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Chemical Compound Review

CHEMBL314612     5-[1-(3,4- dimethoxyphenyl)carbonyl- 3,4...

Synonyms: AG-K-25062, SureCN4322811, EMD-57033, EMD-57439, Emd-53998, ...
 
 
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Disease relevance of Emd-53998

 

High impact information on Emd-53998

  • These changes were greater at slower heart rate or lower [Ca2+]o. The magnitude of increased VO2 with EMD 57033 was greater at 100 bpm than 150 bpm but unaffected by [Ca2+]o. We then investigated the influence of ejection on the response to EMD 57033 (n = 7) [6].
  • On the other hand, it has been suggested that the agent EMD-53998 increases the Ca2+ sensitivity of the contractile proteins without affecting the intracellular Ca2+ transient in cardiac muscle [7].
  • Effects of calcium and EMD-53998 on oxygen consumption in isolated canine hearts [7].
  • EMD 57033 also stimulated the velocity of actin filament sliding on myosin heads adhered to nitrocellulose-coated glass coverslips [8].
  • Intact canine ventricular myocytes responded to the positive enantiomer, EMD 57033, with an increase in the extent of shortening during twitch contractions without increasing the peak amplitude of the Ca2+ transient [8].
 

Chemical compound and disease context of Emd-53998

 

Biological context of Emd-53998

  • Force enhancement without changes in cross-bridge turnover kinetics: the effect of EMD 57033 [10].
  • Detailed chemical shift mapping of the binding sites reveals that the regions encompassing helix G-loop IV-helix H are more affected by EMD 57033, while residues located on helix E-loop III-helix F and the linker between sites III and IV are more affected by cIp [11].
  • EMD 57033 increased cardiac output (up to 27+/-8%) and LVdP/dt(max) (86+/-19%) [1].
  • 4. In 11 resting MI, intravenous EMD 57033 (0.2 - 0.8 mg kg(-1) min(-1)) increased LVdP/dt(max) (57+/-5%) and stroke volume (26+/-6%) with no effect on heart rate, LV filling pressure, and myocardial O(2)-consumption, similar to N [2].
  • In isolated rat hearts EMD 53998 (0.5 to 5 microM) had a dose-dependent effect to increase left ventricular systolic pressure [12].
 

Anatomical context of Emd-53998

  • There was no effect of EMD 57439 on the relation between pCa and actomyosin Mg-ATPase activity of canine heart myofibrils [8].
  • Previous studies have shown a small but significant negative lusitropic effect of the calcium sensitizer EMD 53998 in ferret papillary muscle, although this effect was considered to be outweighed by powerful augmentation of contractility [4].
  • Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998 [4].
  • 2. Haemodynamic measurements of LV pressure, maximum rate of rise of LV pressure (LVdP/dtmax), cardiac output, mean arterial pressure, heart rate, pulmonary artery and pulmonary wedge pressures were made during infusion of solvent (control) and the calcium sensitizer EMD 57033 (0.6 mg min-1 kg-1) [13].
  • The effect of the cardiotonic sensitizing drug EMD 57033 was studied in frog skinned skeletal muscle fibres at 12 degrees C to provide a baseline for skeletal muscle studies and for comparison with cardiac fibres [14].
 

Associations of Emd-53998 with other chemical compounds

  • METHODS AND RESULTS: In 10 isolated, red blood cell-perfused rabbit hearts the effects of EMD 57033 (5.0 to 5.8 mumol/L) on left ventricular (LV) pressure and O2 consumption (VO2) were examined at heart rates of 100 and 150 beats per minute (bpm) and perfusate [Ca2+] ([Ca2+]o) of 2.5 and 1.0 mmol/L (isovolumic contractions) [6].
  • The relationships between [Ca2+] and Tyr fluorescence of hcTnC and between [Ca2+] and bis-ANS fluorescence in the presence of hcTnC were substantially altered by EMD 57033 in the range of [Ca2+] where Ca2+/Mg2+ sites of hcTnC were titrated by Ca2+ [15].
  • Steady-state [Ca2+]i-force relationship in intact twitching cardiac muscle: direct evidence for modulation by isoproterenol and EMD 53998 [16].
  • In this work, we used 2D ¿(1)H, (15)N¿-HSQC NMR spectroscopy to monitor the binding of EMD 57033 to cTnC in the Ca(2+)-saturated state [11].
  • Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium [17].
 

