Cyclic analogues of bradykinin. IV. Structure-function relationships in the series of bradykinin cycloanalogues.

A study of the biological activity of six bradykinin and kallidin cycloanalogues has revealed that all of them exhibit prolonged hypotensive activity except the inactive cyclo-(omega-aminododecanoyl-omega-aminododecanoyl-bradykini n) (CADADB) when assayed in anaesthetized rats in vivo. The threshold dose of cyclo-bradykinin (CB) in these experiments was found to be 250 micrograms/kg of body weight. A single dose (500 micrograms/kg) of this cyclopeptide produces a decrease in the arterial pressure of rats up to 40 mm Hg for more than 2 h. The hypotensive action of other cyclopeptides under the same conditions is characterized by the following values: cyclo-[epsilon-(L-Lys1, Gly6)-bradykinin] (CLGB), alpha-L-Arg-cyclo-[epsilon-(L-Lys1, Gly6)-bradykinin] (ACLGB) and cyclo-epsilon-kallidin (CK) - 5 micrograms/kg, 40 mm Hg, over 2 h; cyclo-(omega-aminododecanoyl-bradykinin) (CADB) - 50 micrograms/kg, 250 micrograms/kg, 40 mm Hg, 35 min. Some cyclopeptides appeared to possess myotropic activity in vitro on isolated rat uterus preparations: CB (alpha = 0.52, pD2 = 7.86), CK (alpha = 1.0, pD2 = 7.56), CADB (alpha = 0.81, pD2 = 6.41). CLGB, ACLGB and CADADB failed to show myotropic activity. In contrast to CLGB and CADB, CK was hypotensive in dogs. CB acts as a weak antagonist of bradykinin (pA2 = 5.09 +/- 0.06) on rat uterus in vitro. It is believed that the hypotensive action within this series of compounds is primarily determined by the cycle size, whilst their myotropic activity is due to the presence of a "common" fragment Arg-Pro-Pro.(ABSTRACT TRUNCATED AT 250 WORDS)

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.