Synthesis and selective vasodilating properties of esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydro-pyridine-3,5-di- carboxylic acid.

This study presents the synthesis of new 1,4-dihydropyridine (DHP) derivatives which are phenoxy- and alkoxyalkyl esters of 2,6-dimethyl-4-(2-difluoromethoxyphenyl)-1,4-dihydropyridine-3,5-dica rbo xylic acid and reports on the biological activity of the compounds. It was found that the DHP derivatives showed high affinity to the DHP receptor of rat brain membranes and antagonize potently the potassium depolarization-induced vasospasm in a fashion compatible with the assumption of a calcium entry blockade. The higher vasodilating potency of especially compound III for the cerebral vasculature might represent an improved selectivity profile due to specific substitution patterns of the DHP molecule by increasing lipophilicity. Thus, the new DHP derivatives might be useful as therapeutic agents for hypertension and impaired cerebral microcirculation.

[Experimental research on the antisecretory and antiulcer activity of (+/-) 15 alpha-OH-11-deoxyprostaglandin E1]. / Eksperimental'noe issledovanie antisekretornoi i protivoiazvennoi aktivnosti (+/-) 15 al'fa-OH-11-dezoksiprostaglandina E1.

(+/-) 15 alpha-OH-11-deoxyprostaglandin E1 was found to possess a pronounced antisecretory activity at stimulation of gastric secretion in cats with pentagastrin. In rats the compound exerted the protective effect of cells of the gastric mucosa, especially on indomethacin and stress models of ulcerogenesis. The cytoprotective effect of the compound seemed to be related to its action on secretion of mucus as well as to its stimulation of zinc accumulation in cells that stabilized cell membranes and suppressed the secretory activity of mast cells.

[Effect of foridon on 45Ca uptake in isolated blood vessels]. / Vliianie foridona na zakhvat 45Ca v izolirovannykh krovenosnykh sosudakh.

In the experiments on rabbit isolated aorta and portal vein phoridone, a vasodilating agent of dihydropyridine series, was shown to exert the blocking effect on the basal uptake of labeled calcium by cells. It was demonstrated in the experiments on rabbit aorta and bovine coronary artery that phoridone inhibits 45Ca uptake stimulated by potassium and noradrenaline. The inhibition of 45Ca uptake enhanced by potassium appeared to be definitely more pronounced in the experiments on coronary artery. The action of phoridone on 45Ca uptake by smooth muscle cells of the vessels did not differ significantly from that of phenyhidine.

Effect of ryodipine on electromechanical parameters of heart and vessels, cAMP phosphodiesterase activity and swelling-contraction cycle of mitochondria.

2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4 -dihydropyridine (ryodipine, PP-1466), an effective Ca2+ channel blocker, diminishes contraction force and decreases duration of action potential in the frog heart ventricle strips. Dissociation constants K0.5 are 2 x 10(-7), 5 x 10(-7), and 10(-6) mol/l for PP-1466, nifedipine and nicardipine, respectively (at 0.25-0.3 Hz stimulation). One molecule of PP-1466 or nifedipine apparently interacts with two receptors on the channel (n = 0.5), nicardipine with one receptor (n = 1). The binding energy of PP-1466 and nifedipine increases at closed and diminishes at open channels which is in contrast to nicardipine, whose effect is irreversible. Thus, the site of nicardipine action differs from that of PP-1466 and nifedipine. PP-1466 (10(-8) mol/l--10(-6) mol/l) suppresses contraction force and diminishes frequency of spontaneous contractions of the rabbit atria, and also displays antagonism to the effect of Ca2+ upon rabbit auricle contractions. In the isolated rabbit aorta and portal vein PP-1466 is more antagonistic to contractions caused by Ca2+ than by epinephrine. Both competitive and non-competitive types of antagonism can be distinguished.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacological and toxicological properties of ryodipine.

2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxy-p hen yl)-1,4-dihydropyridine (ryodipine, PP-1466) causes lasting decrease in systolic and diastolic arterial pressure at intravenous and oral administration to anesthetized animals. In conscious rats with DOCA-salt (des-oxycortone) and spontaneous hypertension, as well as in rats with hypertension provoked by method of cellophane perinephritis, PP-1466 (1 and 10 mg/kg, orally) decreases systolic pressure considerably. Therapeutic doses of PP-1466 do not essentially affect rhythm and frequency of cardiac contractions. High doses of the drug increase the heart rate. PP-1466 increases coronary blood flow. PP-1466 antagonizes considerably the pressor effect of angiotensin. In this respect PP-1466 is superior to SKF-24260 (2,6-dimethyl-3,5-diethoxycarbonyl-4-(o-difluoromethylphenyl)-1, 4-dihydropyridine). PP-1466 reduces hypotensive reaction and tachycardia induced by isoprenaline administration, inhibits decrease in arterial pressure caused by electric stimulation of the vagus nerve and administration of acetylcholine. Hypotension caused by PP-1466 and its negative inotropic effect can be antagonized with calcium chloride. In mice and rats PP-1466 at doses exceeding 10 mg/kg exerts a certain dose dependent depressant effect on the CNS. More protracted depressant effect on the CNS is exerted by nifedipine which was studied parallelly. In rabbits oral PP-1466 decreases in EEG basic rhythm amplitude both in cortical and subcortical structures. High doses of the drug lead to dysrhythmia in bioelectric activity. Acute, subacute and chronic toxicity studies in mice, rats and dogs show that PP-1466 possesses low acute toxicity and is well tolerated at protracted repeated administration of therapeutic and several times higher doses.

[Experimental study on the effect of 11-deoxyprostaglandin E1 on hormonal balance in animals]. / Eksperimental'noe issledovanie vliianiia 11-dezoksiprostaglandina El na gormonal'nyi balans zhivotnykh.

The effects of prostaglandin F2 alpha and (+/-) 11-deoxyprostaglandin E1 (DPGE) on the levels of progesterone and estradiol in the blood plasma or serum of experimental animals were studied and compared. It was found for the first time that the synthetic analog of natural PGE1, DPGE, is capable to substantially reduce the progesterone level in the blood (rats and cows) and to induce the luteolysis of yellow bodies in the cow ovaries. It was demonstrated that DPGE promotes the resolution of both cyclic and persistent yellow bodies. The pattern of the drug action on rat blood steroid hormones depends on the time of pregnancy and is most pronounced in the last trimester of pregnancy.

[Pharmacokinetics of dioxonium]. / Farmakokinetika dioksoniia

An investigation in the pharmacokinetics of a new peripheral muscle relaxant dioxonium and of its carbon-labeled analogue (with respect to the N-methyl groups) was carried out. An intravenous administration of dioxonium-C14 was found to bring about a biphasic change in radioactivity of the blood plasma. The stoppage of curarization, irrespective of a dioxonium dose, is seen to occur at a definite radioactivity level in the blood plasma. Major radioactivity following introduction of dioxonium-C14 is observed in the organism of the rats in the skeletal muscles and in the kidneys. The drug is eliminated from the organism through the kidneys in an unchanged and pharmacologically active form.

[Results of a pharmacological and toxicological study of pentagastrin]. / Rezul'taty farmakologicheskogo i toksikologicheskogo izucheniia pentagastrina

Pentagastrin is found to be a highly active stimulator of the gastric glands secretion. With its intraperitoneal introduction to albino rats the drug displays a low acute toxicity. On its re-administration to rabbits and albino rats in doses significantly exceeding the diagnostic ones no substantial influence on the growth of the animals, hematological, enzymological, proteinological blood indices and morphological condition of internal organs was noted.