Synthesis of 3-(2-pyridylethyl)benzoxazolinone derivatives: potent analgesic and antiinflammatory compounds inhibiting prostaglandin E2.

Fourteen new 3-[2-(2- and/or 4-pyridyl)ethyl]benzoxazolinone derivatives have been synthesized by reacting 2- and/or 4-vinylpyridine and appropriate benzoxazolinones. Their chemical structures have been proven by IR, 1H-NMR, and elemental analysis. Analgesic activities of these compounds were investigated by a "Modified Koster's Test". Except for compounds 10 and 11, all the new derivatives showed higher analgesic activities than aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. The compounds (6, 7, 8, 9, 14, and 17) that showed high antiinflammatory activity were then further screened for their ability to inhibit prostaglandin E2 (PGE2) induced paw edema. Although all the benzoxazolinone derivatives synthesized in this study showed higher antiinflammatory activity compared to indomethacin, those without a substituent at the 6-position of the ring were significantly more active than the rest of the group, and their ulcerogenic activities and ED50 values indicate them as promising derivatives for further study.

Effect of beta-endorphin and cold stress on heart noradrenalin levels in rats.

We investigated cardiac noradrenalin (NA) levels during stress (from cold and from swimming) and after i.p. administration of beta-endorphin. Cardiac NA levels were significantly increased by endorphin, 1.25 mg X kg-1, and decreased by 10 mg X kg-1. Beta-endorphin, 10 mg X kg-1, and cimetidine, 20 mg X kg-1, decreased cardiac NA to control levels in stressed animals. Naloxone given to stressed animals treated either with beta-endorphin or cimetidine elevated NA to control concentrations, but failed to restore NA to the elevated levels induced by stress. These results suggest endorphin involvement in enhanced NA levels in stress and a possible role of H2-receptors in this involvement.

Influence of naloxone on H2-receptor blocker drugs effects in the "behavioral despair" test.

The influence of H2-receptor blockers (ranitidine and cimetidine) in a "behavioral despair" test in mice was studied. Both ranitidine and cimetidine shortened the immobility time at 20 mg X kg-1 and 30 mg X kg-1. Naloxone at 2 mg X kg-1 antagonized this reduction in immobility time.

Effect of changes in swimming area on results of "behavioral despair test".

Our previous observations have revealed that the total time spent in immobility and time to reach complete immobility (latency) vary with the diameter of the cylindric chamber where mice are forced to swim in the behavioral despair test. Therefore, we investigated the effect of changing the test conditions of the original Porsolt test. Mice were forced to swim for 15 min in chambers with 10 cm (original diameter of the Porsolt's forced swimming chamber), 20, 30, and 50 cm diameter in 20 cm deep water. Total time spent in spells of immobility during the observation period from third to sixth (inclusive) minutes and time to reach complete immobility were measured. In addition, a possible correlation between the rotatory locomotor activity of mice during swimming as assessed by the number of tours per minute and effect of antidepressant drugs on it was investigated. Total duration of spells of immobility was shorter and the latency was longer in tests carried out in chambers with 10 cm diameter. Increasing the diameter of the cylinders made it possible to distinguish the antidepressant drugs from caffeine, anticholinergics, and antihistaminics, which gave a false positive response in 10 cm diameter cylinders, but not in cylinders with larger diameters. Increasing the diameter of the chambers to 20 and 30 cm also allowed to study the selective effect of the antidepressants, namely, the rotatory locomotor activity during swimming. The extension of the test period to 15 min increased the reliability of the measurement of the time to reach complete immobility.(ABSTRACT TRUNCATED AT 250 WORDS)

Some new benzoxazolinone derivatives with analgesic and anti-inflammatory activities.

