Experimental study of local anesthetic and antiarrhythmic activities of fluorinated ethynylpiperidine derivatives
Satbayeva E.M. Zhumakova S.S. Khaiitova M.D. Kemelbekov U.S. Tursunkhodzhaeva F.M. Azamatov A.A. Tursymbek S.N. Sabirov V.Kh. Nurgozhin T.S. Yu V.K. Seilkhanov T.M.
2024Associacao Brasileira de Divulgacao Cientifica
Brazilian Journal of Medical and Biological Research
2024#57
The chemical structure of piperidine has a unique ability to combine with other molecular fragments. This fact makes it possible to actively use it as an effective basis for the creation of new drug-like substances. Thus, the aim of the current investigation was to study the acute toxicity, local anesthetic potency, and antiarrhythmic activity of the two new synthesized piperidine derivatives under laboratory codes LAS-286 and LAS-294 (local anesthetic substances). The Bulbring & Wajda animal model and method of determining the nociception threshold during electrical stimulation was used to investigate the action of the substance during infiltration anesthesia. An antiarrhythmic activity was observed by the aconitine-induced rat arrhythmia model. Additionally, these compounds were studied in relation to molecular docking to delineate the structure-activity relationships. The tested piperidine derivatives had a low toxicity in the subcutaneous and intravenous administration routes. The experimental results showed a higher prolonged and pronounced local anesthetic activity for LAS-286 at a 0.5% concentration, compared to the reference preparations. The low dosage of 0.1 mg/kg of LAS-294 demonstrated a pronounced preventive antiarrhythmic effect in 90% of cases on the development of mixed arrhythmia, caused by aconitine. The results of molecular docking confirmed a higher binding affinity of the tested piperidines with the Nav1.4 and Nav1.5 macromolecules. The results of the present study are very promising, because these piperidines have shown a high biological activity, which can suggest a potential therapeutic application in the future.
Antiarrhythmic activity , Local anesthetic activity , Molecular docking , Piperidines , Toxicity
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Department of Pharmacology, School of General Medicine-1, Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan
Laboratory of Synthetic and Natural Medicinal Compounds Chemistry, A.B. Bekturov Institute of Chemical Sciences, Almaty, Kazakhstan
Department of Pharmacology and Toxicology, S.Yu. Yunusov Institute of the Chemistry of Plant Substances, Academy of Sciences of the Republic of Uzbekistan, Tashkent, Uzbekistan
Research Laboratory of Medicinal Plants, South Kazakhstan Medical Academy, Shymkent, Kazakhstan
Laboratory of Structural Chemistry, Tashkent State Technical University, Tashkent, Uzbekistan
Laboratory of Engineering Profile NMR Spectroscopy, Shokan Ualikhanov Kokshetau University, Kokshetau, Kazakhstan
Department of Pharmacology
Laboratory of Synthetic and Natural Medicinal Compounds Chemistry
Department of Pharmacology and Toxicology
Research Laboratory of Medicinal Plants
Laboratory of Structural Chemistry
Laboratory of Engineering Profile NMR Spectroscopy
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