Zatebradine (UL-FS-49) is a potent inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels with an IC₅₀ of 1.96 µM.

Zatebradine reduces the dose-dependently the amplitude of the cardiac pacemaker current (If), without modifying either the voltage dependence or the kinetics of channel activation. Furthermore, Zatebradine blocks the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels, with IC₅₀ values of 1.83 µM, 2.21 µM, 1.90 µM, and 1.88 µM, respectively. Moreover, The use-dependent blockade by Zatebradine of the cardiac pacemaker current from rabbit sino-atrial node cells has an apparent K_i of 480 nM.

Zatebradine reduces the heart rate dose-dependently.

In vivo, Zatebradine (0-20 mg/kg; i.p.; for 30 minutes; male C57/Bl6-mice) reduces the heart rate dose-dependently from 600 to 200 bpm with an ED₅₀ value of 1.8 mg/kg. Besides, Zatebradine induces increasing arrhythmia. Additionally, the experiment result shows acute blood glucose reduction, dose-dependently reduces glycated hemoglobin, significantly prevents the decrease of IRI levels at doses of 3 and 10 mg/kg, and no difference in food intake or body weight.

Zatebradine (i.v.; 1.0 mg/kg) decreases heart rate (fH) at 12 °C by 11% and limits maximum fH to 78.6±5.9 beats min^-1. Besides, this compound has non-pacemaker effects that limit tissue oxygen utilization and its usefulness for in vivo studies.

In a word, Zatebradine is a potent inhibitor of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Besides, Zatebradine blocks the slow inward current through human HCN1, HCN2, HCN3 and HCN4 channels. Furthermore,  Zatebradine reduces the heart rate dose-dependently.

[1] Stieber J, et al. 2006 Apr;69(4):1328-37. Epub 2005 Dec 30.

[2] Van Bogaert PP, et al. Eur J Pharmacol. 2003 Oct 8;478(2-3):161-71.

[3] N.KeenA, et al. Journal of Thermal Biology. 2012 Apr, 201-210.