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Updated: Jun 11, 2025
Dual-Dye Optical Mapping of Hearts from RyR2R2474S Knock-In Mice of Catecholaminergic Polymorphic Ventricular Tachycardia
Published on: December 22, 2023
Structure-activity optimization of ryanodine receptor modulators for the treatment of catecholaminergic polymorphic
Oliver M Moore1, Martha Sibrian-Vazquez2, Jose Alberto Navarro-Garcia3
1Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas; Department of Integrative Physiology, Baylor College of Medicine, Houston, Texas; Department of Neuroscience, Baylor College of Medicine, Houston, Texas.
Background:
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia disorder associated with lethal arrhythmias. Most CPVT cases are caused by inherited variants in the gene encoding ryanodine receptor type 2 (RYR2).
Objective:
The goal of this study was to investigate the structure-activity relationship of tetracaine derivatives and to test a lead compound in a mouse model of CPVT.
Methods:
We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca2+ handling in cardiomyocytes from R176Q/+ mice was tested with confocal microscopy. The effects of lead compound MSV1302 on arrhythmia inducibility and cardiac contractility were tested by programmed electrical stimulation and echocardiography, respectively. Plasma and microsomal stability and cytotoxicity assays were also performed.
Results:
Ca2+ imaging revealed that 3 of 11 compounds suppressed sarcoplasmic reticulum Ca2+ leak through mutant RyR2. Two compounds selected for further testing exhibited a half-maximal effective concentration of 146 nM (MSV1302) and 49 nM (MSV1406). Whereas neither compound altered baseline electrocardiogram intervals, only MSV1302 suppressed stress- and pacing-induced ventricular tachycardia in vivo in R176Q/+ mice. Echocardiography revealed that the lead compound MSV1302 did not negatively affect cardiac inotropy and chronotropy. Finally, compound MSV1302 did not block INa, ICa,L, or IKr; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic.
Conclusion:
Structure-activity relationship studies of second-generation tetracaine derivatives identified lead compound MSV1302 with a favorable pharmacokinetic profile. MSV1302 normalized aberrant RyR2 activity in vitro and in vivo, without altering cardiac inotropy, chronotropy, or off-target effects on other ion channels. This compound may be a strong candidate for future clinical studies to determine its efficacy in CPVT patients.
Insights
Researchers developed a new drug, MSV1302, that effectively treats catecholaminergic polymorphic ventricular tachycardia (CPVT) by normalizing RyR2 activity. This promising compound shows no negative effects on heart function or other ion channels, making it a potential candidate for clinical trials.
Area of Science:
- Cardiovascular Research
- Pharmacology
- Genetics
Background:
- Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmia.
- Mutations in the ryanodine receptor type 2 (RYR2) gene are the primary cause of most CPVT cases.
Purpose of the Study:
- To explore the structure-activity relationship of tetracaine derivatives.
- To evaluate a lead compound, MSV1302, in a mouse model of CPVT.
Main Methods:
- Synthesis and characterization of over 200 tetracaine derivatives.
- Assessment of Ca2+ handling in cardiomyocytes and in vivo arrhythmia suppression.
- Pharmacokinetic and safety evaluations including stability, cytotoxicity, and effects on cardiac function.
Main Results:
- Three derivatives suppressed RyR2-mediated Ca2+ leak in vitro.
- MSV1302 demonstrated potent RyR2 inhibition (EC50 = 146 nM) and suppressed ventricular tachycardia in CPVT mice.
- MSV1302 showed favorable pharmacokinetics, no cytotoxicity, and no adverse effects on cardiac contractility or electrophysiology.
Conclusions:
- MSV1302, a novel tetracaine derivative, effectively normalized aberrant RyR2 activity in CPVT models.
- The compound exhibits a favorable safety profile, with no impact on cardiac function or off-target ion channel activity.
- MSV1302 represents a promising therapeutic candidate for clinical investigation in CPVT patients.
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