Milani, GualtieroBudriesi, RobertaTavazzani, ElisaCavalluzzi, Maria MaddalenaMattioli, Laura BeatriceMiniero, Daniela ValeriaDelre, PietroBelviso, Benny DaniloDenegri, MarcoCuocci, CorradoRotondo, Natalie PaolaDe Palma, AnnalisaGualdani, RobertaCaliandro, RoccoMangiatordi, Giuseppe FeliceKumawat, AmitCamilloni, CarloPriori, Silvia G.Lentini, Giovanni2023-10-162023-10-162023-10Arch Pharm (Weinheim). 2023 Oct;356(10):e2300116.http://hdl.handle.net/20.500.12105/16568Long QT syndrome (LQTS) is a disorder of cardiac electrophysiology resulting in life-threatening arrhythmias; nowadays, only a few drugs are available for the management of LQTS. Focusing our attention on LQT2, one of the most common subtypes of LQTS caused by mutations in the human ether-à-go-go-related gene (hERG), in the present work, the stereoselectivity of the recently discovered mexiletine-derived urea 8 was investigated on the hERG potassium channel. According to preliminary in silico predictions, in vitro studies revealed a stereoselective behavior, with the meso form showing the greatest hERG opening activity. In addition, functional studies on guinea pig isolated left atria, aorta, and ileum demonstrated that 8 does not present any cardiac or intestinal liability in our ex vivo studies. Due to its overall profile, (R,S)-8 paves the way for the design and development of a new series of compounds potentially useful in the treatment of both congenital and drug-induced forms of LQTS.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/MexiletineLong QT SyndromeHumansAnimalsGuinea PigsMolecular Docking SimulationUreaStructure-Activity RelationshipPotassium ChannelsAttribution-NonCommercial-NoDerivatives 4.0 Internacional3746039035610e230011610.1002/ardp.2023001161521-4184Archiv der Pharmazieopen access