5.30657

Myosin ATPase Activator, EMD57003

• Synonym(s): Myosin ATPase Activator, EMD57003, (+)-5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, (+)-6-(3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoline, EMD-57033, Myosin Motor Act, (+)-5-(1-(3,4-Dimethoxybenzoyl)-1,2,3,4-tetrahydroquinolin-6-yl)-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one, (+)-6-(3,6-Dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1-(3,4-dimethoxybenzoyl)-1,2,3,4-tetrahydroquinoline, EMD-57033, Myosin Motor Acti
• Empirical Formula (Hill Notation): C₂₂H₂₃N₃O₄S
• CAS Number: 147527-31-9
• Molecular Weight: 425.50
• UNSPSC Code: 12352200

Properties

• assay: ≥97% (HPLC)
• Quality Level: 100
• form: solid
• manufacturer/tradename: Calbiochem^®
• storage condition: OK to freeze; protect from light
• color: off-white
• solubility: DMSO: 50 mg/mL
• storage temp.: −20°C
• InChI: 1S/C22H23N3O4S/c1-13-20(23-24-22(27)30-13)15-6-8-17-14(11-15)5-4-10-25(17)21(26)16-7-9-18(28-2)19(12-16)29-3/h6-9,11-13H,4-5,10H2,1-3H3,(H,24,27)
• InChI key: IZLRMTJLQCLMKF-UHFFFAOYSA-N

Description

General description

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.

Biochem/physiol Actions

Cell permeable: yes

Primary Target
myosin

Reversible: yes

Packaging

Packaged under inert gas

Warning

Toxicity: Standard Handling (A)

Reconstitution

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

Other Notes

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.

Legal Information

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

Safety Information

• pictograms: GHS07,GHS08
• signalword: Warning
• hcodes: H302 - H319 - H335 - H373
• pcodes: P260 - P264 - P270 - P301 + P312 - P305 + P351 + P338 - P314
• Hazard Classifications: Acute Tox. 4 Oral - Eye Irrit. 2 - STOT RE 2 - STOT SE 3
• target_organs: Respiratory system
• Storage Class: 11 - Combustible Solids
• wgk_germany: WGK 3
• flash_point_f: Not applicable
• flash_point_c: Not applicable