Acetylcholinesterase (AChE) is a pivotal enzyme in neurotransmission. Its inhibition leads to cholinergic crises and could ultimately result in death. A related enzyme butyrylcholinesterase (BChE) may act in the CNS as a co-regulator in terminating nerve impulses and is a natural plasma scavenger upon exposure to organophosphate (OP) nerve agents that irreversibly inhibit both enzymes. With the aim of improving reactivation of cholinesterases phosphylated by nerve agents sarin, VX, cyclosarin, and tabun, ten phenyltetrahydroisoquinoline (PIQ) aldoximes were synthesized by Huisgen 1,3 dipolar cycloaddition between alkyne- and azide-building blocks. The PIQ moiety may serve as a peripheral site anchor positioning the aldoxime moiety at the AChE active site. In terms of evaluated dissociation inhibition constants, the aldoximes could be characterized as high-affinity ligands. Nevertheless, high binding affinity of these oximes to AChE or its phosphylated conjugates did not assure rapid and selective AChE reactivation. Rather, potential reactivators of phosphylated BChE, with its enlarged acyl pocket, were identified, especially in case of cyclosarin, where the reactivation rates of the lead reactivator was 100- and 6-times that of 2-PAM and HI-6, respectively. Nevertheless, the return of the enzyme activity was affected by the nerve agent conjugated to catalytic serine, which highlights the lack of the universality of reactivators with respect to both the target enzyme and OP structure.

中文翻译：

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通过抗三唑连接的高亲和力苯基四氢异喹啉醛肟作为磷酸化胆碱酯酶的再活化剂的评价

乙酰胆碱酯酶 (AChE) 是神经传递中的关键酶。它的抑制导致胆碱能危机并最终导致死亡。相关的丁酰胆碱酯酶 (BChE) 可在 CNS 中作为终止神经冲动的协同调节剂起作用，并且在暴露于不可逆地抑制这两种酶的有机磷酸盐 (OP) 神经毒剂时是一种天然的血浆清除剂。为了提高由神经毒剂沙林、VX、环沙林和塔崩磷化的胆碱酯酶的再活化，通过在炔烃和叠氮化物构件之间的 Huisgen 1,3 偶极环加成反应合成了十种苯基四氢异喹啉 (PIQ) 醛肟。PIQ 部分可用作将醛肟部分定位在 AChE 活性位点的外围位点锚。就评估的解离抑制常数而言，醛肟可以表征为高亲和力配体。然而，这些肟对 AChE 或其磷酸化缀合物的高结合亲和力并不能保证快速和选择性的 AChE 再激活。相反，磷酸化 BChE 的潜在再活化剂及其扩大的酰基口袋被确定，特别是在环沙林的情况下，其中先导再活化剂的再活化率分别是 2-PAM 和 HI-6 的 100 倍和 6 倍。然而，酶活性的恢复受到与催化丝氨酸结合的神经毒剂的影响，这突出了重新激活剂在靶酶和 OP 结构方面缺乏普遍性。相反，磷酸化 BChE 的潜在再活化剂及其扩大的酰基口袋被确定，特别是在环沙林的情况下，其中先导再活化剂的再活化率分别是 2-PAM 和 HI-6 的 100 倍和 6 倍。然而，酶活性的恢复受到与催化丝氨酸结合的神经毒剂的影响，这突出了重新激活剂在靶酶和 OP 结构方面缺乏普遍性。相反，磷酸化 BChE 的潜在再活化剂及其扩大的酰基口袋被确定，特别是在环沙林的情况下，其中先导再活化剂的再活化率分别是 2-PAM 和 HI-6 的 100 倍和 6 倍。然而，酶活性的恢复受到与催化丝氨酸结合的神经毒剂的影响，这突出了重新激活剂在靶酶和 OP 结构方面缺乏普遍性。