A dual-targeted drug inhibits cardiac ryanodine receptor Ca 2+ leak but activates SERCA2a Ca 2+ uptake.

In the heart, genetic or acquired mishandling of diastolic [Ca 2+ ] by ryanodine receptor type 2 (RyR2) overactivity correlates with risks of arrhythmia and sudden cardiac death. Strategies to avoid these risks include decrease of Ca 2+ release by drugs modulating RyR2 activity or increase in Ca 2+ uptake by drugs modulating SR Ca 2+ ATPase (SERCA2a) activity. Here, we combine these strategies by developing experimental compounds that act simultaneously on both processes. Our screening efforts identified the new 1,4-benzothiazepine derivative GM1869 as a promising compound. Consequently, we comparatively studied the effects of the known RyR2 modulators Dantrolene and S36 together with GM1869 on RyR2 and SERCA2a activity in cardiomyocytes from wild type and arrhythmia-susceptible RyR2 R2474S/+ mice by confocal live-cell imaging. All drugs reduced RyR2-mediated Ca 2+ spark frequency but only GM1869 accelerated SERCA2a-mediated decay of Ca 2+ transients in murine and human cardiomyocytes. Our data indicate that S36 and GM1869 are more suitable than dantrolene to directly modulate RyR2 activity, especially in RyR2 R2474S/+ mice. Remarkably, GM1869 may represent a new dual-acting lead compound for maintenance of diastolic [Ca 2+ ].