Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity (original) (raw)
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Naunyn-Schmiedeberg's Archives of Pharmacology, 2011
A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents.
International Journal of Molecular Sciences
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 antiar...
European Journal of Pharmacology, 2011
Keywords: 1-[3-(4-Arylpiperazin-1-yl)-2hydroxypropyl]-pyrrolidin-2-one derivative α-Adrenoceptor blocking activity Hypotensive activity In the search for new hypotensive agents a series of pyrrolidin-2-one derivatives was obtained with αadrenoceptor blocking properties. The aim of the present study was to examine the possible involvement of other mechanisms in the observed hypotensive properties. In the present study the affinities for β 1adrenoreceptors, vasorelaxant effect and the involvement in NO pathway of pyrrolidin-2-one derivatives were assessed. In the next step compounds were also evaluated for their α 1 -adrenoreceptor subtypes in functional bioassays. The data from our experiments indicate that the hypotensive activity of tested pyrrolidin-2-one derivatives is a result of their α-adrenoceptor blocking properties and the compounds have stronger antagonist potency for the α 1D -than for α 1B -subtype. Among investigated compounds EP-46 is the most potent and selective antagonist for the α 1D -and α 1A -than for α 1B -subtype. Compound EP-43 can enhance NO production additionally.
QSAR studies on a number of pyrrolidin-2-one antiarrhythmic arylpiperazinyls
Medicinal Chemistry Research, 2012
The activity of a number of 1-[3-(4-arylpiperazin-1-yl)propyl]pyrrolidin-2-one antiarrhythmic (AA) agents was described using the quantitative structureactivity relationship model by applying it to 33 compounds. The molecular descriptors of the AA activity were obtained by quantum chemical calculations combined with molecular modeling calculations. The resulting model explains up to 91% of the variance and it was successfully validated by four tests (LOO, LMO, external test, and Y-scrambling test). Statistical analysis shows that the AA activity of the studied compounds depends mainly on the PCR and JGI4 descriptors. Keywords 1-[3-(4-Arylpiperazin-1-yl)propyl]pyrrolidin-2-one derivatives Á Antiarrhythmic activity Á QSAR analysis Electronic supplementary material The online version of this article (
Pharmaceuticals, 2021
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 i...
European Journal of Medicinal Chemistry, 2004
In this work, some 2-nonsubstituted/2-methyl-/2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone, derivatives and 2-nonsubstituted/2-methyl-4-[4-(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesised by reacting hexan-2,5-dion or 1-aryl-3-carbethoxypent-1,4-diones with corresponding 2-substituted/nonsubstituted 6-(4'-aminophenyl)-4,5dihydro-3(2H)-pyridazinone or 2-substituted/nonsubstituted-4-(4'-aminophenyl)-(2H)-phthalazinone under Paal-Knorr pyrrole synthesis conditions. The antihypertensive activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.
International Journal of Molecular Sciences
Cardiovascular diseases remain one of the leading causes of death worldwide. Unfortunately, the available pharmacotherapeutic options have limited effectiveness. Therefore, developing new drug candidates remains very important. We selected six novel arylpiperazine alkyl derivatives of salicylamide to investigate their cardiovascular effects. Having in mind the beneficial role of α1-adrenergic receptors in restoring sinus rhythm and regulating blood pressure, first, using radioligand binding assays, we evaluated the affinity of the tested compounds for α-adrenergic receptors. Our experiments revealed their high to moderate affinity for α1- but not α2-adrenoceptors. Next, we aimed to determine the antiarrhythmic potential of novel derivatives in rat models of arrhythmia induced by adrenaline, calcium chloride, or aconitine. All compounds showed potent prophylactic antiarrhythmic activity in the adrenaline-induced arrhythmia model and no effects in calcium chloride- or aconitine-induce...
Journal of Medicinal Chemistry, 2001
A series of new pyridazin-3(2H)-one derivatives (3 and 4) were evaluated for their in vitro affinity toward both R 1 -and R 2 -adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the R 1 -adrenoceptor, with K i values in the low nanomolar range. The polymethylene chain constituting the spacer between the furoylpiperazinyl pyridazinone and the arylpiperazine moiety was shown to influence the affinity and selectivity of these compounds. Particularly, a gradual increase in affinity was observed by lengthening the polymethylene chain up to a maximum of seven carbon atoms. In addition, compound 3k, characterized by a very interesting R 1 -AR affinity (1.9 nM), was also shown to be a highly selective R 1 -AR antagonist, the affinity ratio for R 2 -and R 1 -adrenoceptors being 274. To gain insight into the structural features required for R 1 antagonist activity, the pyridazinone derivatives were submitted to a pharmacophore generation procedure using the program Catalyst. The resulting pharmacophore model showed high correlation and predictive power. It also rationalized the relationships between structural properties and biological data of, and external to, the pyridazinone class.