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Structure-Function Studies of Sponge-Derived Compounds on the Cardiac Ca V 3.1 Channel.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2023 Feb 08; Vol. 24 (4). Date of Electronic Publication: 2023 Feb 08. - Publication Year :
- 2023
-
Abstract
- T-type calcium (Ca <subscript>V</subscript> 3) 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 Ca <subscript>V</subscript> 3 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 Ca <subscript>V</subscript> 3.1 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 Ca <subscript>V</subscript> 3.1 channel with IC <subscript>50</subscript> '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 Ca <subscript>V</subscript> 3.1 channel. A selectivity screening showed that these analogs are also active on hERG channels. Collectively, a new class of Ca <subscript>V</subscript> 3 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 Ca <subscript>V</subscript> channels.
- Subjects :
- Rats
Animals
Myocytes, Cardiac metabolism
Porifera
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 24
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 36834837
- Full Text :
- https://doi.org/10.3390/ijms24043429