Małgorzata Zygmunt

Synthesis, antiarrhythmic, and antihypertensive effects of novel 1-substituted pyrrolidin-2-one and pyrrolidine derivatives with adrenolytic activity

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.

Are anti-inflammatory properties of lipoic acid associated with the formation of hydrogen sulfide?

BACKGROUND Lipoic acid (LA) was shown to possess anti-inflammatory properties. In this study, we present evidence supporting the hypothesis that the anti-inflammatory properties of LA are associated with the formation of hydrogen sulfide (H2S). METHODS The study was conducted on male albino Swiss mice. The animals were treated with carrageenan by subcutaneous (sc) injection into the right hind paw to induce acute inflammation. Animals were treated intraperitoneally (ip) with LA (30, 50 and 100 mg/kg) or indomethacin (20 mg/kg) 30 min before carrageenan administration. The control group was given ip the vehicle (1% Tween 80) 30 min before carrageenan administration. Additional experiment involved ip combined treatment of mice with glibenclamide (10 mg/kg) or glibenclamide (10 mg/kg) and LA(100 mg/kg) 30 min before carrageenan administration. LA, indomethacin and glibenclamide were suspended in 1% Tween 80. At 1, 2 and 3 h after treatment with carrageenan the degree of the paw edema was evaluated by the measurement of the paw volume using aqueous plethysmometer. RESULTS Injection of carrageenan into the mouse hind paw increased paw volume. The increase in paw edema was completely suppressed by pretreatment with LA. The reduction of paw edema by LA was abolished by pretreatment with the K(ATP) channel antagonist, glibenclamide. CONCLUSION Our findings demonstrate for the first time in vivo that the anti-inflammatory activity of LA might be connected with the formation of H2S.

A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor––yohimbine and guanfacine––act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.

Effect of oxovanadium(IV) complexes on nondiabetic and streptozotocin-diabetic rats.

The effects of vanadium complexes with organic ligands, [VO(phen)2]SO42·3H2O, [VO(bpy)2]SO4·2H2O, and [VOCl2(Hmcp)2H2O], on blood glucose and plasma lipid levels were studied in nondiabetic and streptozotocin‐diabetic rats and compared to that of [VO(mal)2] (the reference compound). The present results provide evidence that the compounds examined possess lower toxicity than [VO(mal)2]. One of the compounds examined, viz. [VO(bpy)2]SO4·2H2O, decreases, statistically significantly, the glucose level and a second one, viz. [VOCl2(Hmcp)2H2O], decreases, also significantly, the total cholesterol level.

Structure-activity relationship of some new anti-arrhythmic phenytoin derivatives

The pharmacological activity of nine anti‐arrhythmic phenytoin derivatives was assessed in preventing chloroform‐induced arrhythmia. The compounds were tested in vitro on isolated heart of the rat. Four compounds were chosen as representative of the spatial characteristics of the studied group, and X‐ray structure analyses were carried out on them. Because the protonated form is present in physiological milieu, conformational analysis was performed on the protonated form of the four representatives and in addition on the compound showing the highest anti‐arrhythmic activity. It was found that substitution of the imidazolidinone ring of phenytoin at position 3 by a chain containing a tertiary amine nitrogen atom changes the affinity profile from inactivated (phenytoin‐like) to activated (quinidine‐like) cardiac sodium channels. The activity of the studied compounds relies on the presence of protonated tertiary nitrogen atom, at least one phenyl ring, and flexibility of the molecule, which enables the spacer to assume a desired length.

Pyrrolidin-2-one derivatives may reduce body weight in rats with diet-induced obesity.

UNLABELLED Obesity affects an increasing number of individuals in the human population and significant importance is attached to research leading to the discovery of drug which would effectively reduce weight. The search for new drugs with anorectic activity and acting within the adrenergic system has attracted the interest of researchers. This study concerns the experimental effects on body weight of α2-adrenoceptor antagonists from the group of pyrrolidin-2-one derivatives in rats with diet-induced obesity. METHODS The intrinsic activity of the test compounds at the α-adrenoreceptors was tested. Obesity in rats was obtained by the use of fatty diet and then the influence of the test compounds on body weight, food and water intakes, lipid and glucose profiles and glycerol and cortisol levels were determinated. The effects of the compounds on locomotor activity, body temperature, blood pressure and heart rate were tested. RESULTS One of the test compounds (1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one) reduces the animals body weight and the amount of peritoneal adipose tissue during chronic administration, at the same time it does not cause significant adverse effects on the cardiovascular system. This compound decreases temperature and elevates glycerol levels and does not change the locomotor activity and cortisol level at anti-obese dose. CONCLUSIONS Some derivatives of pyrrolidin-2-one that act as antagonists of the α2-adrenoreceptor may reduce body weight. Reducing body weight for 1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one can be associated with decrease in food intake, body fat reduction, reduction of blood glucose, and increased thermogenesis and lipolysis. This effect cannot be the result of changes in spontaneous activity or stress.

