20.500.12556/RUL-144330 Structure-function studies of sponge-derived compounds on the cardiac CaV3.1 channel T-type calcium (CaV3) channels are involved in cardiac automaticity, development, and excitation–contraction coupling in normal cardiac myocytes. Their functional role becomes more pronounced in the process of pathological cardiac hypertrophy and heart failure. Currently, no CaV3 channel inhibitors are used in clinical settings. To identify novel T-type calcium channel ligands, purpurealidin analogs were electrophysiologically investigated. These compounds are alkaloids produced as secondary metabolites by marine sponges, and they exhibit a broad range of biological activities. In this study, we identified the inhibitory effect of purpurealidin I (1) on the rat CaV3.1 channel and conducted structure–activity relationship studies by characterizing the interaction of 119 purpurealidin analogs. Next, the mechanism of action of the four most potent analogs was investigated. Analogs 74, 76, 79, and 99 showed a potent inhibition on the CaV3.1 channel with IC50′s at approximately 3 µM. No shift of the activation curve could be observed, suggesting that these compounds act like a pore blocker obstructing the ion flow by binding in the pore region of the CaV3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of CaV3 channel inhibitors has been discovered and the structure–function studies provide new insights into the synthetic design of drugs and the mechanism of interaction with T-type CaV channels. T-type calcium channels ion channels purpurealidin I bromotyrosines marine-derived bioactive compounds T-tip kalcijevih kanalčkov purpurealidin I bromotirozini bioaktivne spojine morskega izvora farmacevtska kemija ionski kanalčki true false true Angleški jezik Slovenski jezik Članek v reviji 2023-02-15 07:46:07 2023-02-15 07:46:11 2023-02-16 03:41:12 0000-00-00 00:00:00 2023 0 0 15 str. iss. 4, art. 3429 Vol. 24 2023 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 577.352:615.4:54 1422-0067 10.3390/ijms24043429 141468419 ijms-24-03429-v2.pdf ijms-24-03429-v2.pdf 1 4AECD2977AF08632722720EDF3FDB220 510a96b3716d32f354861079d14b008bca7d586f540426986f185af75a0b0a97 a0dcff2a-acfd-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166586 https://www.mdpi.com/1422-0067/24/4/3429 1 1c4e46ca-acfc-11ed-9c94-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=166585 Fakulteta za farmacijo 0 0 0