Racanská E

Synthesis and structure-activity relationships of new β-adrenoreceptor antagonists. Evidence for the electrostatic requirements for β-adrenoreceptor antagonists

Abstract A series of mono- and disubstituted phenoxypropanolamines, structurally related to practolol and acebutolol, has been synthesized and tested for β-adrenoreceptor blocking activity. Structure—activity relationships are discussed. The reasons for the lack of activity of compounds 3n and 4n have also been examined. The results suggest that the negative electrostatic potential above the phenyl ring of phenoxypropanolamines is essential for binding activity and point to the presence of an electropositive residue in the β-adrenoreceptor binding site.

The Evaluation of Efficacy of Pycnogenol® Fractions on Endothelial Dysfunction

The present study evaluates antihyperglycemic activity of fractionated Pycnogenol® and its ability to improve endothelial dysfunction in diabetic animals. The aim of this study was to isolate from Pycnogenol® mixture its active compounds and compare their efficacy on observed parameters. Pycnogenol® mixture was fractioned by re-extracting with petroleum ether, chloroform, ethyl acetate and butanol, subsequently. Pycnogenol® mixture and fractions (butanolic, water, ethyl acetate) were administered during 6 weeks to diabetic rats. Blood glucose levels were assessed from the arterio-venous blood at the beginning of experiment and at the end of experiment. Endothelial dysfunction was evaluated as the contractile responses to phenylephrine and acetylcholine. The amount of collagen I and III was assessed from thoracic aorta after picrosirius red staining. For the confirmation of the changes on molecular level, we determinated endothelial NO synthase (eNOS) and heat shock protein 90 (Hsp90) expression from left ventricle. Overall, the result suggest, that fractions are not so effective on observed parameters as Pycnogenol® mixture itself, indicating synergistic effect of the plant constituents.

Agrimonia eupatoria L. and Cynara cardunculus L. Water Infusions: Comparison of Anti-Diabetic Activities

Diabetes mellitus (DM) is frequently diagnosed at a time when patients already suffer from several cardiovascular complications. Our previously published data (Molecules 201520 (11): 20538-50) on the anti-oxidative properties of Agrimonia eupatoria L. (AE) and Cynara cardunculus L. (CC) prompted us to extend the available evidence on their possible protective activities on selected DM-related parameters in a streptozotocin-induced DM rat model and in a series of in vitro experiments. Male rats were divided into four groups: control group, untreated diabetic group, AE and CC treated diabetic groups. During a five-week period, changes in blood glucose and body weight were monitored. Then, rats were sacrificed and subjected to the assessment of changes in the reactivity of aortas and measurement of butyrylcholinesterase activity. To complete the panel of experiments, α-glucosidase activity was assessed in vitro. Our results demonstrate that both tested extracts exert similar anti-diabetic activities. However, better anti-oxidant activity of the A. eupatoria extract indicates its higher clinical potential in the prevention and/or adjuvant therapy of developing cardiovascular complications related to DM and diseases associated with oxidative stress.

Synthesis and In Vitro Pharmacological Evaluation of 5-(Alkoxymethyl)-2-(3-alkylamino-2-hydroxypropoxy)phenylethanones Related to Acebutolol and Celiprolol

The structure–activity relationships of 13 analogs of aryloxyaminopropanol type derived from 2‐hydroxyphenylethanone as potential β‐blockers are described. The synthesized compounds possess an isopropyl or a tert‐butyl group in the hydrophilic part of the molecule and an alkoxymethyl substitution in the lipophilic moiety. The target compounds were prepared by an established four‐step method and their structures were confirmed by interpretation of their UV, IR, 1H NMR and 13C NMR spectra, and by elemental analysis. The β‐adrenolytic efficacy of the prepared racemic compounds was determined on isolated guinea pig atria (β1) and trachea (β2) and expressed as pA2 values against isoprenaline tachycardia. The assumed cardioselectivity was expressed as β1/β2 ratio and the values of compounds with an alkoxy group (CH3O, iC3H5O, C5H11O, CH2CHCH2O, CH3OCH2CH2O) in the lipophilic part and with tert‐butyl in the hydrophilic part of the molecule were found to be comparable or higher than those of the standards acebutolol and celiprolol. All evaluated substances at a concentration of 10−7 mol/dm3 showed also negative chronotropic effects.

