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Brunon Kwiecień,
Magdalena Dudek,
Anna Bilska-Wilkosz,
Joanna Knutelska,
Marek Bednarski,
Inga Kwiecień,
Małgorzata Zygmunt,
Małgorzata Iciek,
Maria Sokołowska-Jeżewicz, Jacek Sapa,
Lidia Włodek
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ABSTRACT: Background: In mammals lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) function as cofactors for multienzymatic complexes catalyzing the decarboxylation of α-ketoacids. Moreover, LA is used as a drug in a variety of diseases including inflammatory diseases. The aim of the study was to examine anti-inflammatory properties of LA metabolites. Material/methods:The present paper reports the chemical synthesis of 2,4-bismethylthio-butanoic acid (BMTBA) and tetranor-dihydrolipoic acid (tetranor-DHLA). BMTBA is one of the biotransformation products of LA, while tetranor-DHLA is an analogue of DHLA. Structural identity of these compounds was confirmed by 1H NMR. These compounds were assessed for their anti-inflammatory activity in mice. For this purpose, the zymosan-induced peritonitis and the carrageenan-induced hind paw edema animal models were applied. Results/conclusions: The obtained results indicated that the early vascular permeability measured at 30 min of zymosan-induced peritonitis was significantly inhibited in groups receiving BMTBA (10, 30, 50 mg/kg). The early infiltration of neutrophils measured at 4 hours of zymosan-induced peritonitis was inhibited in the group receiving BMTBA (50 mg/kg) and tetranor-DHLA (50 mg/kg). The results indicated that the increase in paw edema was significantly inhibited in the groups receiving BMTBA (50, 100 mg/kg) and tetranor-DHLA (30, 50 mg/kg). In summary, the present studies clearly demonstrated that both BMTBA and tetranor-DHLA were able to act as anti-inflammatory agents. This is the first study examining in vivo the anti-inflammatory properties of LA metabolites.
Postępy Higieny i Medycyny Doświadczalnej (Advances in Hygiene and Experimental Medicine) 01/2013; 67:331-8.
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ABSTRACT: 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.
Archiv für Experimentelle Pathologie und Pharmakologie 01/2011; 383(1):13-25. · 2.65 Impact Factor
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ABSTRACT: The present work describes the synthesis of a pyrazinopurinedione derivative which was together with a series of pyrimidopurinedione derivatives tested for potential antiparkinsonian activity in two tests: the "oxotremorine" and the "reserpine" test. For the studies compounds which had shown affinity for the adenosine A(2A) receptor were chosen. One compound, a pyrazinopurinedione derivative, without affinity for A(2A) receptors, but showing adenosine A(1) receptor affinity was also investigated. The performed preliminary tests indicated that, contrary to the pyrazinopurinedione all pyrimidopurinediones demonstrated antiparkinsonian effects. As a result of present studies it may be concluded that antiparkinsonian effects of the examined compounds are correlated with the antagonistic activity toward adenosine A(2A) receptors in this class of compounds. However a direct correlation of the potency of both effects was not observed possibly due to different pharmacokinetic properties of the compounds. The most active derivatives of the present series were aryl-substituted pyrimidopurinediones.
Archiv der Pharmazie 01/2011; 344(1):20-7. · 1.71 Impact Factor
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ABSTRACT: A series of novel arylpiperazines bearing a 3,3-diphenylpyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha(1)- and alpha(2)-adrenoceptors (ARs), as well as their antiarrhythmic, and antihypertensive activities. The highest affinity for the alpha(1)-AR was displayed by 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (7), which binds with a pK(i)=7.28. The highest affinity for the alpha(2)-AR was shown by 1-{3-[4-(2-methoxy-phenyl)-piperazin-1-yl]-2-hydroxy-propyl}-3,3-diphenylpyrrolidin-2-one (5), which binds with a pK(i)=6.68. Compound 7 was additionally evaluated in in vitro functional tests for its affinity for alpha(1B)- and alpha(1D)-AR, which gave pA(2) alpha(1B)=6.55 and pA(2) alpha(1D)=7.26. Among the compounds tested, compound 7 also had the highest prophylactic antiarrhythmic activity in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50) value was 1.1mg/kg (i.v.). The compounds significantly decreased systolic and diastolic pressure in normotensive anaesthetized rats at doses of 2.5-5.0mg/kg (i.v.) and their hypotensive effects lasted for longer than 1h. It was found that the introduction of two phenyl ring substituents into the 3rd position of the pyrrolidin-2-one fragment gave compounds with affinity for both alpha(1)- and alpha(2)-AR. The substitution of the 2nd position in the phenyl piperazinyl fragment of the molecule was crucial for activity. To determine detailed information concerning the structure-activity relationship, a preliminary molecular modeling study was undertaken.
European journal of medicinal chemistry 05/2009; 44(10):3994-4003. · 3.27 Impact Factor
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ABSTRACT: A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the alpha(1)- and alpha(2)-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK(i) = 6.71 for alpha(1)-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED(50 )value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.
