The role of external Ca²âº in the action of Ca²âº-channel agonists and antagonists on isolated human thoracic arteries.

In systemic atherosclerosis develops the abnormal vascular tone which is associated with elevated calcium influx into smooth muscle cells and their calcification that may be proportional to the extent and severity of atherosclerotic disease. The goal of the present study was to investigate the responses of isolated human arterial samples to Ca²âº-channel agonists and antagonists by varying the external Ca²âº concentration. Two dihydropyridine type calcium-channel blockers, amlodipine and cerebrocrast, were used in this study. The benzodiazepine-type calcium-channel blocker diltiazem, the benzimidazole derivative 1-acetyl-5,6-dimethoxy-2-methylthiobenzimidazole and 3,4'-bipyridine derivative milrinone were also used. Experiments were carried out on isolated human thoracic artery samples obtained from 74 patients, aged 38-88 years, during conventional myocardial revascularisation operations. The contraction of artery samples was recorded using an iFOT10 force transducer. Cumulative concentration-contraction curves of the tested agents (10⁻7 to 10⁻4 M) were established by varying the external Ca²âº concentration from 0.9 mM to 2.7 mM. Cerebrocrast, regardless of the Ca²âº concentration significantly increased arterial contraction, particularly at the lower Ca²âº (≈77%). Diltiazem, the benzimidazole derivative and milrinone caused the artery samples to relax at 10⁻4 M concentrations by 55%, 55% and 44%, respectively, when the external Ca²âº corresponded to the physiological standard. Shifting to lower or higher Ca²âº concentrations significantly altered the response of vessel samples by increasing their contraction. In conclusion, the present study shows that the response of isolated human thoracic artery samples to both the slow calcium channel suppressant diltiazem and to agonists of that channel (milrinone and the benzimidazole derivative) is regulated by the amount of calcium present in the physiological solution. Treatment with a slow calcium channel inhibitor, the 1,4-dihydropyridine derivative cerebrocrast, resulted in a response that was independent of the external Ca²âº concentration.

3,4-trans-4-Aryl-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolates--new group of potential cardiotonic drugs.

3,4-trans-4-Aryl-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolates 6-11 were prepared by a Michael reaction of N-acetonylpyridinium chloride with 3-aryl-2-cyanothioacrylamides or by a one-pot three-carbon condensation of N-acetonylpyridinium chloride, aromatic aldehyde and 2-cyanothioacetamide, and their cardiotonic properties were studied. 3,4-trans-5-cyano-2-hydroxy-2-methyl-4-(3-nitrophenyl)-3-(1-pyridinio)-1,2,3,4-tetrahydropyridine-6-thiolate 8 was considered as a lead compound in this series since it in vitro experiments (spontaneously beating rat atria) showed a cardiotonic activity similar to that of milrinone 2, however compound 8 induced activity at lover concentrations and without influence on chronotropic action of the heart. Unlike milrinone 2, thiolate 8 in vivo experiments (anaesthetized rats) did not influence blood pressure and heart rate. The acute toxicity of compound 8 was more than 10 times lower than that of milrinone 2.

(6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acid and related compounds exhibiting anti-inflammatory activity.

Base-promoted hydrolysis of methyl or ethyl esters 1a-c gave the (6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)- and (5-ethyl-6-methyl-2-methylsulfanyl-4-oxo-3,4-dihydro-3-pyrimidinyl)acetic acids 2a, b. Under the reaction of ester 1a or acid 2a with nucleophilic reagents a series of derivatives 3-7 of acid 2a were synthesized and evaluated for their anti-inflammatory activity. Most of them were found to be more active than acetylsalicylic acid, and compounds 2a, 6a, b, 7a, f were significantly more active than ibuprofen. The compounds exhibiting the best anti-inflammatory activity showed negative inotropic effect.

Synthesis and antitumor activity of substituted 3-(5-imidazo[2,1-b]thiazolylmethylene)-2-indolinones.

The synthesis of 3-(5-imidazo]2,1-blthiazolylmethylene)-2-indolinones, analogs of compounds recently published, is described. The EIZ isomerism was studied by means of nuclear Overhauser effect experiments and X-ray crystallography. All the compounds were tested as potential antitumor agents. They were also tested as potential inhibitors of cyclin-dependent kinase 1 (CDK1), in order to determine if the antitumor activity was related to this mechanism of action. The results showed that under certain substitution conditions (5-methoxy group for the indole benzene ring and 2-methyl group for the imidazothiazole system), an interesting antitumor activity was found for some compounds. From the analysis of the antitumor data, 3-1(2,6-dimethylimidazo[2,1-bJ-thiazol-5-yl)methylenel-5-methoxy-2-indolinone was the most active of the whole series.

Potential antitumor agents. Part 29(1): synthesis and potential coanthracyclinic activity of imidazo[2,1-b]thiazole guanylhydrazones.

This paper reports the synthesis of new imidazo[2,1-b]thiazole guanylhydrazones which were tested as potential antitumor agents. Three of these derivatives (those bearing a 3- or 4-nitrophenyl group) were the most potent and one of these showed a mild effect as CDK1 inhibitor. These same three derivatives were also tested as positive inotropic agents and two of them were more potent than amrinone at 10(-5) M. These two guanylhydrazones could be useful coanthracyclinic agents.

[Synthesis and cardiotonic activity of pyrazolylpyrimidines]. / Synthese und kardiotone Aktivität von Pyrazolylpyrimidinen.

A series of pyrazolylpyrimidines was prepared by the reaction of hydrazinopyrimidines and pyrimidinecarbohydrazides with acetylacetone, and was screened for cardiotonic activity in papillary muscles and atrium of guinea-pig hearts. Many of these compounds were found to be active, and 2-(4,5-dimethyl-pyrazol-1-yl)-4-thioxo-6-methyl-4 H-pyrimidine (1c), 2-methylthio-pyrimidine-4-yl-hydroxyacet-(5-hydroxy-3,5-dimethyl)- 1-5 H-pyrazolide (7a) and 2-methylthio-4-oxo-4 H-pyrimidine-3-yl-acet-(5-hydroxy-3,5-dimethyl)-1-5 H-pyrazolide (7b) showed the most positive-inotropic effects. The ED50 values are close to those of milrinone.

Synthesis and positive inotropic effects of 1-acyl-5,6-diethoxy-2-methylthiobenzimidazoles.

A series of 1-acyl-5,6-diethoxy-2-methylthiobenzimidazoles was synthesized and evaluated for inotropic activity. The compounds caused a concentration-dependent positive inotropic effect in isolated guinea-pig papillary muscles. According to the estimated ED50 value, the efficacy of methyl (1) and isonicotinoyl derivatives (6) was similar to that of milrinone. Carbachol markedly reduced the increase of contraction force of compounds 1, 2, 5 and 9. The inotropic effect of compounds 6 and 9 does not seem to be mediated by the direct stimulation of beta-adrenergic receptors. At that time the beta-agonistic properties of the compounds 1 and 2 might be partially involved in the positive inotropic action of these agents. All tested derivatives, as well as milrinone, increased the amplitude of the late component P2 of the biphasic contraction in guinea-pig papillary muscles. These results indicate that benzimidazole derivatives exert their inotropic effect by increasing Ca influx via slow calcium channel into myocardial cells.