Synthesis and Biological Evaluation of New Combined α/β-Adrenergic Blockers

The synthesis, characterization, and pharmacological evaluation of new aryloxyaminopropanol compounds based on substituted (4‐hydroxyphenyl)ethanone with alterations in the alkoxymethyl side chain in position 2 and with 2‐methoxyphenylpiperazine in the basic part of the molecule are reported. For the in vitro pharmacological evaluation, isolated aorta and atria from normotensive Wistar rats were used. Compared to naftopidil, compounds with ethoxymethyl, propoxymethyl, butoxymethyl, and methoxyethoxymethyl substituent displayed similar α1‐adrenolytic potency. Compounds with methoxymethyl, ethoxymethyl, and propoxymethyl substituent caused a significant decrease in both spontaneous and isoproterenol‐induced beating of isolated rat atria. Naftopidil and the tested substances containing a butoxymethyl and methoxyethoxymethyl substituent had no effect on the spontaneous or isoproterenol‐induced beating. The tested substance that had the most pronounced effect was the compound with a propoxymethyl substituent. Its antihypertensive efficacy was investigated in vivo on spontaneously hypertensive rats (SHRs). The systolic blood pressure was found to be significantly lower in SHRs subjected to the treatment for 2 weeks than in untreated SHRs. Naftopidil had no significant effect.

Pharmacological Evaluation of the Effects of Phenylcarbamic Acid Derivatives on Cardiovascular Functions in Rats

Abstract Four phenylcarbamic acid derivatives, (1-(4-fluorophenyl)- 4-[3-(4-methoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (1), (1-(2-methylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (2), (1-(2-methylphenyl)-4-[3-(4-ethoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (3) and (1-(3-trifluoromethylphenyl)-4-[3-(4-methoxyphenylcarbamoyloxy)- 2-hydroxypropyl]piperazinium chloride) (4) were investigated for their ability to affect various cardiovascular functions and to establish their chemical structure-biological activity relationship. The compounds were evaluated for their antiarrhythmic efficacy using ouabain-induced rhythm disturbances and the ability to inhibit the positive chronotropic effect of isoproterenol in isolated atria of Wistar rats. Electrocardiogram (ECG) parameters in isolated hearts of spontaneously hypertensive rats (SHR) perfused according to the Langendorff method and ability to decrease phenylephrine- -induced contraction of the aortic strips after repeated administration of the compounds were also analyzed. Only compound 3 delayed significantly the evaluated parameter of arrhythmogenicity and was able to antagonize the isoproterenol- induced positive chronotropic effect in normotensive rats’ atria. Similarly, in SHR rats, only compound 3 was able to decrease heart frequency significantly without influencing the duration of QT (time between the start of the Q wave and the end of the T wave) and QTc (frequency corrected QT) intervals. The evaluated endothelial function was improved after administration of compound 2. Fluorine-containing structures (1 and 4) were less effective compared to 2´-methylphenylpiperazine derivatives (2 and 3). The latter two compounds showed suitable efficacy, which supported their use for futher pharmacological research.

The efficacy of newly synthesised agent and natural antioxidant treatment in diabetic and hypertensive rats

The efficacy of newly synthesised agent and natural antioxidant treatment in diabetic and hypertensive rats Hypertension that develops as the result of cardiovascular damage in diabetes is one of the serious complications of diabetes. The aim of this study was to evaluate the changes in levels of oxidative stress and in endothelial NO synthase (eNOS) and heat shock protein 90 (Hsp90) expressions after the treatment of diabetic rats with a newly synthesised heteroarylaminoethanolic derivative 4/1E with potentially beta-adrenergic blockade effects and a strong antioxidant Pycnogenol®. The treatment of 6-weeks duration was indicated in the group of diabetic Wistar rats (DL; streptozotocin (STZ) 3×25 mg/kg i.p.) and hypertensive rats (HL, STZ) with 4/1E in the dose 10 mg/kg i.p. or with Pycnogenol® (DP, HP) in the dose 20 mg/kg p.o. Animals in control groups (C, H, D) received vehiculum. The levels of oxidative stress were assessed in kidney andliver as the activity of N-acetyl-β-D-glucosaminidase (NAGA) and the levels of thiobarbituric acid reactive substances (TBARs). The expression of eNOS and Hsp90 was assessed from the hearts of all animals using SDS-Page and Western blotting. In our study the effects of newly synthesised drug 4/1E and Pycnogenol® on the levels of oxidative stress were comparable only in diabetic animals. The expression of eNOS was decreased in diabetic, but not hypertensive animals. The treatment with 4/1E did not affect the expression of eNOS unlike the treatment with Pycnogenol® after which the expression was significantly increased. The expression of Hsp90 was increased in both hypertensive and diabetic animals. The treatment with 4/1E was more effective in decreasing Hsp90 expression in both groups of animals than the treatment with Pycnogenol®. Hodnotenie účinnosti novosyntetizov aného derivátu a prírodného antioxidantu v liečbe diabetických a hypertenzných potkanov Hypertenzia, ktorá sa rozvíja v dôsledku kardiovaskulárneho poškodenia v diabete patrí medzi vážne diabetické komplikácie. Cieľom tejto štúdie bolo zhodnotiť zmeny hladín oxidačného stresu a expresie endotelovej NO syntázy (eNOS) a heat shock proteínu 90 (Hsp90) po liečbe novosyntetizovaným potenciálnym beta-blokátorom 4/1E a prírodným antioxidantom Pycnogenolom® u diabetických a hypertenzných potkanov. Šesťtýždňová liečba bola indikovaná v skupine diabetických Wistar potkanov (DL, streptozotocín (STZ) 3×25 mg/kg i.p.) a hypertenzných potkanov (HL, STZ) látkou 4/1E v dávke 10 mg/kg i.p. alebo Pycnogenolom® (DP, HP) v dávke 20 mg/kg, p.o. Zvieratá v kontrolných skupinách (C, H, D) dostávali vehikulum. Hladiny oxidačného stresu boli stanovené v obličke a pečeni ako aktivita N-acetyl-β-D-glukózaminidázy (NAGA) a hladina reaktívnych foriem kyseliny tiobarbiturovej (TBARs). Expresia eNOS a Hsp90 bola stanovená zo srdca použitím metódy SDS-PAGE a Western Blotting. Účinok novosyntetizovanej látky 4/1E a Pycnogenolu® na hladiny oxidačného stresu bol porovnateľný len pri aplikácii u diabetických, nie hypertenzných zvierat. Expresia eNOS a Hsp90 bola znížená u diabetických, nie však hypertenzných zvierat. Liečba látkou 4/1E neovplyvnila expresiu eNOS, narozdiel od Pycnogenolu®, kedy došlo k signifikantnému zvýšeniu expresie eNOS. Expresia Hsp90 bola zvýšená u hypertezných aj diabetických zvierat. Liečba látkou 4/1E bola účinnejšia v znižovaní expresie Hsp90 u oboch skupín zvierat než podávanie Pycnogenolu®. Práca bola podporená grantmi: UK/32/2010 and FaF UK/25/2009.

