Myosin ATPase Activator, EMD57003

A cell-permeable, bioavailable positive optical isomer of the racemate EMD-53998 that binds to the allosteric pocket of myosin motor domain (K_D = 7.3 µM) and stimulates actomyosin ATPase activity (AC₅₀ = 7.0 µM for β-cardiac myosin and 15.1 µM for skeletal muscle myosin). Exerts a positive inotropic effects on cardiac muscle and enhances diastolic performance while reducing oxygen cost of contraction in a canine canine model of tachycardia-induced heart failure. Acts as a pharmacological chaperone to protect β-cardiac myosin against heat stress and thermal denaturation and can induce refolding and reactivation of heat-inactivated myosin ATPase.

The cell-permeable (+) enantiomer of the racemic tetrahydroquinoline EMD-53998 is reported to enhance myosin motor function via an 1:1 allosteric interaction with motor N-terminal SH3-like βbarrel subdomain (K_D = 7.3 & 23 µM, respectively, using 100 nM porcine β-cardiac myosin S1 & rabbit fast skeletal muscle heavy meromyosin/HMM), restoring the ATP-binding activity of misfolded moysin as well as enhancing both basal and actin-dependent ATPase activity of myosin preparations (AC₅₀ in µM = 7.0/porcine β-cardiac myosin S1, 15.1/rabbit HMM, 25.8/amoeba Dictyostelium discoideum Dd myosin-2, and 35.4/Dd myosin-5b), while being ineffective toward fully denatured myosin or βbarrel subdomain-lacking Dd myosin-1B/-1C/-1D/-1E. Pro-hypertrophic effect of EMD 57033 is demonstrated in serum-free neonatal rat cardiomyocyte cultures in vitro under both normal and hyperthermia conditions (cell size enlargement by 60% at 37 °C and by 24% at 42 °C; 10 µM EMD 57033 for 24 hr) with a drastic decline in cellular atrial natriuretic peptide only under hyperthermia condition (% of 37 °C control ANP level = 47% vs. 140%, respectively, with or without 10 µM EMD 57033 for 24 h at 42 °C), while positive inotropic efficacy is reported in vivo (0.4 mg/kg/min for 20 min) in a canine model of tachycardia-induced heart failure. The (-) enantiomer EMD 57439 is a known PDE3 inhibitor with little potency toward myosin ATPase activity.

Cell permeable: yes

Primary Target
myosin

Reversible: yes

Packaged under inert gas

Following reconstitution, aliquot and freeze (-20°C). Stock solutions are stable for up to 6 months at -20°C.

Radke, M.B., et al. 2014. ELife3, e01603.

Senzaki, H., et al., 2000. Circulation101, 1040.
Gambassi, G., et al. 1993. Am. J. Physiol.264, H728.
Solaro, R.J., et al.1993. Circ. Res.73, 981.

CALBIOCHEM is a registered trademark of Merck KGaA, Darmstadt, Germany

Toxicity: Standard Handling (A)