[Anti-calcium effects of 4-hydroxypropiophenone derivatives--potential beta-adrenoreceptor blockers]. / Antikalciový efekt derivátov 4-hydroxypropiofenónu--potenciálnych blokátorov beta-adrenoreceptorov.

The present paper carries out the pharmacological evaluation of 4-(2-hydroxy-3-isopropylaminopropoxy)-3-(alkoxymethyl) propiophenones with an ethoxy, propoxy and butoxy-group, whose structures are typical of the blockers of beta-adrenergic receptors. In the above-mentioned compounds the anticalcium effect on the frequency and the amplitude and the negative chronotropic and the negative inotropic effects were evaluated by means of the method of spontaneously pulsing guinea-pig atria within a concentration range of 4-16 microgram.cm-3. The obtained results confirmed a significant anticalcium effect on the heart rate in the compounds with a propoxy and a butoxy group, and in the standard verapamil. In all three compounds as well as in the standard verapamil, no anticalcium effect on the amplitude was found. The results of this membrane efficacy are in agreement with the preceding evaluation of the antidysrhythmic and anti-isoprenaline activity with the most marked effect in the compound with a propoxy group. On the basis of these results it is possible to conclude that in these derivatives of 4-hydroxypropiophenone also the anticalcium effect can participate, besides the beta-adrenolytic and the membranostabilizing effects, in the antidysrhythmic activity.

[Pharmacologic evaluation of p-hydroxyacetophenone derivatives as potential beta-adrenolytics]. / Farmakologické hodnotenie derivátov p-hydroxyacetofenónu ako potenciálnych beta-adrenolytík.

The anti-isoprenaline and negative inotropic activity in the electrically stimulated guinea-pig left atria as well as the local anaesthetic activity of three 4-(2-hydroxy-3-isopropyl-aminopropoxy)-3-(alkoxymethyl) acetophenone derivatives were evaluated. The efficiency of the compounds was compared with the beta-adrenolytic drug atenolol. All of the compounds tested exhibited a statistically significant anti-isoprenaline activity, which increased from the propoxy- to heptyloxyderivative. However, the nonspecific cardiodepressive and local anaesthetic effects of the drugs increased in the same order: propoxy- < pentyloxy- < heptyloxyderivative.

[Derivatives of para-hydroxyacetophenone and para-hydroxypropiophenone as a potential new beta-adrenolytic agent]. / Deriváty para-hydroxyacetofenónu a para-hydroxypropiofenónu ako nové potenciálne beta-adrenolytiká.

Within the framework of the study of the structure-effect relationship, a series of novel potential beta-adrenolytic agents derived from p-hydroxyacetophenone and p-hydroxypropiophenone with an alyloxymethyl and a cycloalkyloxymethyl group in the lipophilic part of the molecule and an isopropyl and a tert-butyl group in the hydrophilic part on the basic nitrogen were prepared by means of a well-tried method. The structure of the prepared drugs was confirmed on the basis of interpretation of the IR, UV, 1H-NMR and mass spectra. The results of pharmacological evaluation of selected drugs show that the agents poses beta-adrenolytic and antiarrhythmic activity. From the viewpoint of comparison of the individual drugs subjected to testing the presence of an alyl seems more advantageous than that of a cyclohexyl. The characteristic of the prepared drugs was supplemented by the determination of their partition coefficients, surface tension and acute toxicity.

Antiarrhythmic activity of heptacaine and some of its derivatives.

In the evaluation of experimental antiarrhythmic effect in guinea pigs, by a method of antagonizing ouabain arrhythmogenity, there was found a maximum effect of N-[2-(2-heptyloxy-phenylcarbamoyloxy)-ethyl]-piperidinium-chloride (heptacaine). The shortening or prolongation of the alkoxy substitution in the ortho-position, or the shift of hexyloxy substitution to the meta- or para-position, respectively, causes a decrease in activity. Negative chronotropic effect of heptacaine is increased and prolonged during the 5th min after acute i.v. application. The effect of lidocaine was short-lasting and decreased. In antagonizing experimental adrenaline (epinephrine) arrhythmogenity, heptacaine showed an important antiarrhythmic effect, too. In the relative hypotensive activity evaluation, there was an important effect in the 1st min after i.v. application and this decreased to the same values as those of lidocaine in the 5th min. Hypotensive effect evaluation of lidocaine and heptacaine after higher doses than therapeutic ones showed that the hypotensive effect of heptacaine takes place at the same rate as that of lidocaine and by the 10th min reaches control values. Values of experimental partition coefficient showed an increase in relation to prolongation of ortho-alkoxy substitution in the sequence: propoxy less than pentyloxy less than heptyloxy less than nonyloxy. Submaximal value by the heptacaine may reflect an optimal hydrophylic-lipophylic balance of its molecule. But in the evaluation on antiouabain effect and partition coefficient, there is no simple direct correlation in structure-activity relationship.