Archiv der Pharmazie 10/2007; 340(9):466-75. · 1.71 Impact Factor
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ABSTRACT: A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a-12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the alpha1- and alpha2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg(-1), and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected alpha1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.
Il Farmaco 11/2005; 60(10):793-803.
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ABSTRACT: Synthesis of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (10-14, 18-21) is described. In the "writhing syndrome" test all compounds studied exhibited potent analgesic activity which was superior than that of acetylsalicylic acid. In the "hot plate" test imides 10, 12, 13, 18-20 acted also stronger than aspirin. Furthermore all compounds tested significantly suppressed the spontaneous locomotor activity of mice and prolonged barbiturate sleep of these animals.
Il Farmaco 02/2005; 60(1):53-9.
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ABSTRACT: The synthesis of 1-N and 3-N aminoalkyl derivatives of 5,5-diphenylhydantoin is described. Structural elucidation based on X-ray analysis was performed for two representative compounds 4a and 9b. The effect of tested compounds on the electrocardiogram was examined in vitro in the non-working heart perfusion test and antiarrhythmic activity in the rat coronary artery ligation-reperfusion model. The most active 1-N derivatives 4a and 7b have shown properties of the compounds belonging to class Ia, according to the Vaughan Williams classification. The spatial organisation of the chosen compounds necessary for their pharmacological activity was discussed.
European Journal of Medicinal Chemistry 07/2003; 38(6):555-66. · 3.35 Impact Factor
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ABSTRACT: A series of 1-substituted pyrrolidin-2-one and pyrrolidine derivatives were synthesised and tested for electrocardiographic, antiarrhythmic, and antihypertensive activity as well as for alpha(1)- and alpha(2)-adrenoceptors binding affinities. Among the newly synthesised derivatives several compounds with 3-(4-arylpiperazin-1-yl)propyl moiety displayed strong antiarrhythmic (7a-12a) and antihypertensive (7a-11a) activities. Compound 11a, 1-[2-acetoxy-3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one, was the most potent in this series. The pharmacological results and binding studies suggest that their antiarrhythmic and hypotensive effects may be related to their alpha-adrenolytic properties, and that those properties depend on the presence of the 1-phenylpiperazine moiety with a methoxy- or chloro- substituent in the ortho position in the phenyl ring.
European Journal of Medicinal Chemistry 04/2002; 37(3):183-95. · 3.35 Impact Factor
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ABSTRACT: Synthesis of N-substituted derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (17-26) is described. The chlorides, containing OH group, used in the above synthesis can exist in two isomeric forms: chain (12, 14-16) and cyclic (12a, 14a-16a). All final imides studied exhibited analgesic activity in the "writhing syndrome" test which was superior than that of acetylsalicylic acid. In the "hot plate" test only two compounds (19, 20) were active as antinociceptive agents. Furthermore, all compounds tested significantly suppressed the spontaneous locomotor activity of mice.
Acta poloniae pharmaceutica 63(4):245-54. · 0.66 Impact Factor
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ABSTRACT: Synthesis of 1-[2-hydroxy-3-(4-o,m,p-halogenophenyl)- and 3-(4-m-chlorophenyl)-1-piperazinyl]propyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (18, 20-23, 25, 27-30 and 19, 24, 26) is described. All substances were active as analgesic agents in "writhing syndrome" test and except of 18 and 23 they acted stronger than acetylsalicylic acid. All final derivatives tested significantly suppressed the spontaneous locomotor activity of mice.
Acta poloniae pharmaceutica 64(4):369-76. · 0.66 Impact Factor
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ABSTRACT: A series of new 1-[3-(4-arylpiperazinyl-1-yl)-2-(N-alkylcarbamoyloxy)propyl]-pyrrolidin-2-one derivatives (4a–12a) were synthesised and tested for their electrocardiographic, antiarrhythmic and antihypertensive activity, as well as for the α1- and α2-adrenoceptor binding affinities. Of the newly synthesised derivatives, 1-{2-(N-2-methylethylcarbamoiloxy)-3-[4-(2-methoxyphenyl)piperazin-1-yl)]propyl}pyrrolidin-2-one dihydrochloride (10a) was the most active in prophylactic antiarrhythmic tests, its ED50 value equalling 2.7 mg kg–1, and the therapeutic index being 75.2; moreover, compound 10a was also found to possess hypotensive activity. A preliminary molecular modelling study suggested that the selected α1-AR antagonist distances and angles between pharmacophoric features, estimated for the tested compounds, were in good agreement with the parameters evaluated for ligands.
Il Farmaco.
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Jacek Sapa
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ABSTRACT: A six new analogs of MG-1(S), 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-pyrrolidin-2-one, with adrenolytic properties were tested for electrocardiographic and antiarrhythmic activity in model ventricular arrhythmias associated with coronary artery occlusion and reperfusion in the non-working isolated perfused rat heart and additionally in barium chloride-induced arrhythmia in vivo. All tested compounds slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. The antiarrhythmic effects of all tested compounds were weaker than the reference compound MG-1(S).
