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
• 负责人: DONALD W LANDRY
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8416866
• 关键词: Acetylcholinesterase; Active Sites; Adverse effects; Amodiaquine; Anti-Inflammatory Agents; Antidotes; Antimalarials; Biochemical; Blood - brain barrier anatomy; Brain; Cavia; Chemical Warfare; Chemoprophylaxis; Chloroquine; Chronic; Complex; Development; Dose; Drug Kinetics; Exposure to; Family; Foundations; Funding; Generations; Goals; Human; In Vitro; Kinetics; Lead; Life; Medical; Mus; Organophosphates; Oximes; Paraoxon; Pesticides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Poisoning; Positioning Attribute; Process; Prophylactic treatment; Recovery; Reporting; Residual state; Rodent Model; Structure; Testing; Toxic effect; adduct; aged; analog; base; brain tissue; design; fluorophosphate; improved; in vivo; insight; lipophilicity; member; nerve agent; organophosphate poisoning; preclinical study; process optimization; research study; scaffold

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. PUBLIC HEALTH RELEVANCE: The successful medical management of organophosphate poisoning requires completely new leads that can enable reversal of the effects of exposure to nerve agents and pesticides. We propose that a well- established and broadly used anti-malarial drug represents such a lead, being the first member of a new class of reactivators of acetylcholinesterase (AChE) from its complexes with organophosphorous compounds. We describe studies that will (i) demonstrate in vivo activity of this drug on inhibited AChE in brain and (ii) provide mechanistic and structural insights into the reactivation process, enabling rational design of even better agents.

描述（由申请人提供）：一旦乙酰胆碱酯酶（AChE）与为化学战而开发的有机磷化合物（OPC）发生反应，在现实生活中发生大规模危机时，任何人都无能为力。部分问题在于，尚未开发出能够逆转 OPC 暴露影响的广谱解毒剂。我们最近发现，阿莫地喹是一种成熟的抗疟疾药物，是此类解毒剂的良好候选者：它通过与有机磷化合物 (OPC) 的加合物通过尚未定义的但不是乙酰胆碱酯酶 (AChE) 的再激活剂发挥作用。基于肟的机制。在本提案中，我们将测试亲脂性阿莫地喹适合在体内用作有机磷中毒的暴露后治疗的假设。我们还将研究再激活的机制，并证明我们可以使用阿莫地喹和相关化合物作为支架，在更优化的条件下实现再激活。我们将追求三个目标： 在目标 1 中，我们将提供阿莫地喹及其紧密结构类似物与 AChE 以及 AChE 与有机磷化合物形成的不同加合物相互作用的详细生化和机制表征。 在目标 2 中，我们将获得阿莫地喹及其选定的类似物与天然和 OPC 抑制的 AChE 的晶体结构，以促进有效重激活剂的合理设计。 在目标 3 中，我们将研究阿莫地喹在体内逆转有机磷化合物影响的能力，特别关注大脑中 AChE 的重新激活。我们的实验结果将坚定地确立阿莫地喹作为新型乙酰胆碱酯酶再激活剂的第一个成员，从而使 OPC 暴露后治疗的临床前研究成为可能。我们的机制研究还将帮助我们产生适合长期给药（化学预防）的其他类似物。 公共健康相关性：有机磷中毒的成功医疗管理需要全新的线索，能够逆转接触神经毒剂和杀虫剂的影响。我们认为，一种成熟且广泛使用的抗疟疾药物代表了这样的先导药物，它是乙酰胆碱酯酶（AChE）与有机磷化合物复合物的新型乙酰胆碱酯酶（AChE）再激活剂的第一个成员。我们描述的研究将（i）证明该药物对大脑中受抑制的 AChE 的体内活性，以及​​（ii）提供重新激活过程的机制和结构见解，从而能够合理设计更好的药物。