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Discovery and Structure-Activity Relationship of a Ryanodine Receptor 2 Inhibitor.
- Source :
-
Chemical & pharmaceutical bulletin [Chem Pharm Bull (Tokyo)] 2024; Vol. 72 (4), pp. 399-407. - Publication Year :
- 2024
-
Abstract
- Ryanodine receptor 2 (RyR2) is a large Ca <superscript>2+</superscript> -release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca <superscript>2+</superscript> from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far. Here, we identified an RyR2-selective inhibitor 1 from the chemical compound library and synthesized it from glycolic acid. Synthesis of various derivatives to investigate the structure-activity relationship of each substructure afforded another two RyR2-selective inhibitors 6 and 7, among which 6 was the most potent. Notably, compound 6 also inhibited Ca <superscript>2+</superscript> release in cells expressing the RyR2 mutants R2474S, R4497C and K4750Q, which are associated with cardiac arrhythmias such as catecholaminergic polymorphic ventricular tachycardia (CPVT). This inhibitor is expected to be a useful tool for research on the structure and dynamics of RyR2, as well as a lead compound for the development of drug candidates to treat RyR2-related cardiac disease.
- Subjects :
- Humans
Calcium metabolism
Dose-Response Relationship, Drug
Drug Discovery
HEK293 Cells
Molecular Structure
Structure-Activity Relationship
Anti-Arrhythmia Agents chemistry
Anti-Arrhythmia Agents pharmacology
Tachycardia, Ventricular drug therapy
Tachycardia, Ventricular genetics
Ryanodine Receptor Calcium Release Channel drug effects
Ryanodine Receptor Calcium Release Channel genetics
Ryanodine Receptor Calcium Release Channel metabolism
Calcium Channel Blockers chemistry
Calcium Channel Blockers pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1347-5223
- Volume :
- 72
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Chemical & pharmaceutical bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 38644198
- Full Text :
- https://doi.org/10.1248/cpb.c24-00114