Abstract
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.
Highlights
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
Pirenzepine is a well-established parasympatholytic drug, which is in clinical use since the late 1 970s5. It acts as antagonist for the muscarinic acetylcholine receptors, with a strong preference for the mAChR subtype M1
We went on to characterize this structural isomer, study its mAChR affinity profile and determine the rearrangement reaction leading to its formation. mAChR research uses in addition to pirenzepine the structural relative telenzepine, which we found to undergo a similar rearrangement
Summary
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. Despite intensive investigations on the synthesis of pirenzepine, only few reports provide experimental details of the final step, the reaction of pirenzepine to its dihydrochloride (Fig. 1)[15,19,20]. We obtained pirenzepine dihydrochloride from a fine chemical distributor for displacement studies on mAChR M128.
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