Zatebradine hydrochloride

Blocks hyperpolarization-activated current (If) CAS# 91940-87-3

Zatebradine hydrochloride

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Chemical structure

Zatebradine hydrochloride

3D structure

Chemical Properties of Zatebradine hydrochloride

Cas No. 91940-87-3 SDF Download SDF
PubChem ID 3045335 Appearance Powder
Formula C26H37ClN2O5 M.Wt 493.04
Type of Compound N/A Storage Desiccate at -20°C
Synonyms UL-FS 49
Solubility H2O : 11.11 mg/mL (22.53 mM; Need ultrasonic)
Chemical Name 3-[3-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]propyl]-7,8-dimethoxy-2,5-dihydro-1H-3-benzazepin-4-one;hydrochloride
SMILES CN(CCCN1CCC2=CC(=C(C=C2CC1=O)OC)OC)CCC3=CC(=C(C=C3)OC)OC.Cl
Standard InChIKey ZRNKXJHEQKMWCH-UHFFFAOYSA-N
Standard InChI InChI=1S/C26H36N2O5.ClH/c1-27(13-9-19-7-8-22(30-2)23(15-19)31-3)11-6-12-28-14-10-20-16-24(32-4)25(33-5)17-21(20)18-26(28)29;/h7-8,15-17H,6,9-14,18H2,1-5H3;1H
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of Zatebradine hydrochloride

DescriptionBradycardic agent that produces use-dependent inhibition of hyperpolarization-activated current If (HCN channel) in sinoatrial node cells (EC50 = 480 nM) and Purkinje fibres. Displays negative chronotropic activity in isolated guinea pig atria (EC50 of 13.4 μM).

Zatebradine hydrochloride Dilution Calculator

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Preparing Stock Solutions of Zatebradine hydrochloride

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.0282 mL 10.1412 mL 20.2823 mL 40.5647 mL 50.7058 mL
5 mM 0.4056 mL 2.0282 mL 4.0565 mL 8.1129 mL 10.1412 mL
10 mM 0.2028 mL 1.0141 mL 2.0282 mL 4.0565 mL 5.0706 mL
50 mM 0.0406 mL 0.2028 mL 0.4056 mL 0.8113 mL 1.0141 mL
100 mM 0.0203 mL 0.1014 mL 0.2028 mL 0.4056 mL 0.5071 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on 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.

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References on Zatebradine hydrochloride

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.

Description

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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