Evaluation of potential antiinflammatory activity of copper (ii) and zinc(ii) benzene-1, 4-diylbis(oxyacetates), free benzene-1, 4-diylbis(oxyacetic)acid and their mixtures in rats

Evaluation of potential antiinflammatory activity of copper (ii) and zinc(ii) benzene-1, 4-diylbis(oxyacetates), free benzene-1, 4-diylbis(oxyacetic)acid and their mixtures in rats Using rat paw dextran- and/or carageenan-induced edemas, the antiinflammatory activity of copper(II) and zinc(II) benzene-1,4-diylbis(oxyacetates) (compexes 1c and 1z) and free benzen-1,4-diylbis(oxyacetic)acid (1a) and their equimolar mixtures (1cz, 1ac and 12az) were evaluated plethysmometrically. All the tested compounds were administered intraperitoneally in the single dose 50μmol/kg of body weight (calculated for the carboxylate fragment) 30 minutes before injecting the irritant. The antiphlogistic activity of the compounds (expressed as a mean edema reduction) was found as: 1a 27.6 % / -23,0 % < 1c 44.2 % / 34.7 < 1z 69.2 % / 30.3 % < 1cz 59.7 % / 67.0 % < 1ac 53.1 % / 77.6 % < 1az 83.8 % / 85.5 %. The relationships between the coordination-chemical properties and the biological effects on the corresponding compounds are discussed. Hodnotenie potenciálnej protizápalovej aktivity kuprum(ii) a zinkum(ii) benzen-1, 4-diylbis(oxyacetatu), voľnej benzen-1, 4 diylbis(oxyoctovej kyseliny) a ich zmesí u potkanov Protizápalová aktivita kuprum(II) a zinkum(II) benzén-1,4-diylbis(oxyacetátu) (komplexy 1c a 1z) a voľná benzén-1,4-diylbi-(octová kyselina) (kyselina 1a) a ich ekvimólové zmesi (1cz, 1 ac a 1az) bola hodnotená pletyzmometricky na dextranovom, resp. karagenínovom edéme na potkanoch. Všetky testované látky boli podané i.p. v jednorázovej dávke 50μmol/kg telesnej hmotnosti zvieraťa (počítané na karboxylátový fragment) 30 min. pred injikovaním iritanta. Priemerná antiflogistická aktivita látok (vyjadrená ako miera redukcie edému) bola zistená v tomto poradí: 1a 27.6 % / -23,0 % < 1c 44.2 % / 34.7 < 1z 69.2 % / 30.3 % < 1cz 59.7 % / 67.0 % < 1ac 53.1 % / 77.6 % < 1az 83.8 % / 85.5 %. Diskutujeme vzťahy medzi koordinačno-chemickými vlastnosťami a biologickým účinkom príslušných komplexov