Anne-Sophie Depuydt (Avtor), Piyush A. Patel (Avtor), Žan Toplak (Avtor), Chinmaya Bhat (Avtor), Manuela Voráčová (Avtor), Irene Eteläinen (Avtor), Fiammetta Vitulano (Avtor), Nives Hribernik (Avtor), Tihomir Tomašić (Avtor), Lucija Peterlin-Mašič (Avtor)

Povzetek

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.

Ključne besede

T-type calcium channels;ion channels;purpurealidin I;bromotyrosines;marine-derived bioactive compounds;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: UL FFA - Fakulteta za farmacijo
UDK: 577.352:615.4:54
COBISS: 141468419 Povezava se bo odprla v novem oknu
ISSN: 1422-0067
Št. ogledov: 4
Št. prenosov: 5
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarni jezik: Slovenski jezik
Sekundarne ključne besede: T-tip kalcijevih kanalčkov;purpurealidin I;bromotirozini;bioaktivne spojine morskega izvora;Farmacevtska kemija;Ionski kanalčki;
Vrsta dela (COBISS): Članek v reviji
Strani: 15 str.
Letnik: ǂVol. ǂ24
Zvezek: ǂiss. ǂ4, art. 3429
Čas izdaje: 2023
DOI: 10.3390/ijms24043429
ID: 18011581