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Information × Registration Number 0225U002769, (0123U102103) , R & D reports Title Rational design of muscarinic acetylcholine receptor type 2 activators as potential components of acute myocardial infarction and myocardial wound therapy popup.stage_title Аналіз залежності активності від хімічної структури та створення стратегії оптимізації активності та селективності сполук. Head Nyporko Oleksii Yu., Кандидат біологічних наук Registration Date 02-04-2025 Organization Taras Shevchenko National University of Kyiv popup.description1 The strategic aim of the project is to search for and/or develop compounds - high-affinity and selective activators of muscarinic acetylcholine receptors of type 2, which can be effectively used in the emergency treatment of both acute myocardial infarction and wound injuries, which is especially relevant in war and post-war rehabilitation. popup.description2 The effects of compounds 146539 and 248008 (1 mg/kg) on heart rate, electrocardiogram and blood oxygenation level in rats in vivo were studied. Compound 248008 reduced heart rate by 21.1%, but did not change the cardiogram or oxygenation level. In contrast, 146539 reduced heart rate by 39.7 %, but caused cardiac arrhythmias and oxygenation fluctuations. Compound 146539 in nanomolar concentrations (10-⁹ - 10-⁸ M) enhanced acetylcholine-induced intestinal contractions. When blocking mAChRs3 with the 4-DAMP antagonist (10-⁷ M), 146539 activated the contractions, while blocking mAChRs2 with AF-DX 116 (10-⁴ M) eliminated the effect. Thus, the main point of action of 146539 is mAChRs2. The maximum effective concentration of 146539 was 10-⁸ M: the phase component of contractions was 296%, and the tonic component was 234.3%. Higher concentrations (10-⁷ - 10-⁶ M) may affect other cellular targets of smooth muscle. The Allium assay showed that high concentrations of 146539 (10-⁷ - 10-⁶ M) halved the mitotic index and caused chromosomal aberrations, while low concentrations had no cytotoxic effect. Compound 248008 was chosen as a scaffold for the search for new selective mAChRs2 agonists. Virtual screening of the ‘Alexandria’ library revealed compounds 247999 and 112514 with potential high activity and selectivity for mAChRs2. Provided that their non-toxicity is proven, compounds 248008 and 146539 can be used for the treatment of acute myocardial infarction, wound injuries, and normalisation of the contractile function of the smooth muscles of the urogenital system and digestive system. Product Description popup.authors Yemelianov Volodymyr I. Voiteshenko Ivan S. Drahan Anatolii I. Morozova Nadiia M. Musiienko Andrii M. Savchenko Oleksandr V. Symonenko Yurii V. Tsymbaliuk Olha V. popup.nrat_date 2025-04-02 Close