TNO, Department of Chemical Toxicology, P.O. Box 45, 2280 AA Rijswijk, The Netherlands.
Toxicol Lett. 2011 Sep 25;206(1):54-9. doi: 10.1016/j.toxlet.2011.04.004. Epub 2011 Apr 8.
Commonly employed pyridinium-oxime (charged) reactivators of nerve agent inhibited acetylcholinesterase (AChE) do not readily pass the blood brain barrier (BBB) because of the presence of charge(s). Conversely, non-ionic oxime reactivators often suffer from a lack of reactivating potency due to a low affinity for the active site of AChE. It was therefore hypothesized that an extra contribution in affinity may be achieved by covalently connecting a peripheral site ligand (PSL) to a non-ionic reactivator, which may result in a higher reactivation potency of the total construct. This validity of this approach, which proved successful for charged pyridinium oximes in earlier work, is now further exemplified with the covalent linkage of a neutral PSL via a spacer to a non-ionic and otherwise almost non-reactivating α-ketoaldoxime. It is demonstrated that the linkage of the PSL resulted in a remarkable increase in reactivation potency of the hybrid compounds. Although the molecules reported here are still inefficient reactivators compared to the current pyridinium oximes, the presented approach holds promise for the future design and synthesis of non-ionic oxime reactivators with improved BBB penetration and may be suited as well for non-oxime reactivators thus further widening the scope in the ongoing search for broad-spectrum reactivators.
常用的吡啶嗡（带电荷）重活化剂不能轻易穿透血脑屏障（BBB），因为其带有电荷。相反，非离子型肟重活化剂由于与乙酰胆碱酯酶（AChE）的活性部位亲和力低，常常缺乏重活化效力。因此，人们假设通过将外围配体（PSL）共价连接到非离子型重活化剂上，可以额外提高亲和力，从而提高总构建体的重活化效力。这种方法在早期的带电荷吡啶嗡肟研究中已经得到了验证，现在通过将中性 PSL 通过间隔物与非离子型且几乎没有重活化作用的α-酮醛肟共价连接，进一步证明了其有效性。结果表明，PSL 的连接导致了混合化合物重活化效力的显著提高。尽管与目前的吡啶嗡肟相比，这里报道的分子仍然是低效的重活化剂，但所提出的方法为未来设计和合成具有改善的 BBB 穿透性的非离子型肟重活化剂提供了希望，并且可能也适用于非肟重活化剂，从而进一步扩大了广谱重活化剂的研究范围。
