[Synthesis of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxy-propoxy}-phenylcarbamic acid alkylesters and in vitro evaluation of their beta-antiadrenergic and vasodilatative activities]. / Syntéza alkylesteru kyseliny 2-{3-[4-(4-fluorfenyl)-piperazin-1-yl]-2-hydroxy- propoxy}-fenylkarbamové a in vitro : . ' hodnoceni jejich beta-antiadrenergní a vazodilatacní aktivity.

Synthesis of 2-{3-[4-(4-fluorophenyl)-1-piperazinyl]-2-hydroxy-propoxy}-phenylcarbamic acid alkylesters and in vitro evaluation of their beta-antiadrenergic and vasodilatative activities In effort to obtain effective compounds able to favourably influence pathologically changed cardiovascular functions, such as hypertension and ischemic cardiac disease, a new series of aryloxyaminopropanols were synthesized. Four of the compounds, which differ in the alkyl substitution of phenylcarbamate (methyl, ethyl, propyl, butyl), were chosen for basic in vitro pharmacological analyses. In experiments on the isolated spontaneously beating guinea pig atria all compounds at conc. of 1.0.10(-6) mol.l(-1) decreased the basic heart rate (7.6-13.6%) and inhibited the positive chronotropic effect of isoprenaline (pA2 = 6.28-6.81). The compounds manifest only a slight relaxation effect on KCl pre-contracted aortal strips of rats (not until conc. of 1.0.10(-5) mol.l(-1)). The compounds with propyl and butyl substitution appear more effective than the methyl and ethyl derivatives.

[Study of a newly synthesized substance with a potential to stimulate beta3-adrenergic receptors]. / Testování nove syntetizované látky s potencionálním beta-adrenergne agonistickým úcinkem.

beta3-Adrenoreceptor agonists can stimulate lipolysis in the white adipose tissue and thermogenesis in the brown adipose tissue. These activities could be useful in the treatment of obesity and the associated metabolic syndrome. The effects of six-week oral administration of the newly synthesized substance B496 (methyl-4-[2-[2-hydroxy-3-(4-ethylcarbamoyl)phenoxyprophyl]amino]etyl)-phenoxyacetate hydrochloride) on serum glucose, triglycerides, total cholesterol, and leptin levels were studied in male Wistar rats fed with a high-fat diet. The animals were divided into a group treated with B496 (5 mg dissolved in 1 litre of water) and a control group. The results indicated a significant reduction in serum glucose levels (-26 %, p<0,01), triacylglyceride levels (-21 %, p<0,05) and leptin levels (-43 %, p<0,01). Further the effect of a single intraperitoneal dose (1 mg/kg) of B496 and BRL-37344 on serum leptin levels in the C57Bl/6J mouse was investigated. Administration of BRL-37344 resulted in a significant decrease in serum leptin levels (-55 %, p<0,001). This reduction was not demonstrated by newly synthesized substance B496.

[Analytical profile of 1-(4-fluorophenyl)-4-[3-(3-propoxyphenylcarbamoyloxy)-2-hydroxypropyl]piperazinium chloride (6f)]. / Analytické hodnotenie 1-(4-fluorfenyl)-4-[3-(3-propoxy- fenylkarbamoyloxy)-2- hydroxypropyl]piperazíniumchloridu (látka 6f).

The paper presents the results of an analytical evaluation and a study of some physicochemical properties of a potential antiarrhythmic agent marked as 6f. The melting point, spectral properties, solubility and chromatographic behaviour of the drug on the thin layer were investigated. For the content determination, spectrophotometry in the ultraviolet region of the spectrum at the wavelength of the second absorption maximum of the substance and high-performance liquid chromatography were used.

[A study of physicochemical properties of 2-, 3-, 4-alkoxyphenylcarbamic acid derivatives with a substituted N-phenylpiperazine moiety in the basic part]. / Stúdium fyzikálno-chemických vlastností derivátov kyseliny 2-, 3-, 4-alkoxyfenylkarbámovej s bázickou castou tvorenou substituovaným N-fenylpiperazínom.