Gene context of Emd-53998

  • This is in contrast to their relative potencies to inhibit isolated myocardial phosphodiesterase III: EMD 54650 greater than EMD 53998 greater than EMD 54622 [18].
  • The normalized extra-Ca2+-tension relation became shallow by EMD 57033 (EMD) (one of the Ca2+ sensitizers) and by an increase in Ca2+ concentration in the solution ([Ca2+]o) in a concentration-dependent manner [19].
  • Effects of troponin-I extraction with vanadate and of the calcium sensitizer EMD 53998 on the rate of force generation in skinned cardiac muscle [20].
  • The apparent TnI-isoform dependence of the effects elicited by EMD 53998 suggests that its actions are modulated by the regulatory proteins of the thin filament [21].
  • In isolated 32P-labeled guinea pig ventricular cardiomyocytes, EMD 57033 increased the phosphorylation state of phospholamban as well as the inhibitory subunit of troponin, which are usually linked to reductions in contraction time [22].
 

Analytical, diagnostic and therapeutic context of Emd-53998

References

  1. Cardiovascular profile of the calcium sensitizer EMD 57033 in open-chest anaesthetized pigs with regionally stunned myocardium. de Zeeuw, S., Trines, S.A., Krams, R., Verdouw, P.D., Duncker, D.J. Br. J. Pharmacol. (2000) [Pubmed]
  2. Beneficial effects of the Ca2+ sensitizer EMD 57033 in exercising pigs with infarction-induced chronic left ventricular dysfunction. Duncker, D.J., Haitsma, D.B., Liem, D.A., Heins, N., Stubenitsky, R., Verdouw, P.D. Br. J. Pharmacol. (2001) [Pubmed]
  3. A new cardiotonic drug reduces the energy cost of active tension in cardiac muscle. Gross, T., Lues, I., Daut, J. J. Mol. Cell. Cardiol. (1993) [Pubmed]
  4. Negative lusitropy and abnormal calcium handling in hypoxic cardiac myocytes exposed to the calcium-sensitizer EMD 53998. Webster, K.A., Bodi, I., McNamara, J.P., Tracy, M., Discher, D.J., Bishopric, N.H. J. Mol. Cell. Cardiol. (1993) [Pubmed]
  5. EMD 57033 enhances arrhythmias associated with increased wall-stress in the working rat heart. Evans, S.J., Levi, A.J., Lee, J.A., Jones, J.V. Clin. Sci. (1995) [Pubmed]
  6. Effects of EMD 57033 on contraction and relaxation in isolated rabbit hearts. Hgashiyama, A., Watkins, M.W., Chen, Z., LeWinter, M.M. Circulation (1995) [Pubmed]
  7. Effects of calcium and EMD-53998 on oxygen consumption in isolated canine hearts. de Tombe, P.P., Burkhoff, D., Hunter, W.C. Circulation (1992) [Pubmed]
  8. Stereoselective actions of thiadiazinones on canine cardiac myocytes and myofilaments. Solaro, R.J., Gambassi, G., Warshaw, D.M., Keller, M.R., Spurgeon, H.A., Beier, N., Lakatta, E.G. Circ. Res. (1993) [Pubmed]
  9. Calcium sensitizer EMD 57033, but not the beta1-adrenoreceptor agonist dobutamine, increases mechanical efficiency in stunned myocardium. Trines, S.A., Smits, C.A., van der Moer, J., Slager, C.J., Verdouw, P.D., Krams, R. J. Cardiovasc. Pharmacol. (2002) [Pubmed]
  10. Force enhancement without changes in cross-bridge turnover kinetics: the effect of EMD 57033. Kraft, T., Brenner, B. Biophys. J. (1997) [Pubmed]
  11. Interaction of cardiac troponin C with Ca(2+) sensitizer EMD 57033 and cardiac troponin I inhibitory peptide. Li, M.X., Spyracopoulos, L., Beier, N., Putkey, J.A., Sykes, B.D. Biochemistry (2000) [Pubmed]
