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Description

A cell-permeable, orally active benzothiazepine that effectively blocks leaky intracellular calcium release by preventing the dissociation/depletion of calstabin from the ryanodine receptor (RyR) complex due to receptor modifications, such as oxidation, S-nitrosylation, hyperphosphorylation, or mutation (complete blockage of 1 mM tetracaine-induced leakage in murine RyR2 S2808D+/+ myocytes at 1 µ,M). Shown to prevent stress-induced cognitive dysfunction by stabilizing RyR2-calstabin-2 (FKBP12.6) interaction in brain (75 mg/kg/day, p.o.) and maintain exercise capacity by stabilizing RyR1-calstabin-1 (FKBP12) interaction in skeletal muscle (2.5 µ,g/0.25µ,L/h/animal, s.c) in mice, as well as restore normal cardiac function (20 mg/kg/day, s.c) in mice with R2474S or S2808D RyR2 mutation in vivo.Please note that the molecular weight for this compound is batch-specific due to variable water content. Please refer to the vial label or the certificate of analysis for the batch-specific molecular weight. The molecular weight provided represents the baseline molecular weight without water., A cell-permeable, orally active benzothiazepine derivative that effectively blocks leaky intracellular calcium release by preventing the dissociation/depletion of calstabin from the ryanodine receptor (RyR) complex due to receptor modifications, such as oxidation, S-nitrosylation, PKA-mediated hyperphosphorylation, or mutation (complete blockage of 1 mM tetracaine-induced leakage in murine RyR2 S2808D+/+ myocytes at 1 µ,M). Oral administration in mice (75 mg/kg/day via drinking water) is shown to prevent stress-induced cognitive dysfunction by stabilizing RyR2-calstabin-2 (FKBP12.6) interaction in brain of stressed animals. Likewise, s.c. administration (2.5 µ,g/0.25 µ,L/h/animal, by s.c. via neck dorsal surface osmotic pump implant) is reported to maintain mice exercise capacity by stabilizing RyR1-calstabin-1 (FKBP12) interaction in skeletal muscle following intensive exercise regimes. Also demonstrated to exhibit in vivo efficacy in restoring normal cardiac function in mice with R2474S (5 mg/kg/h, by s.c. via osmotic pump) or S2808D (20 mg/kg/day, by s.c. via osmotic pump) RyR2 mutation.