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Chemical Compound Review

Zatebradina     4-[3-[2-(3,4- dimethoxyphenyl)ethyl- methyl...

Synonyms: Zatebradine, Zatebradinum, UL-FS-49, UL-FS 49, CHEMBL69679, ...
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Disease relevance of Zatebradine


Psychiatry related information on Zatebradine


High impact information on Zatebradine

  • BACKGROUND: Zatebradine is a bradycardic agent that inhibits the hyperpolarization-activated current (I(f)) in the rabbit sinoatrial node [7].
  • CONCLUSIONS: These results indicate that (1) zatebradine is an open-channel blocker of hKv 1.5, (2) binding occurs in the internal mouth of the ion pore, (3) unbinding is required before the channel can close, and (4) zatebradine-induced block is use dependent because of slower recovery kinetics in the presence of the drug [7].
  • These zatebradine doses lowered heart rate from 116 +/- 5 to 55 +/- 1 beats per minute (P < .05) but had no effect on SLS of stunned and not-stunned myocardium [1].
  • Zatebradine and exercise tolerance [8].
  • In a single-blind placebo run-in, randomized double-blind, placebo-controlled, multicenter study, patients already receiving extended-release nifedipine (30 to 90 mg once a day) were randomized to receive zatebradine (5 mg twice a day [n = 64]) or placebo (n = 60) [3].

Chemical compound and disease context of Zatebradine


Biological context of Zatebradine

  • This use-dependent block of the If channel can account for most of the pharmacological characteristics of zatebradine and is probably the mechanism of heart rate reduction caused by this agent [2].
  • In the group that received zatebradine, mean (+/- SE) heart rate decreased from 143 +/- 8 to 99 +/- 4 beats/min (p < 0.01) and there was no significant change in either peak left ventricular systolic pressure, dP/dt or tau [4].
  • Isolated isovolumetric pig hearts were prepared and left ventricular pressure, its first derivative (dP/dt), tau and heart rate were measured both before and after administration of either 0.975 mg of zatebradine (Group I, n = 8) or 125 micrograms of verapamil (Group II, n = 8) [4].
  • Action potential recordings in the SHHF rats demonstrated abnormal automaticity, which was abolished by the addition of an I(f) blocker (10 muM zatebradine) [13].
  • Zatebradine improved stroke volume index in all treated rats but increased left ventricular volume in rats with small MI (2.43 +/- 0.10 vs. 1.81 +/- 0.10 ml/kg, P < 0.05) but not in rats with large MI (2.34 +/- 0.09 vs. 2.35 +/- 0.11 ml/kg, not significant) [14].

Anatomical context of Zatebradine

  • We also assessed the effects of zatebradine and verapamil on coronary vascular tone by measuring flow in the left anterior descending coronary artery in intact anesthetized open chest pigs both before and after the intracoronary administration of these drugs (n = 8 for each) [4].
  • Zatebradine also attenuated the increased rate by 53% and shifted the EAR from the anterior to the posterior-superior right atrium [15].
  • Since the cation conductance activated by hyperpolarization seems to represent an ubiquitous class of membrane channel in mammals, the present study was undertaken to evaluate the influence of specific bradycardic agents [UL-FS 49 (zatebradine) and its derivative DK-AH 268] on excitable cells of the central nervous system [16].
  • The different actions of two I(h) channel blockers, zatebradine (UL-FS 49) and ZD7288, on rod photoresponses were analysed by computer simulation using a newly revised ionic current model of the rod photoreceptor, based on Hodgkin-Huxley equations [17].
  • Alinidine lengthened the effective refractory period (ERP) in the AV node (p < 0.01), whereas zatebradine did not induce a statistically significant prolongation [18].

Associations of Zatebradine with other chemical compounds


Gene context of Zatebradine

  • Zatebradine reduced rest heart rate both at 4 weeks ([mean +/- SEM] 12.9 +/- 1.23 vs. 2.3 +/- 1.6 [placebo] beats/min, p < 0.0001) and at the end of comparable stages of Bruce exercise (16.7 +/- 1.2 vs. 3.4 +/- 1.2 [placebo] beats/min, p < 0.0001) [3].
  • Zatebradine (0.5 mg/kg i.v.) reduced heart rate in MI-rats from 400 +/- 15 to 350 +/- 19 and in SH-rats from 390 +/- 19 to 324 +/- 6 beats/min without changing mean arterial pressure [5].
  • Inhibition of the hHCN1-mediated current by ZD 7288 was apparently independent of prior channel activation (i.e. non-use-dependent), whereas that induced by zatebradine was use-dependent [22].