Acta poloniae pharmaceutica 67(5):537-42. · 0.66 Impact Factor
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ABSTRACT: The compound MG-1(R,S), (1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl]-pyrrolidin-2-one, and its enantiomers were tested for electrocardiographic, antiarrhythmic and hypotensive activities. The racemic mixture (MG-1(R,S)) and its S-enantiomer significantly decreased systolic and diastolic blood pressure and possessed antiarrhythmic activity. The S-enantiomer displayed the greatest effect. The R-enantiomer did not show antiarrhythmic or hypotensive activity. The results suggest that the antiarrhythmic and hypotensive effects of these compounds are related to their adrenolytic properties.
Pharmacological reports: PR 63(2):455-63. · 2.44 Impact Factor
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ABSTRACT: The present study was designed to investigate the central nervous system activity of 23 novel phenylpiperazine pyrrolidin-2-one derivatives. These compounds had marked antiarrhythmic and hypotensive activities and revealed affinity for α1- and α2-adrenoceptors. These effects may be related to their α-adrenolytic properties. We assessed their antidepressant-like effect in the forced swimming test, influence of spontaneous locomotor activities and binding to 5-HT1A and 5-HT2 receptors. Our study demonstrated the strong antidepressant-like activity of compound EP-65 in the forced swimming test. The effect of EP-65 was stronger than results obtained with the classical antidepressants imipramine and mianserin. Other compounds, EP-41, EP-42, EP-44, EP-47, EP-48, EP-49, EP-50, EP-62, EP-66, EP-70, EP-75 and EP-76, showed significantly weaker activities in this test. Compound EP-42 showed the strongest affinity for 5-HT1A (Ki=24.5 nM), and compound EP-50 showed the strongest affinity for the 5-HT2 receptor (Ki=109.1 nM). All tested compounds significantly suppressed the spontaneous locomotor activity of mice. Currently, it is not possible to determine which mechanisms are involved in the witnessed antidepressant-like activity of novel phenylpiperazine pyrrolidin-2-one derivatives.
Pharmacological reports: PR 63(1):71-8. · 2.44 Impact Factor
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ABSTRACT: A series of novel phenylpiperazine and phenylpiperidine derivatives bearing a 3,3-disubstituted pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha1-adrenoceptors (ARs) and for their antiarrhythmic and antihypertensive activities. The highest affinity for alpha1-ARs was displayed by 1-[2-hydroxy-3-(4-phenylpiperazin-l-yl)-propyl]-3-phenyl-3-n-propyl-pyrrolidin-2-one (10 a), which binds with pK(i) = 6.43. Among the compounds tested, 1-(2-hydroxy-3-(4-phenylpiperidin-1-yl)-propylpyrrolidin-2-one (5) was the most active in the prophylactic antiarrhythmic activity in adrenaline induced arrhythmia in anesthetized rats. Its ED50 value was 4.9 mg/kg intravenously (i.v.). Some of the compounds tested significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dose of 5.0 mg/kg i.v. and their hypotensive effects lasted for longer than an hour.
Acta poloniae pharmaceutica 66(6):649-62. · 0.66 Impact Factor
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ABSTRACT: A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment were synthesized and evaluated for their binding affinity for alpha1- and alpha2-adrenoceptors (ARs) as well as their antiarrhythmic and antihypertensive activities. The highest affinity for the alpha1-AR was displayed by 1-{3-[4-(2-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 7, which binds with a pKi = 7.13. The highest affinity for the alpha2-AR was shown by 1-{3-[4-(4-chloro-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 18, which binds with a pKi = 7.29. Among the compounds tested, 1-{3-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-propyl}-pyrrolidin-2-one 13 had the highest prophylactic antiarrhythmic activity in epinephrine-induced arrhythmia in anesthetized rats. Its ED50 value was 1.0 mg/kg intravenously (iv). The compounds with a hydroxy group in the 4-position of the phenyl ring or two substituents such as fluorine atoms in the 2 and 4 positions of the phenyl ring significantly decreased systolic and diastolic pressure in normotensive anesthetized rats at a dose of 2.5 mg/ kg iv, and their hypotensive effects lasted for longer than an hour.
Pharmacological reports: PR 62(1):68-85. · 2.44 Impact Factor
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ABSTRACT: Synthesis of 2-(2-hydroxy-3-amino)propyl derivatives of 4-alkoxy-6-methyl-1H-pyrrolo[3,4-c]pyridine-1,3(2H)-diones (24-35) is described. The chlorides used in the above synthesis exist mainly in the cyclic forms (18, 20-23). Only chloride with benzhydryl substituent at the nitrogen atom of piperazine has the chain structure (19). Among the studied imides the most active analgesics in the "writhing" syndrome test proved to be compounds 30 and 31 (with LD50 > 2000 mg/kg) containing 4-benzylpiperidino group. Furthermore, all imides suppressed significantly spontaneous locomotor activity of mice.
Acta poloniae pharmaceutica 66(1):57-63. · 0.66 Impact Factor
