Development of amodiaquine and its analogs as reactivators of organophosphate-inh

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（OPCs）反应，在大规模现实危机的情况下，任何人都无能为力。问题的一部分是，逆转OPC暴露影响的广谱解毒剂尚未开发。我们最近发现，阿莫地喹，一种成熟的抗疟疾药物，是这样一种解毒剂的一个很好的候选者：它通过一种尚未确定的，但不是基于肟的机制，从与有机磷化合物（OPCs）的加合物中作为乙酰胆碱酯酶（AChE）的再活化剂。在本提案中，我们将检验亲脂性阿莫地喹适用于体内作为有机磷中毒暴露后治疗的假设。我们还将研究再活化的机制，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活化。我们将追求三个目标：  在目标1中，我们将提供详细的阿莫地喹及其结构类似物与乙酰胆碱酯酶和不同的加合物，乙酰胆碱酯酶与有机磷化合物形成的相互作用的生化和机械特性。  在目标2中，我们将获得阿莫地喹及其选择的类似物与天然和OPC抑制AChE的晶体结构，以促进有效的再活化剂的合理设计。  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的作用的能力，特别是集中在脑中AChE的再激活上。我们的实验结果将坚定地确立阿莫地喹作为一类新的乙酰胆碱酯酶再活化剂的第一个成员，使OPC暴露后治疗的临床前研究成为可能。我们的机制研究也将帮助我们产生适合长期给药（化学预防）的其他类似物。

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.