In vivo anti-inflammatory activity of lipoic acid derivatives in mice.

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.

Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one.

In an effort to develop α‐adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin‐2‐one derivatives. The α1‐ and α2‐adrenorecepor affinities of the new pyrrolidin‐2‐one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward α1A‐ and α1B‐adrenoceptors and in vitro for antiarrhythmic activity in epinephrine‐induced arrhythmia in rats. The highest affinity for the α1‐adrenoceptor (pKi = 7.01) was displayed by 1‐{4‐[4‐(2‐methoxy‐5‐chlorophenyl)‐piperazin‐1‐yl]‐methyl}‐pyrrolidin‐2‐one (9). 1‐[4‐(2‐Fluorophenyl)‐piperazin‐1‐yl]‐methyl‐pyrrolidin‐2‐one (7) showed the highest affinity toward the α2‐adrenoceptor (pKi = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α1A‐ (EC50 = 0.5 nM) and α1B‐ (EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13–7.99)). New derivatives of pyrrolidin‐2‐one with α1‐adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α1A‐ and α1B‐adrenoceptors.

Synthesis of 8-alkoxy-1,3-dimethyl-2, 6-dioxopurin-7-yl-substituted acetohydrazides and butanehydrazides as analgesic and anti-inflammatory agents

Abstract A series of new 8-alkoxy-1,3-dimethyl-2,6-dioxopurin-7-yl-substituted acetohydrazides and butanehydrazides 6–12 was synthesized and evaluated for the analgesic activity in two in vivo models: the writhing syndrome and the hot-plate tests. Among the investigated derivatives, compounds with N′-arylidenehydrazide moiety 9–12 show analgesic activity significantly higher than that of acetylsalicylic acid, which may indicate the importance of this structural element for analgesic properties. The lack of the activity in the hot-plate test may suggest that the analgesic activity of the newly synthesized compounds is mediated by a peripheral mechanism. The selected compounds 7 and 12 inhibit tumor necrosis factor α production in a rat model of lipopolysaccharide-induced endotoxemia, similarly to theophylline, which may confirm their anti-inflammatory properties.

[Pharmacotherapy of Parkinson's disease: progress or regress?].

Parkinsons disease (PD) is a chronic, progressive disease of the central nervous system (CNS), characterized by a slow loss of dopaminergic neurons in the substantia nigra, leading to significant decrease in dopamine (DA) levels in the striatum. Currently used drugs, such as levodopa (L-DOPA), amantadine, dopamine agonists (D) or anticholinergic drugs, are not effective enough, and do not eliminate the causes of disease. Many research centers are conducting research on new forms of currently used drugs (e.g. Duodopa, XP21279, IPX066), new drugs of already known groups (e.g. safinamide), medicines that suppress side effects of L-DOPA (e.g. AFQ056, fipamezole), and, finally, compounds with a novel mechanism of action (e.g. PMY50028, A2A receptor antagonists). A lot of scientific reports indicate an important role of A2A receptors in the regulation of the central movement system, so a new group of compounds - selective antagonists of A2A receptors (e.g. istradefylline, preladenant, SYN115) - has been developed and their potential use in PD has been examined. Clinical studies of A2A receptor antagonists have shown that this group of compounds can shorten off periods and at the same time they do not worsen dyskinesias in patients with PD. Moreover, there is ongoing research on new forms of treatment, such as gene therapy. Attempts to apply the viral vector AAV-2, which will be able to infect neurons with a variety of genes, including the gene of glutamate decarboxylase (GAD), neurturin (NTN), or aromatic L-amino acid decarboxylase, are currently being carried out. The results of phase I and II clinical studies showed some efficacy of this form of treatment, but the method requires further studies. An analysis of potential future therapies of Parkinsons disease suggests that some progress in this field has been made.