Key result
Several 4-hydroxycoumarin imine analogues showed improved potency (IC50 <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to the lead compound BHC.
Why the study?
Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation.
Effect estimate: IC50 <1 μM
Synthesized 4-hydroxycoumarin imine analogues demonstrate potent and selective inhibition of skeletal myosin II, suggesting potential as therapeutics for conditions requiring muscle relaxation.
Preclinical only; leaves open whether these selective skeletal myosin inhibitors can advance to human muscle relaxation therapies.
Inhibitors of muscle myosin ATPases are needed to treat conditions that could be improved by promoting muscle relaxation. The lead compound for this study ((3-( N -butylethanimidoyl)ethyl)-4-hydroxy-2 H -chromen-2-one; BHC) was previously discovered to inhibit skeletal myosin II. BHC and 34 analogues were synthesized to explore structure–activity relationships. The properties of analogues, including solubility, stability, and toxicity, suggest that the BHC scaffold may be useful for developing therapeutics. Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity were measured. Several analogues with aromatic side arms showed improved potency (half-maximal inhibitory concentration (IC 50 ) <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to BHC. Several analogues blocked neurotransmission, suggesting that they are selective for nonmuscle myosin II over skeletal myosin. Competition and molecular docking studies suggest that BHC and blebbistatin bind to the same site on myosin.
No takes yet. Share an insight, caveat, or question.
Brawley et al. (2020) studied Conditions that could be improved by promoting muscle relaxation. BHC and 34 analogues (4-Hydroxycoumarin Imines) vs. BHC was evaluated on Inhibition of actin-activated ATPase activity of fast skeletal and cardiac muscle myosin II, inhibition of skeletal muscle contractility ex vivo, and slowing of in vitro actin-sliding velocity (IC50 <1 μM). Several 4-hydroxycoumarin imine analogues showed improved potency (IC50 <1 μM) and selectivity (≥12-fold) for skeletal myosin versus cardiac myosin compared to the lead compound BHC.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: