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）与用于化学战的有机磷化合物（OPCs）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影响的广谱解毒剂。我们最近发现，一种公认的抗疟疾药物阿莫地喹是这种解毒剂的良好候选者：它通过一种尚未确定但不是肟基的机制，作为与有机磷化合物（OPCs）加合物的乙酰胆碱酯酶（AChE）的再激活剂。在本提案中，我们将测试亲脂性阿莫地喹适合在体内使用作为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。我们将努力实现三个目标：

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.