20.500.12556/RUL-148297 New aryl and acylsulfonamides as state-dependent inhibitors of Na$_v$1.3 voltage-gated sodium channel Voltage-gated sodium channels (Na$_v$s) play an essential role in neurotransmission, and their dysfunction is often a cause of various neurological disorders. The Na$_v$1.3 isoform is found in the CNS and upregulated after injury in the periphery, but its role in human physiology has not yet been fully elucidated. Reports suggest that selective Na$_v$1.3 inhibitors could be used as novel therapeutics to treat pain or neurodevelopmental disorders. Few selective inhibitors of this channel are known in the literature. In this work, we report the discovery of a new series of aryl and acylsulfonamides as state-dependent inhibitors of Na$_v$1.3 channels. Using a ligand-based 3D similarity search and subsequent hit optimization, we identified and prepared a series of 47 novel compounds and tested them on Na$_v$1.3, Na$_v$1.5, and a selected subset also on Na$_v$1.7 channels in a QPatch patch-clamp electrophysiology assay. Eight compounds had an IC$_{50}$ value of less than 1 μM against the Na$_v$1.3 channel inactivated state, with one compound displaying an IC$_{50}$ value of 20 nM, whereas activity against the inactivated state of the Na$_v$1.5 channel and Na$_v$1.7 channel was approximately 20-fold weaker. None of the compounds showed usedependent inhibition of the cardiac isoform Na$_v$1.5 at a concentration of 30 μM. Further selectivity testing of the most promising hits was measured using the two-electrode voltage-clamp method against the closed state of the Na$_v$1.1-Na$_v$1.8 channels, and compound 15b displayed small, yet selective, effects against the Na$_v$1.3 channel, with no activity against the other isoforms. Additional selectivity testing of promising hits against the inactivated state of the Na$_v$1.3, Na$_v$1.7, and Na$_v$1.8 channels revealed several compounds with robust and selective activity against the inactivated state of the Na$_v$1.3 channel among the three isoforms tested. Moreover, the compounds were not cytotoxic at a concentration of 50 μM, as demonstrated by the assay in human HepG2 cells (hepatocellular carcinoma cells). The novel state-dependent inhibitors of Na$_v$1.3 discovered in this work provide a valuable tool to better evaluate this channel as a potential drug target. voltage-gated sodium channel Na$_v$ channel Na$_v$1.3 inhibitor arylsulfonamide acylsulfonamide napetostno odvisni natrijev kanal Na$_v$ kanal Na$_v$1.3 zaviralci arilsulfonamid acilsulfonamid nevrologija farmacevtska kemija true false true Angleški jezik Slovenski jezik Članek v reviji 2023-08-10 15:27:41 2023-08-10 15:27:44 2025-08-08 13:22:30 0000-00-00 00:00:00 2023 0 0 23 str. Vol. 258, art. 115530 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 615.4:54:616.8 0223-5234 10.1016/j.ejmech.2023.115530 156075779 1-s2.0-S0223523423004968-main.pdf 1-s2.0-S0223523423004968-main.pdf 1 C21701098078E7F8DADA300C98B3E5E6 4688aa238147c6f76dae2d3a3b138b8ee8765983ca0171799f70bbb2c72ac76c eb759bc0-3781-11ee-b9d7-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=172387 https://www.sciencedirect.com/science/article/pii/S0223523423004968 1 af99d4dc-3781-11ee-b9d7-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=172386 Fakulteta za farmacijo 0 0 0