The paper presents the study of some physicochemical properties of 2-, 3-, 4-alkoxyphenylcarbamic acid derivatives with various substituted N-phenylpiperazin-1-yl moiety in the basic part of the molecule. Elemental analysis, melting point, solubility, surface activity, dissociation constant and some lipophilicity parameters i.e.--partition coefficient, capacity factor obtained from HPLC, and R(M) values from reversed-phase thin-layer chromatography were determined.

[Adsorption of substances on active charcoal. Part 2: basic esters of phenylcarbamic acid with beta-adrenolytic effect]. / Adsorpcia látok na aktívne uhlie 2. cast. Bázické estery kyseliny fenyl- karbámovej s beta-adrenolytickým úcinkom.

The paper is concerned with the study of adsorption on active charcoal in a set of selected substances from the group of aryloxyaminopropanol derivatives with carbamate substitution on the benzene ring with beta-adrenolytic effect (Group A) and a set of substances, derivatives of [(arylcarbonyl)oxylaminopropanol with the identical, but assumed ultra-short effect (Group B), where the effect was produced by replacing the phenolether group with a metabolically unstable ester functional group. The course of adsorption in buffer solution with pH 7 in dependence on time and concentration is examined. Adsorptivity of substances is evaluated according to Freundlich and Langmuir models. Affinity of substances of Group A to adsorption material decreases with increasing hydrophilicity.

[Analytical evaluation of 1-(dipropalamino-3-piperidine-propane-1-yl)-3-pentyloxyphenylcarbamate (CK-3635)]. / Analytické hodnotenie 1-(dipropylamino-3-piperidino-propán-1-yl)-3-pentylox-yfenylkarbamátu (CK-3635).

The paper presents the results of analytical and pharmacological evaluation and study of some physicochemical properties of a potential drug marked as CK-3635 with high local anaesthetic activity. The structure of the substance has been confirmed by IR and UV spectroscopy. The melting point, solubility, partition coefficient, capacity factor, surface activity, and dissociation constant were determined. The chromatographic behaviour of the drug on a thin layer was also investigated. For the content determination, spectrophotometry in the ultraviolet region of the spectrum at the wavelenght of the second absorption maximum of the substance, the titration in the two-phases ambient, and high-performance liquid chromatography were used.

[TCL and HPLC separation of positional isomers of alkylester acids of 2-, 3-, 4-[2-hydroxy-3-[(4-diphenylmethyl) piperazine-1-yl]propoxy]phenylcarbamic acid and their lipohydrophilic properties]. / TLC a HPLC separace polohových izomeru alkylesteru kyseliny 2-, 3-, 4- [2-hydroxy-3-[(4-difenylmethyl)piperazin-1-yl]propoxy]fenylkarbamové a jejich lipo-hydrofilní vlastnosti.

The paper deals with chromatographic separations of newly prepared substances, aryloxyaminopropanol derivatives. The derivatives represent three homological series of four carbons and four groups of positional isomers (methyl- to butyl- in positions 2-, 3, and 4-). Thin-layer adsorption chromatography employed the foil Silufol UV 254 as the stationary phase and partition chromatography, commercially produced glass plates DC Fertigplatten MERCK RP-8 F254 S. High-performance liquid chromatography was used to separate positional isomers on the column Supelkosil ABZ + PLUS. The mobile phase was methanol and acetonitrile in graded rations with water and various flow rates of the mobile phase were tested. Partition chromatography, determination of partition coefficient in the system octanol-water, and the values of capacity factors k' of the substances was employed to evaluate their lipophilicity.

Synthesis and pharmacological evaluation of novel potential ultrashort-acting beta-blockers.

The basic relationship between chemical structure and pharmacological activity of eight newly developed potential ultrashort-acting beta-adrenergic blockers was evaluated. The compounds studied are derivatives of arylcarbonyloxyaminopropanols and were prepared by four-step synthesis. All the compounds evaluated showed weak antiisoprenaline (beta-adrenergic receptor blocking) activity and antiarrhythmic (antiouabain) activity.

