Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, Vienna, Austria.
X-Ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Sci Rep. 2021 Dec 3;11(1):23397. doi: 10.1038/s41598-021-02732-y.
Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole. The rearrangement occurs under highly acidic conditions, which were believed to favour the dihydrochloride formation of pirenzepine. The rearranged products of pirenzepine and the structurally related telenzepine have significantly decreased affinity for the muscarinic acetylcholine receptor, the pharmacological target of these compounds. Fortunately, in situ rearrangement after oral application is no safety issue, as we show that reaction kinetics in gastric acid prevent rearrangement. The research community should consider appropriate measures to perform reliable receiving inspections in the commercial supply of well described and frequently used chemicals, in particular if experiments yield unexpected results.
药物警戒旨在更好地了解药物引发的分子事件，以预防不良反应，尽管我们在分析手段上取得了重大进展，但直到今天，药物仍存在不良反应。在这项研究中，我们发现临床开方和市售的哌仑西平可能不是正确的化合物。哌仑西平可能会从药物活性成分（API）发生意想不到的骨架重排，形成以前未被描述的苯并咪唑。这种重排发生在高度酸性条件下，人们认为这有利于哌仑西平二盐酸盐的形成。哌仑西平和结构相关的替仑西平的重排产物对毒蕈碱乙酰胆碱受体的亲和力显著降低，而毒蕈碱乙酰胆碱受体是这些化合物的药理靶点。幸运的是，口服后发生原位重排不是安全问题，因为我们表明，在胃酸中反应动力学可以阻止重排。如果实验产生意想不到的结果，研究界应考虑采取适当措施，对商业供应的描述良好且常用的化学物质进行可靠的接收检查。
