Zatebradine hydrochloride

Zatebradine(UL-FS49) Hcl is a potent HCN channels antagonist, which decreased the heartbeat in a reversible manner; 92% inhibition of the hHCN1-mediated current at 10 uM. IC50 value: 10 uM(92% 92% inhibition of the hHCN1) [1] Target: hHCN channel antagonist The pharmacological properties of hHCN1-mediated currents resembled those of native hyperpolarization-activated currents (I(h)), that is, blockade by Cs(+) (99% at 5 mm), ZD 7288 (98% at 100 microm) and zatebradine (92% at 10 microm) [1]. When voltage-clamp pulse trains were applied, cilobradine induced a use-dependent blockade of If that was stronger and faster than that with zatebradine. Recovery from blockade during prolonged hyperpolarization was significantly faster with zatebradine [2]. The selective HCN blocker zatebradine reduced the activity of oriens-lacunosum moleculare interneurons in wild-type but not HCN2(-/-) mice and decreased the frequency of spontaneous inhibitory currents in postsynaptic CA1 pyramidal cells [3].

References:
[1]. Gill CH, et al. Characterization of the human HCN1 channel and its inhibition by capsazepine. Br J Pharmacol. 2004 Oct;143(3):411-21. [2]. Van Bogaert PP, et al. Use-dependent blockade of cardiac pacemaker current (If) by cilobradine and zatebradine. Eur J Pharmacol. 2003 Oct 8;478(2-3):161-71. [3]. Matt L, et al. HCN2 channels in local inhibitory interneurons constrain LTP in the hippocampal direct perforant path. Cell Mol Life Sci. 2011 Jan;68(1):125-37.

Design, synthesis and preliminary biological evaluation of zatebradine analogues as potential blockers of the hyperpolarization-activated current.[Pubmed:15670930]

Bioorg Med Chem. 2005 Feb 15;13(4):1211-20.

A series of zatebradine analogues, differing in the basic moiety and in the methylene spacer, have been synthesized; their negative chronotropic activity has been determined in guinea pig atria. The most active compounds have been studied for their blocking properties on the hyperpolarization-activated current If (which is one of the main currents underlying automatic activity in the sinus node) measured on ventricular myocytes of old spontaneously-hypertensive rats (SHR) by means of the patch-clamp technique. The majority of the substances were able to block If, with one of them (15) being slightly more potent than zatebradine. Surprisingly one analogue (6), while showing good negative chronotropic activity, was found to inhibit If only at high concentration and to markedly reduce outward currents, suggesting for this substance a different mechanism of action responsible for the negative chronotropic effect.

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.[Pubmed:8222132]

Circulation. 1993 Nov;88(5 Pt 1):2389-401.

BACKGROUND: Zatebradine (UL-FS 49) is a drug with a specific bradycardiac electrophysiological profile. It reduces heart rate by lengthening the duration of diastolic depolarization in the sinoatrial (SA) node. The ionic basis of this action, however, is not clarified. METHODS AND RESULTS: We used the whole-cell patch-clamp technique to study the effects of zatebradine on ionic currents underlying diastolic depolarization of isolated rabbit SA node cells. Low concentrations of zatebradine simultaneously reduced diastolic depolarization rate and the pacemaker current I(f). The drug blocked the pacemaker current, I(f), in a use-dependent manner without causing a shift of its activation curve. At hyperpolarized potentials, unblock of I(f) occurred. Clinically relevant concentrations of the drug have little effect on the L-type calcium current or delayed rectifier potassium current. CONCLUSIONS: 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. Thus, the sinus node inhibitor zatebradine belongs to a new class of "I(f) blockers" with possible advantages over currently available drugs for the treatment of ischemic heart disease.

Use- and frequency-dependent blockade by UL-FS 49 of the if pacemaker current in sheep cardiac Purkinje fibres.[Pubmed:2272362]

Eur J Pharmacol. 1990 Oct 9;187(2):241-56.

The mechanism by which the bradycardiac agent UL-FS 49 blocks the if pacemaker current was investigated in sheep Purkinje fibres using the two microelectrode voltage-clamp technique. If was activated by 1 s pulses applied between -30 mV and -120 mV at 0.4 Hz in a modified Tyrode solution containing BaCl2 and MnCl2, and with TRIS replacing most of the Na+. UL-FS 49 caused an exponential decline of the if current amplitude during a train of pulses. Both the rate and extent of the if reduction increased with drug concentration, without there being a resting blockade. Recovery from blockade followed a single exponential time course during prolonged hyperpolarizations. The recovery rate was extremely slow and increased with more negative voltages, as did the extent of steady state recovery from blockade. A frequency-dependent reduction of the diastolic depolarization rate resulted from a use-dependent blockade of the pacemaker current.

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

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