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Novel Compound, 84f2, Inhibits Calmodulin Deficient Ryr2, Robert Carl Klipp

Dissertations and Theses

The cardiac ryanodine receptor (RyR2) plays a key role in excitation-contraction coupling (ECC). Mutations in RyR2 are known to be linked to the arrhythmogenic disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT), a deadly disease which is characterized by a leak of calcium from sarcoplasmic reticulum and a decrease in calmodulin (CaM) binding. A novel drug, 84F2, shown to inhibit arrhythmias in RyR2-R176Q heterozygous CPVT mouse hearts (2.5 µg/kg), decrease spark frequency in cells derived from CPVT mice (IC₅₀ = 35 nM), and inhibit RyR2 single channel activity at low nanomolar concentrations (IC₅₀ = 8 nM). When CaM is added …