Analytical, diagnostic and therapeutic context of Zatebradine


  1. Myofibrillar Ca2+ sensitization predominantly enhances function and mechanical efficiency of stunned myocardium. Soei, L.K., Sassen, L.M., Fan, D.S., van Veen, T., Krams, R., Verdouw, P.D. Circulation (1994) [Pubmed]
  2. Use-dependent block of the pacemaker current I(f) in rabbit sinoatrial node cells by zatebradine (UL-FS 49). On the mode of action of sinus node inhibitors. Goethals, M., Raes, A., van Bogaert, P.P. Circulation (1993) [Pubmed]
  3. Addition of zatebradine, a direct sinus node inhibitor, provides no greater exercise tolerance benefit in patients with angina taking extended-release nifedipine: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group study. The Zatebradine Study Group. Frishman, W.H., Pepine, C.J., Weiss, R.J., Baiker, W.M. J. Am. Coll. Cardiol. (1995) [Pubmed]
  4. Effect of zatebradine on contractility, relaxation and coronary blood flow. Breall, J.A., Watanabe, J., Grossman, W. J. Am. Coll. Cardiol. (1993) [Pubmed]
  5. The bradycardic agent zatebradine enhances baroreflex sensitivity and heart rate variability in rats early after myocardial infarction. Krüger, C., Landerer, V., Zugck, C., Ehmke, H., Kübler, W., Haass, M. Cardiovasc. Res. (2000) [Pubmed]
  6. Bradycardic and proarrhythmic properties of sinus node inhibitors. Stieber, J., Wieland, K., Stöckl, G., Ludwig, A., Hofmann, F. Mol. Pharmacol. (2006) [Pubmed]
  7. Class III antiarrhythmic effects of zatebradine. Time-, state-, use-, and voltage-dependent block of hKv1.5 channels. Valenzuela, C., Delpón, E., Franqueza, L., Gay, P., Pérez, O., Tamargo, J., Snyders, D.J. Circulation (1996) [Pubmed]
  8. Zatebradine and exercise tolerance. Boudoulas, H., Leier, C.V. J. Am. Coll. Cardiol. (1996) [Pubmed]
  9. Selective inhibition by zatebradine and discrete parasympathetic stimulation of the positive chronotropic response to sympathetic stimulation in anesthetized dogs. Furukawa, Y., Nakano, H., Oguchi, T., Kasama, M., Hoyano, Y., Chiba, S. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  10. Increases in inotropic state without change in heart rate: combined use of dobutamine and zatebradine in conscious dogs. Hettrick, D.A., Pagel, P.S., Lowe, D., Tessmer, J.P., Warltier, D.C. Eur. J. Pharmacol. (1996) [Pubmed]
  11. Effects of zatebradine and propranolol on canine ischemia and reperfusion-induced arrhythmias. Naito, H., Furukawa, Y., Chino, D., Yamada, C., Hashimoto, K. Eur. J. Pharmacol. (2000) [Pubmed]
  12. Effects of zatebradine on ouabain-, two-stage coronary ligation- and epinephrine-induced ventricular tachyarrhythmias. Furukawa, Y., Xue, Y.X., Chiba, S., Hashimoto, K. Eur. J. Pharmacol. (1996) [Pubmed]
  13. Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats. Sridhar, A., Dech, S.J., Lacombe, V.A., Elton, T.S., McCune, S.A., Altschuld, R.A., Carnes, C.A. Am. J. Physiol. Heart Circ. Physiol. (2006) [Pubmed]
  14. Heart rate reduction by zatebradine reduces infarct size and mortality but promotes remodeling in rats with experimental myocardial infarction. Hu, K., Naumann, A., Fraccarollo, D., Gaudron, P., Kaden, J.J., Neubauer, S., Ertl, G. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  15. Effects of verapamil, zatebradine, and E-4031 on the pacemaker location and rate in response to sympathetic stimulation in dog hearts. Furukawa, Y., Miyashita, Y., Nakajima, K., Hirose, M., Kurogouchi, F., Chiba, S. J. Pharmacol. Exp. Ther. (1999) [Pubmed]
  16. Specific bradycardic agents block the hyperpolarization-activated cation current in central neurons. Pape, H.C. Neuroscience (1994) [Pubmed]
  17. A simulation analysis on mechanisms of damped oscillation in retinal rod photoreceptor cells. Ogura, T., Satoh, T.O., Usui, S., Yamada, M. Vision Res. (2003) [Pubmed]
  18. Electropharmacology of the bradycardic agents alinidine and zatebradine (UL-FS 49) in a conscious canine ventricular arrhythmia model of permanent coronary artery occlusion. Aidonidis, I., Brachmann, J., Rizos, I., Zacharoulis, A., Stavridis, I., Toutouzas, P., Kübler, W. Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy. (1995) [Pubmed]
  19. Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium. Wynsen, J.C., O'Brien, P.D., Warltier, D.C. J. Am. Coll. Cardiol. (1994) [Pubmed]
  20. Haemodynamic actions of a novel sino-atrial node function modulator, ZENECA ZD7288, in the anaesthetized dog: a comparison with zatebradine, atenolol and nitrendipine. Rouse, W., Johnson, I.R. Br. J. Pharmacol. (1994) [Pubmed]
  21. Zatebradine, a specific bradycardic agent, alters the hemodynamic and left ventricular mechanical actions of levosimendan, a new myofilament calcium sensitizer, in conscious dogs. Pagel, P.S., Harkin, C.P., Hettrick, D.A., Warltier, D.C. J. Pharmacol. Exp. Ther. (1995) [Pubmed]
  22. Characterization of the human HCN1 channel and its inhibition by capsazepine. Gill, C.H., Randall, A., Bates, S.A., Hill, K., Owen, D., Larkman, P.M., Cairns, W., Yusaf, S.P., Murdock, P.R., Strijbos, P.J., Powell, A.J., Benham, C.D., Davies, C.H. Br. J. Pharmacol. (2004) [Pubmed]
  23. Zatebradine: pharmacokinetics of a novel heart-rate-lowering agent after intravenous infusion and oral administration to healthy subjects. Roth, W., Bauer, E., Heinzel, G., Cornelissen, P.J., van Tol, R.G., Jonkman, J.H., Zuiderwijk, P.B. Journal of pharmaceutical sciences. (1993) [Pubmed]
  24. Blockade of the pacemaker current by intracellular application of UL-FS 49 and UL-AH 99 in sheep cardiac Purkinje fibers. Van Bogaert, P.P., Goethals, M. Eur. J. Pharmacol. (1992) [Pubmed]
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