Antiarrhythmic properties of some 1,4-disubstituted piperazine derivatives with α1-adrenoceptor affinities

Kubacka, Monika; Mogilski, Szczepan; Filipek, Barbara; Marona, Henryk

doi:10.1016/j.ejphar.2013.10.021

Cited by 12 publications

(6 citation statements)

References 32 publications

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“…Our findings are in agreement with the results obtained by other researchers, showing that phenylpiperazine derivatives possessed α 1 -adrenolytic properties, as well as prophylactic and/or therapeutic activity in adrenaline-induced arrhythmia (Dylag et al, 2004 ; Handzlik et al, 2012 ; Kubacka et al, 2013a , b ).…”

Section: Discussionsupporting

confidence: 93%

“…Scientists reported that 2-methoxyphenylpiperazine derivatives often interact with adrenergic receptors (Handzlik et al, 2008 ; Kubacka et al, 2013a ; Rapacz et al, 2014 , 2015a , b ). Thus, we evaluated the affinity of the studied compounds for α 1 -and β 1 -adrenoceptors.…”

Section: Discussionmentioning

confidence: 99%

“…This proves that α 1 -adrenoceptors may have role in preventing cardiac arrhythmias. Numerous animal studies confirmed this theory, showing antiarrhythmic properties of α 1 -adrenolytics (Sapa et al, 2011 ; Kubacka et al, 2013a ; Rapacz et al, 2014 , 2015b ).…”

Section: Introductionmentioning

confidence: 90%

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Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

et al. 2016

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Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values—it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18–0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

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Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

et al. 2016

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“…Furthermore, α 1 receptors antagonists such as prazosin and phentolamine showed antiarrhythmic properties in ischemia-induced arrhythmias in animal models [31][32][33][34][35]. In addition, many novel compounds targeting α 1 receptors possess a strong antiarrhythmic activity e.g., in the adrenaline-or barium chloride-induced model of arrhythmia or in the rat coronary artery ligation-reperfusion model, which is due to the α 1 -adrenolytic properties [36][37][38].…”

Section: Introductionmentioning

confidence: 99%

The Antiarrhythmic Activity of Novel Pyrrolidin-2-one Derivative S-75 in Adrenaline-Induced Arrhythmia

et al. 2021

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Arrhythmia is a quivering or irregular heartbeat that can often lead to blood clots, stroke, heart failure, and other heart-related complications. The limited efficacy and safety of antiarrhythmic drugs require the design of new compounds. Previous research indicated that pyrrolidin-2-one derivatives possess an affinity for α1-adrenergic receptors. The blockade of α1-adrenoceptor may play a role in restoring normal sinus rhythm; therefore, we aimed to verify the antiarrhythmic activity of novel pyrrolidin-2-one derivative S-75. In this study, we assessed the influence on sodium, calcium, potassium channels, and β1-adrenergic receptors to investigate the mechanism of action of S-75. Lack of affinity for β1-adrenoceptors and weak effects on ion channels decreased the role of these adrenoceptors and channels in the pharmacological activity of S-75. Next, we evaluated the influence of S-75 on normal ECG in rats and isolated rat hearts, and the tested derivative did not prolong the QTc interval, which may confirm the lack of the proarrhythmic potential. We tested antiarrhythmic activity in adrenaline-, aconitine- and calcium chloride-induced arrhythmia models in rats. The studied compound showed prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia, but no significant activity in the model of aconitine- or calcium chloride-induced arrhythmia. In addition, S-75 was not active in the model of post-reperfusion arrhythmias of the isolated rat hearts. Conversely, the compound showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia, reducing post-arrhythmogen heart rhythm disorders, and decreasing animal mortality. Thus, we suggest that the blockade of α1-adrenoceptor might be beneficial in restoring normal heart rhythm in adrenaline-induced arrhythmia.

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“…MH-78 dose-dependently inhibited the isoprenaline-induced chronotropic effect, which indicated that it has β-blocking activity. However, in the case of MH-78, the observed bradycardia may not only be a result of β-adrenoceptor blockade but also of its presumed sodium channel blockade [19] .…”

Section: Discussionmentioning

confidence: 99%

The Nitric Oxide/Soluble Cyclic Guanylase/Cyclic Guanosine Monophosphate Pathway Is Involved in the Cardiovascular Effects of a Novel α<sub>1</sub>- and β-Adrenoceptor Antagonist

Kubacka

Mogilski²,

Bednarski³

et al. 2014

Pharmacology

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The compound MH-78 ((+/-)-1-(2,6-dimethylphenoxy)-3-{4-[2-(2-methoxyphenoxy)ethyl]-piperazin-1-yl}propan-2-ol dihydrochloride) contains structural elements that are typical for α1- and β-blockers. This study aimed to investigate the hypotensive activity as well as the in vitro and in vivo cardiovascular effects of a novel α1- and β-adrenoceptor antagonist (MH-78) and compare it with carvedilol and urapidil. The procedures were performed on aortic rings of normotensive anesthetized rats. MH-78 decreased the blood pressure and heart rate after intravenous and oral administration. MH-78 possesses both α1- and β-adrenoceptor blocking activity, which was confirmed in the in vivo study. In biofunctional assays, MH-78 displayed vasorelaxant activity due to α1-adrenoceptor antagonism and calcium channel blocking properties. Moreover, in endothelium-intact aortic rings, pretreatment with Nω-nitro-L-arginine methyl ester (L-NAME) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) reduced the MH-78-induced vasorelaxation to a level that is characteristic for MH-78 affinity to α1-adrenoceptors. Our results demonstrated that MH-78 possesses α1- and β-adrenoceptor blocking properties and induces potent hypotensive and vasorelaxant effects. Moreover, it relaxes vascular smooth muscle not only due to α1-adrenoceptor blocking activity, but also via the endothelium-dependent nitric oxide/soluble guanylyl cyclase/cyclic guanosine monophosphate signalling pathway.

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Antiarrhythmic properties of some 1,4-disubstituted piperazine derivatives with α1-adrenoceptor affinities

Cited by 12 publications

References 32 publications

Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats

The Antiarrhythmic Activity of Novel Pyrrolidin-2-one Derivative S-75 in Adrenaline-Induced Arrhythmia

The Nitric Oxide/Soluble Cyclic Guanylase/Cyclic Guanosine Monophosphate Pathway Is Involved in the Cardiovascular Effects of a Novel α<sub>1</sub>- and β-Adrenoceptor Antagonist

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