Moore Oliver M, Sibrian-Vazquez Martha, Navarro-Garcia Jose Alberto, Aguilar-Sanchez Yuriana, Turkieltaub-Paredes Mara R, Lahiri Satadru K, Ni Li, Word Tarah A, Miyake Christina Y, Strongin Robert M, Wehrens Xander H T
Cardiovascular 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.
Department of Chemistry, Portland State University, Portland, Oregon.
Heart Rhythm. 2024 Oct 2. doi: 10.1016/j.hrthm.2024.09.062.
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).
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.
We synthesized >200 tetracaine derivatives and characterized 11 of those. The effects of these compounds on Ca 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.
Ca imaging revealed that 3 of 11 compounds suppressed sarcoplasmic reticulum Ca 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 I, I, or I; it exhibited excellent stability in plasma and microsomes, and it was not cytotoxic.
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.
儿茶酚胺能多形性室性心动过速（CPVT）是一种与致死性心律失常相关的遗传性心律失常疾病。大多数CPVT病例是由编码2型兰尼碱受体（RYR2）的基因中的遗传变异引起的。
本研究的目的是研究丁卡因衍生物的构效关系，并在CPVT小鼠模型中测试一种先导化合物。
我们合成了200多种丁卡因衍生物，并对其中11种进行了表征。用共聚焦显微镜测试了这些化合物对R176Q/+小鼠心肌细胞钙处理的影响。分别通过程序电刺激和超声心动图测试了先导化合物MSV1302对心律失常诱导性和心脏收缩性的影响。还进行了血浆和微粒体稳定性及细胞毒性测定。
钙成像显示，11种化合物中的3种抑制了突变型RyR2引起的肌浆网钙泄漏。选择进一步测试的两种化合物的半数有效浓度分别为146 nM（MSV1302）和49 nM（MSV1406）。两种化合物均未改变基线心电图间期，但只有MSV1302抑制了R176Q/+小鼠体内应激和起搏诱导的室性心动过速。超声心动图显示，先导化合物MSV1302对心脏收缩性和变时性没有负面影响。最后，化合物MSV1302不阻断I、I或I；它在血浆和微粒体中表现出优异的稳定性，且无细胞毒性。
第二代丁卡因衍生物的构效关系研究确定了具有良好药代动力学特征的先导化合物MSV1302。MSV1302在体外和体内使异常的RyR2活性正常化，而不改变心脏收缩性、变时性或对其他离子通道的脱靶效应。该化合物可能是未来临床研究中确定其对CPVT患者疗效的有力候选药物。
