Wein Thomas, Wanner Klaus T, Rappenglück Sebastian, Sichler Sonja, Niessen Karin V, Seeger Thomas, Worek Franz, Thiermann Horst
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-Universitat München, Butenandtstr, 5-13, 81377 Munich, Germany.
Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, 80937 Munich, Germany.
Curr Comput Aided Drug Des. 2019;15(1):104-109. doi: 10.2174/1573409914666180703120201.
Irreversible inhibition of the acetylcholinesterase upon intoxication with organophosphorus compounds leads to an accumulation of acetylcholine in the synaptic cleft and a subsequent desensitization of nicotinic acetylcholine receptors which may ultimately result in respiratory failure. A direct intervention at the nicotinic acetylcholine receptor (nAChR) was proposed as an alternative therapeutic approach to the treatment with atropine and oximes.
The bispyridinium compound MB327 has been found to recover functional activity of nAChR thus representing a promising starting point for the development of new drugs for the treatment of organophosphate poisoning. Recent solid-supported membrane-based electrophysiological experiments have identified symmetrically substituted bispyridinium compounds e.g. MB327, MB583, and PTM0001 that are able to resensitize nAChR of Torpedo californica. In addition, six compounds have been found not to show any resensitizing potential and were thus classified as inactive. This set of active and inactive bispyridinium compounds was taken to develop a pharmacophore model and in silico screening of a virtual database of bispyridinium compounds to identify new compounds that are able to restore the functional activity of desensitized nAChR.
Screening of a virtual compound database of symmetrically substituted bispyridinium compounds with the derived pharmacophore yielded several promising compounds which satisfy the pharmacophore and ought to have the same or even better resensitizing effect on nAChR as the parent compound MB327.
有机磷化合物中毒会导致乙酰胆碱酯酶不可逆抑制，致使乙酰胆碱在突触间隙积聚，进而使烟碱型乙酰胆碱受体脱敏，最终可能导致呼吸衰竭。有人提出直接作用于烟碱型乙酰胆碱受体（nAChR）作为阿托品和肟治疗之外的另一种治疗方法。
已发现双吡啶化合物MB327可恢复nAChR的功能活性，这代表着开发治疗有机磷中毒新药的一个有前景的起点。最近基于固体支持膜的电生理实验已鉴定出对称取代的双吡啶化合物，例如MB327、MB583和PTM0001，它们能够使加州电鳐的nAChR重新敏感化。此外，还发现有六种化合物没有任何重新敏感化潜力，因此被归类为无活性。利用这组有活性和无活性的双吡啶化合物构建药效团模型，并对双吡啶化合物虚拟数据库进行计算机筛选，以识别能够恢复脱敏nAChR功能活性的新化合物。
用推导的药效团对对称取代双吡啶化合物虚拟化合物数据库进行筛选，得到了几种有前景的化合物，它们符合药效团，并且对nAChR的重新敏感化作用应该与母体化合物MB327相同甚至更好。
