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

描述(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)发生反应，在发生大规模现实生活危机的情况下，任何人都几乎无能为力。部分问题是，尚未开发出逆转OPC暴露影响的广谱解毒剂。我们最近发现，阿莫地喹，一种成熟的抗疟疾药物，是这种解毒剂的一个很好的候选药物：它通过一种尚未确定但不是基于肟的机制来激活与有机磷化合物(OPC)加合物形成的乙酰胆碱酯酶(AChE)。在这项建议中，我们将检验亲脂性阿莫地喹适合在VIV中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理，并证明可以使用阿莫地喹和相关化合物作为支架，在更理想的条件下实现再激活。我们将追求三个目标： 在目标1中，我们将对阿莫地喹及其与AChE的紧密结构类似物以及AChE与有机磷化合物形成的不同加合物的相互作用进行详细的生化和机理表征。 在目标2中，我们将获得阿莫地喹及其与天然和OPC抑制的AChE类似物的晶体结构，以便于合理设计有效的复活剂。 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，特别是在脑内AChE的重新激活方面。我们的实验结果将坚定地确立阿莫地喹作为新一类AChE再激活剂的第一个成员，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更多适用于慢性给药(化学预防)的类似物。

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.