[Preparation and physico-chemical properties of alkyl esters of 2-, 3-, 4-(2-hydroxy-3-[4-diphenylmethyl) piperazine-1-yl] propoxy) phenylcarbamide]. / Príprava a fyzikálne chemické vlastnosti alkylesteru kyseliny 2-, 3-, 4-(2-hydroxy-3-[(4-difenylmethyl)piperazin-1-yl] propoxy) fenylkarbamové.

The paper is devoted to the synthesis and study of some physico-chemical properties of a group of substances--potential antagonists of beta-adrenergic receptors. The substances are derivatives of aryloxyaminopropanol, where the basic part consists of diphenylmethylpiperazine and the aromatic part is modified with alkyl esters (methyl to butyl) of carbamic acid in positions 2-, 3-, 4-. The representation of the elements was confirmed by elemental analysis. The substances were characterized by melting point, IR and UV spectra. Their solubility and surface activity were determined. The purity of prepared substances was examined by means of TLC.

[Effect of Consupren, Carvedilol and BL-443 on the composition of lactate dehydrogenase in tissues of rats with cyclosporin nephropathy]. / Ucinky preparátu Consuprenu, carvedilolu a BL-443 na tkánové slození laktátdehydrogenasy u potkanu s cyklosporinovou nefropatií.

L-Lactate dehydrogenase pattern in tissues was determined by polyacrylamide gel electrophoresis adjusted to be more sensitive to LD1 and LD2. Three groups of rats (Wistar) were treated for 18 days with single oral daily doses of 45 mg consuprene/kg body weight to induce cyclosporine nephropathy. Two treated groups were further medicated either with carvedilol or BL-443 in single daily doses of 10 mg/kg b.w., unmedicated rats were given single i.p. daily doses of 1 ml saline. No significant difference in the LD(1-4) isoenzyme pattern in the liver between intact rats, rats with cyclosporine nephropathy, and rats with cyclosporine nephropathy medicated with carvedilol or BL-443 was found by F-test and t-test (p < 0.05). However, a significant difference in the LD(1-4) isoenzyme pattern in the myocardium between rats with cyclosporine nephropathy and intact rats was found. The present study reports the preliminary results of the effects of consupren on the LD(1-4) pattern in the muscle, spleen, and lung, as well as the effects of carvedilol and BL-443 in the tissues under the conditions of experimental cyclosporine nephropathy. The tissues with an increased risk of affection can be identified by evaluation of LD patterns that may become an additional tool to microscopic examination of the sample.

[Analytic evaluation of BL 443 pivalate]. / Analytické hodnotenie látky BL 443 pivalátu.

The paper presents the results of an analytical evaluation and a study of some physicochemical properties of a new potential drug of the prodrug type--the substance BL 443 pivalate with an assumed antidysrhythmic effect. The structure of the substance has been confirmed by elemental analysis, IR and UV spectroscopy. The following parameters were determined: melting point, solubility, dissociation constant, experimental partition coefficient in four different systems, and surface activity. The chromatographic behaviour of the drug on a thin layer (adsorption and partition chromatography) was also investigated. Acidimetric titration in non-aqueous medium and spectrophotometry in the ultraviolet region of the spectrum at the wavelength of the second absorption maximum of the drug was employed to determine the content of the drug in pure substance.

[Pharmaco-toxicologic evaluation of newly synthesized analogs of propafenone]. / Farmakologicko-toxikologické hodnotenie novosyntetizovaných analógov propafenonu.

The basic pharmacological evaluation of five analogues of propafenone was the aim of the present paper. Antiarrhythmic activity of the compounds at 10(-5) mol.kg-1 was established in guinea-pigs using experimental arrhythmias induced by ouabain and aconitine. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. All of the compounds studied were local-anaesthetically active and their indexes of efficiency were 1-5 fold higher in comparison with the standards cocaine and procaine. The acute toxicity of the compounds was within acceptable limits.