Fourteen new 6-acyl-2-benzoxazolinone, ethyl-(6-acyl-2-benzoxazolinone) acetate and (6-acyl-2-benzoxazolinone-3-yl) acetic acid derivatives were synthesized, and their physical properties and UV absorption data were determined. Their chemical structures were elucidated by IR, 1H-NMR and elemental analysis. The analgesic activities of these compounds were investigated by a modified Koster's test. It was shown that the respective activities of compounds 1-4 and 10-14 were higher than that of acetylsalicylic acid. Therefore, they were screened for additionally anti-inflammatory activities using the carrageenan mouse paw edema test. The compounds were further screened for their ability to inhibit prostaglandin E2 (PGE2) induced paw edema and compared to indometacin. Compounds 12 and 13 were very potent in inhibiting PGE2 induced edema.

Synthesis of some 1,4,5,6,7,8-hexahydroquinoline derivatives and their calcium antagonistic activity.

Twenty-seven new 2-methyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives have been prepared. Their structures were confirmed by UV, IR, 1H-NMR and elementary analysis. The calcium antagonistic activity of these compounds was tested in K(+)-depolarized taenia coli precontracted with 1 mmol/l Ca+2.

Synthesis of some 1,4-dihydropyridine derivatives and their calcium antagonistic activity.

Seven new 2,6-dimethyl-3,5-diacetyl-4-aryl-1,4-dihydropyridine derivatives have been prepared. Their structures have been elucidated by UV, IR, 1H-NMR and elementary analysis. The calcium antagonistic activity of these compounds were tested in K(+)-depolarized taenia coli precontracted with 1 mmol/l Ca2+.

Analgesic activity of some 3-(arylpiperidinomethyl)-2-benzoxazolinone derivatives.

In our previous study, the antimicrobial activities of 16 new compounds synthetized by reacting 2-benzoxazolinones with derivatives of piperidine were determined. In this study, the analgesic activities of these compounds, using modified Koster's test is investigated. The analgesic activities of these compounds are higher than that of O-acetyl salicilic acid.

Synthesis and antidepressant activity of some new 8-thiocarbamoyl-7,8-diazabicyclo[4.3.0]non-6-ene derivatives.

Several 8-thiocarbamoyl-7,8-diazabicyclo[4.3.0]non-6-enes were prepared by condensing two alpha,beta-unsaturated ketones (2-benzylidene and 2,6-dibenzylidene cyclohexanones) with hydrazine hydrate and reacting the resulting compounds with various isothiocyanates. The structures of the synthesized compounds were confirmed by spectra (IR, 1H-NMR) and microanalysis; they were tested for antidepressant activity using Porsolt's behavioural despair test.

Studies on the synthesis and antidepressant activity of some 1-thiocarbamoyl-3,5-diphenyl-2-pyrazolines.

Several 1-thiocarbamoyl-3,5-diphenyl-2-pyrazoline derivatives have been synthesized by reacting 1,3-diphenyl-2-propen-1-one (chalcones) with thiosemicarbazide, or hydrazine hydrate and then with various isothiocyanates. Their chemical structures have been proven by UV, IR, 1H-NMR and elemental analysis. Antidepressant activities were investigated by "Porsolt's Behavioural Despair Test". 1-Thiocarbamoyl-3-(phenyl and 4-chlorophenyl-5-(4-methyl and 4-methoxyphenyl-2-pyrazoline (compounds III, IV, VII, VIII) and 3-(4-methylphenyl)-5-(4-methoxyphenyl)-2-pyrazoline (compound XII) showed equivalent or higher activity than pargyline hydrochloride and tranylcypromine sulfate.

Synthesis and screening of analgesic and anti-inflammatory activity of 6-acyl-3-(4-substituted benzoylmethyl)-2(3H)-benzoxazolones.

In this study, the synthesis and analgesic and anti-inflammatory activities of some new 6-acyl-3-(4-substituted benzoylmethyl)-2(3H)-benzoxazolone derivatives are reported. Their structures were confirmed by microanalysis, IR and NMR spectral analysis. Their analgesic activities were determined by using modified Koster method, and antiinflammatory activities were determined by using Peacock Dial Thickness Gauge Ozaki.