Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

Sapa, Jacek; Nowaczyk, Alicja; Kulig, Katarzyna

doi:10.1007/s00210-010-0566-x

Cited by 14 publications

(7 citation statements)

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“…Pyrrolidyn-2-one derivatives have been shown to interact with adrenergic receptors [39,45,54]. Due to the highest affinity for α 1 -adrenergic receptors assessed in our previous study, we chose the compound S-75 for further experimentation [50].…”

Section: Discussionmentioning

confidence: 99%

“…After 15 min, the clamp was removed, and ECG changes were monitored for 30 min (reperfusion period). The tested compound was added to the perfusion solution 15 min before coronary artery clamping [39]. The point scale described by Bernauer [35] was used to assess the antiarrhythmic activity in this arrhythmia model.…”

Section: Antiarrhythmic Activity In the Post-reperfusion Model In Isolated Rat Heartmentioning

confidence: 99%

“…The ECG was recorded for the first 2 min and then at 5, 10 and 15 min of the experiment. The criterion of antiarrhythmic activity was the decrease or complete absence of extrasystoles, atrioventricular blocks and bradycardia in the ECG recording in comparison with the control group [39].…”

Section: Therapeutic Antiarrhythmic Activity In Adrenaline-induced Arrhythmiamentioning

confidence: 99%

“…Numerous studies have shown that pyrrolidin-2-one derivatives have significant antiarrhythmic and hypotensive properties [39][40][41][42][43][44][45][46]. This effect is possibly mediated via α 1 receptor blockade as these derivatives bind strongly to adrenergic receptors, especially when they have arylpiperazine fragment and hydrogen bond acceptor [47][48][49].…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Antiarrhythmic Activity In the Post-reperfusion Model In Isolated Rat Heartmentioning

confidence: 99%

Section: Therapeutic Antiarrhythmic Activity In Adrenaline-induced Arrhythmiamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…Pyrrolidin-2-one derivatives are a group of compounds that are proven not only to bind strongly to the α 1 -adrenergic receptor but also show antiarrhythmic properties in animal models [ 19 , 20 ]. Our former studies on S-75, a pyrrolidin-2-one derivative, demonstrated its α 1 -adrenolytic properties and significant antiarrhythmic activity in rat arrhythmia models [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α1-Adrenolytic Properties

Lustyk

Sałaciak

Siwek

et al. 2022

IJMS

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Heart rhythm abnormalities are a cause of many deaths worldwide. Unfortunately, the available antiarrhythmic drugs show limited efficacy and proarrhythmic potential. Thus, efforts should be made to search for new, more effective, and safer pharmacotherapies. Several studies suggested that blocking the α1-adrenoceptors could restore normal heart rhythm in arrhythmia. In this study, we aimed to assess the antiarrhythmic potential of S-61 and S-73, two novel pyrrolidin-2-one derivatives with high affinity for α1-adrenergic receptors. First, using radioligand binding studies, we demonstrated that S-61 and S-73 did not bind with β1-adrenoceptors. Next, we assessed whether S-61 and S-73 could protect rats against arrhythmia in adrenaline-, calcium chloride- and aconitine-induced arrhythmia models. Both compounds showed potent prophylactic antiarrhythmic properties in the adrenaline-induced arrhythmia model, but the effect of S-61 was more pronounced. None of the compounds displayed antiarrhythmic effects in calcium chloride- or aconitine-induced arrhythmia models. Interestingly, both derivatives revealed therapeutic antiarrhythmic activity in the adrenaline-induced arrhythmia, diminishing heart rhythm irregularities. Neither S-61 nor S-73 showed proarrhythmic potential in rats. Finally, the compounds decreased blood pressure in rodents. The hypotensive effects were not observed after coadministration with methoxamine, which suggests the α1-adrenolytic properties of both compounds. Our results confirm that pyrrolidin-2-one derivatives possess potent antiarrhythmic properties. Given the promising results of our experiments, further studies on pyrrolidin-2-one derivatives might result in the development of a new class of antiarrhythmic drugs.

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Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective α-adrenoceptor antagonist

Kotańska

Kulig

Marcinkowska

et al. 2017

J Endocrinol Invest

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PurposePrevious studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since α1-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the α2-adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective α-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration of a non-selective α-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives.MethodsThe α1- and α2-adrenoreceptor affinities of the tested compound—1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a high-fat diet, and additionally we measured the spontaneous activity and body temperature.ResultsThe intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of α1B and α2A-adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals’ spontaneous activity and body temperature.ConclusionNon-selective α-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe α2A-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.

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Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

Cited by 14 publications

References 61 publications

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

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

The Antiarrhythmic and Hypotensive Effects of S-61 and S-73, the Pyrrolidin-2-one Derivatives with α1-Adrenolytic Properties

Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective α-adrenoceptor antagonist

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