Structure-activity relationship studies on benzofuran analogs of propafenone-type modulators of tumor cell multidrug resistance.

A series of benzofurylethanolamine analogs of propafenone (1a) have been prepared and evaluated for multidrug resistance-reversing activity in two in vitro assay systems. As for propafenones, an excellent correlation of biological data with calculated lipophilicity values was found for benzofurans, whereby the latter generally had lower activity/lipophilicity ratios. Almost identical slopes of the regression lines were obtained for both propafenones and benzofurans. Multiple linear regression analysis of the complete data set yielded an equation with excellent predictive power (r2 cross-valid = 0.968). Interaction measurements with artificial membranes indicated that the differences in activity between these two series of compounds are not due to differences in the interaction pattern with biological membranes.

[Piperazine analogs of aryloxyaminopropanols and a study of their effects on a model of the isolated guinea pig ileum]. / Piperazinové analogy aryloxyaminopropanolu a studium jejich úcinku na modelu izolovaného morcecího ilea.

Seven compounds belonging to the group of aryloxyaminopropanols with carbamate substitution of the aromatic ring and with derivatives of N-phenylpiperazine in the lipophilic part were prepared by a well-tried method. Selected drugs were pharmacologically evaluated by in vitro experiments. Aryloxyaminopropanol drugs confirmed their anti-calcium activity on the intestinal model. Significant anti-calcium activity of agents IIIq and IIIb (pA2 = 6,83 +/- 1,47; 7, 12 +/- 1, 12 was comparable to that found for the standards verapamil and flunarizine. These compounds were selected for in vivo experiments and evaluated for their effect on reperfusion-induced arrhythmias in anaesthetized rats. Results of these evaluations are given in the next article.

[Preparation of aryloxyaminopropanol derivatives with potential effects on the cardiovascular system]. / Príprava derivátu aryloxyaminopropanolu s potenciálním úcinkem na kardiovaskulární systém.

The synthesis of nine compounds belonging to the group of aryloxyaminopropanols with carbamate substitutions of the aromatic ring is described and pharmacologically evaluated. The results suggest that an addition of N-phenyl-piperazine derivatives to the main basic moiety can exert a positive influence on their beta-adrenolytic, antiarrhytmic or antihypertensive activity.

Local anesthetic effect of carbisocaine and its enantiomers.

The optically active isomers of carbisocaine [1-methyl-2-diethylaminoethyl ester of 2-(n)-heptyloxycarbonilic acid] were prepared. The blocking activity of equimolar concentrations of the carbisocaine and its corresponding enantiomers was tested on isolated rat sciatic nerves. There were no significant differences between the anesthetic action of racemic form and enantiomers, however, lower activity for the (--)-enantiomer was observed. The results may indicate negligible stereoselectivity of action of highly lipophilic local anesthetic carbisocaine in the excitable membrane.

Carbamate analogues of tocainide.

A series of the new aminoalkyl esters of chlor-, methyl- and alkoxy carbanilates was synthesized. All the compounds prepared were found to exhibit antiarrhythmic activities comparable with those of mexiletine.

[Preparation and pharmacologic profile of derivatives of alkoxyphenylcarbamic acid with potential effects on the cardiovascular system]. / Príprava a farmakologický profil derivátov kyseliny alkoxyfenyl-karbámovej s potenciálnym úcinkom na kardiovaskulárny systém.

In a systematic study of the relationship between the chemical structure and beta-adrenolytic activity, eleven derivatives of the 4-alkoxysubstituted phenylcarbamic acids were prepared. The beta-adrenolytic efficiency of the compounds was studied in the isolated spontaneously beating guinea-pig atria and expressed as pA2 values against isoprenaline tachycardia. Negative chronotropic and antidysrhythmic activity were also evaluated. All of the compounds studied were local anesthetically active and their indexes of efficiency were 3-50 fold higher in comparison with standards cocaine and procaine. The acute toxicity of the compounds was within the acceptable limits.