  12. A novel positive inotropic substance enhances contractility without increasing the Ca2+ transient in rat myocardium. Ferroni, C., Hano, O., Ventura, C., Lakatta, E.G., Klockow, M., Spurgeon, H., Capogrossi, M.C. J. Mol. Cell. Cardiol. (1991) [Pubmed]
  13. Beneficial effect of the calcium-sensitizing drug EMD 57033 in a canine model of dilated heart failure. Drake-Holland, A.J., Lee, J.A., Hynd, J., Clarke, S.B., Noble, M.I. Clin. Sci. (1997) [Pubmed]
  14. The effects of the inotropic agent EMD 57033 on activation and relaxation kinetics in frog skinned skeletal muscle. Lipscomb-Allhouse, S., Mulligan, I.P., Ashley, C.C. Pflugers Arch. (2001) [Pubmed]
  15. Interaction of cardiotonic thiadiazinone derivatives with cardiac troponin C. Pan, B.S., Johnson, R.G. J. Biol. Chem. (1996) [Pubmed]
  16. Steady-state [Ca2+]i-force relationship in intact twitching cardiac muscle: direct evidence for modulation by isoproterenol and EMD 53998. Dobrunz, L.E., Backx, P.H., Yue, D.T. Biophys. J. (1995) [Pubmed]
  17. Different effect of the Ca(2+) sensitizers EMD 57033 and CGP 48506 on cross-bridge cycling in human myocardium. Brixius, K., Mehlhorn, U., Bloch, W., Schwinger, R.H. J. Pharmacol. Exp. Ther. (2000) [Pubmed]
  18. Novel diazinone derivatives separate myofilament Ca2+ sensitization and phosphodiesterase III inhibitory effects in guinea pig myocardium. Ventura, C., Miller, R., Wolf, H.P., Beier, N., Jonas, R., Klockow, M., Lues, I., Hano, O., Spurgeon, H.A., Lakatta, E.G. Circ. Res. (1992) [Pubmed]
  19. Evaluation of the cross-bridge-dependent change in the Ca2+ affinity of troponin C in aequorin-injected ferret ventricular muscles. Ishikawa, T., O-Uchi, J., Mochizuki, S., Kurihara, S. Cell Calcium (2005) [Pubmed]
  20. Effects of troponin-I extraction with vanadate and of the calcium sensitizer EMD 53998 on the rate of force generation in skinned cardiac muscle. Arner, A., Strauss, J.D., Svensson, C., Rüegg, J.C. J. Mol. Cell. Cardiol. (1995) [Pubmed]
  21. Replacement of troponin-I in slow-twitch skeletal muscle alters the effects of the calcium sensitizer EMD 53998. Kögler, H., Plathow, C., Al-Hillawi, E., Trayer, I.P., Rüegg, J.C. Pflugers Arch. (1998) [Pubmed]
  22. Comparison of the stereoselective effects of a thiadiazinone derivative on contractile parameters and protein phosphorylation in the mammalian ventricle. Neumann, J., Bokník, P., Schmitz, W., Scholz, H., Zimmermann, N. J. Cardiovasc. Pharmacol. (1995) [Pubmed]
  23. Specific enhancement of sarcomeric response to Ca2+ protects murine myocardium against ischemia-reperfusion dysfunction. Arteaga, G.M., Warren, C.M., Milutinovic, S., Martin, A.F., Solaro, R.J. Am. J. Physiol. Heart Circ. Physiol. (2005) [Pubmed]
  24. Effects of Ca2+ sensitizers on contraction, [Ca2+]i transient and myofilament Ca2+ sensitivity in diabetic rat myocardium: potential usefulness as inotropic agents. Ishitani, T., Hattori, Y., Sakuraya, F., Onozuka, H., Makino, T., Matsuda, N., Gando, S., Kemmotsu, O. J. Pharmacol. Exp. Ther. (2001) [Pubmed]
  25. Enantiomeric dissection of the effects of the inotropic agent, EMD 53998, in single cardiac myocytes. Gambassi, G., Capogrossi, M.C., Klockow, M., Lakatta, E.G. Am. J. Physiol. (1993) [Pubmed]
 
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