将检验以下假设:亲脂性氨二喹适合在体内用作有机磷中毒的暴露后治疗。我们还将研究重新激活的机制,并证明我们可以将氨喹和相关化合物用作支架,以在更最佳的条件下实现重新激活。我们将追求三个目标:
在AIM 1中,我们将提供详细的生化和机械表征,即氨二喹及其与ACHE的紧密结构类似物的相互作用,以及与有机磷化合物形成的不同加合物。
在AIM 2中,我们将获得Amodiaquine的晶体结构及其与天然和OPC抑制ACHE的所选类似物,以促进有效的重新激活剂的合理设计。
在AIM 3中,我们将研究氨二喹逆转体内有机磷化合物的作用的能力,尤其是专注于大脑ACHE的重新激活。我们的实验结果将牢固地确立Amodiaquine作为ACHE的新反应剂的第一个成员,从而实现了对OPC后暴露治疗的临床研究。我们的机械研究还将帮助我们产生适合慢性给药(化学预防)的其他类似物。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.
- DOI:10.1002/cbic.201500348
- 发表时间:2015-10-12
- 期刊:
- 影响因子:0
- 作者:Katz FS;Pecic S;Tran TH;Trakht I;Schneider L;Zhu Z;Ton-That L;Luzac M;Zlatanic V;Damera S;Macdonald J;Landry DW;Tong L;Stojanovic MN
- 通讯作者:Stojanovic MN
New therapeutic approaches and novel alternatives for organophosphate toxicity.
- DOI:10.1016/j.toxlet.2018.03.028
- 发表时间:2018-07
- 期刊:
- 影响因子:3.5
- 作者:Katz FS;Pecic S;Schneider L;Zhu Z;Hastings-Robinson A;Luzac M;Macdonald J;Landry DW;Stojanovic MN
- 通讯作者:Stojanovic MN
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{{ truncateString('DONALD W LANDRY', 18)}}的其他基金
Development of amodiaquine and its analogs as reactivators of organophosphate-inh
作为有机磷-inh再激活剂的阿莫地喹及其类似物的开发
- 批准号:
8416866 - 财政年份:2012
- 资助金额:
$ 40万 - 项目类别:
Metabolism in Heart Failure Translational Research Center
心力衰竭代谢转化研究中心
- 批准号:
7859108 - 财政年份:2009
- 资助金额:
$ 40万 - 项目类别:
Metabolism in Heart Failure Translational Research Center
心力衰竭代谢转化研究中心
- 批准号:
7937864 - 财政年份:2009
- 资助金额:
$ 40万 - 项目类别:
High-activity mutants of cocaine esterase for treatment of drug addiction
用于治疗药物成瘾的可卡因酯酶高活性突变体
- 批准号:
7674510 - 财政年份:2008
- 资助金额:
$ 40万 - 项目类别:
High-activity mutants of cocaine esterase for treatment of drug addiction
用于治疗药物成瘾的可卡因酯酶高活性突变体
- 批准号:
8286381 - 财政年份:2008
- 资助金额:
$ 40万 - 项目类别:
High-activity mutants of cocaine esterase for treatment of drug addiction
用于治疗药物成瘾的可卡因酯酶高活性突变体
- 批准号:
7506455 - 财政年份:2008
- 资助金额:
$ 40万 - 项目类别:
High-activity mutants of cocaine esterase for treatment of drug addiction
用于治疗药物成瘾的可卡因酯酶高活性突变体
- 批准号:
7883683 - 财政年份:2008
- 资助金额:
$ 40万 - 项目类别:
High-activity mutants of cocaine esterase for treatment of drug addiction
用于治疗药物成瘾的可卡因酯酶高活性突变体
- 批准号:
8084218 - 财政年份:2008
- 资助金额:
$ 40万 - 项目类别:
COCAINE CATALYTIC ANTIBODIES: NOVEL TECHNOLOGY FOR DEMAND REDUCTION
可卡因催化抗体:减少需求的新技术
- 批准号:
6258830 - 财政年份:1997
- 资助金额:
$ 40万 - 项目类别:
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