[Studies on heterocyclic compounds. XXXIII. Synthesis of furo[3,2-c]-pyrazole derivatives. (1). Synthetic investigation of furo[3,2-c]pyrazoles (author's transl)].
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Furans↗
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[Studies on heterocyclic compounds. XXXIV. Synthesis of furo[3,2-c]pyrazole derivatives. (2). Electrophilic substitution of 1,3-diphenylfuro[3,2-c]pyrazole (author's transl)].
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Chemical Phenomena↗
[Studies on heterocyclic compounds. XXXV. Synthesis of furo[3,2-c]pyrazole derivatives. (3). Synthesis of 5-bromomethyl-1,3-diphenylfuro [3,2-c]pyrazole and its derivatives (author's transl)].
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Bacteria↗
[Studies on heterocyclic compounds. XXXVI. Synthesis of furo[3,2-c]pyrazole derivatives. (4) Synthesis of 1,3-diphenylfuro[3,2-c]pyrazole-5-carboxaldehyde and its derivatives (author's transl)].
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Bacteria↗
[Studies on heterocyclic compounds. XXXVII. Synthesis of furo[3,2-c]pyrazole derivatives. (5). Synthesis of alpha-methyl-1-(p-substituted phenyl)-3-phenylfuro[3,2-c]pyrazole-5-acetic acids (author's transl)].
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Furans↗
Pyrazole, an alcohol dehydrogenase inhibitor, has dual effects on N-methyl-D-aspartate receptors of hippocampal pyramidal cells: agonist and noncompetitive antagonist.
Electrophysiological and biochemical studies demonstrated that pyrazole, an inhibitor of alcohol dehydrogenase and a proposed therapeutic agent for treatment of alcoholic intoxication, activated and blocked the N-methyl-D-aspartate (NMDA) receptor and did not interact significantly with the end-plate nicotinic acetylcholine receptor (AChR). Pyrazole, at concentrations as low as 0.5 microM, applied to outside-out patches excised from the membrane of cultured rat hippocampal neurons, elicited single-channel currents of 48 pS which were blocked by DL-2-amino-5-phosphorovaleric acid, a competitive antagonist of NMDA. In addition, binding studies showed that pyrazole displaced 1-(cis-2-carboxypiperidine-4-yl)methyl-1-phosphoric acid from the agonist recognition site of the NMDA receptor in a concentration-dependent manner and enhanced the binding of (+)-5-methyl-10,11-dihydro-5H- dibenzo[a,d]cyclohepten-5,10-imine to this complex. These data indicate that pyrazole is an agonist at NMDA receptors. However, at higher concentrations, open and burst times as well as the frequency of single-channel currents activated by pyrazole were reduced significantly, a finding which suggests that this compound is also an open channel blocker. In agreement with these results, it was shown biochemically that pyrazole was able to stimulate influx of Ca++ into rat brain microsomes via NMDA receptors and on the other hand to block the influx of Ca++ induced by NMDA. Pyrazole was unable to affect the neuromuscular transmission of frog sartorius muscle-sciatic nerve preparations. Additionally, pyrazole did not interact either with the agonist recognition site or with noncompetitive sites of the AChR. However, this drug had a very weak agonist-like action on the AChR of the Torpedo electric organ, most likely via binding sites different from those described previously for acetylcholine. Therefore, the therapeutic efficacy of pyrazole may be related at least in part to its effects on the NMDA receptor. Furthermore, this compound, because of the small size and rigidity of its molecular structure, becomes a promising drug for the study of the NMDA receptor. Indeed its use may allow a better understanding of the physiological and pathological processes involving this receptor.
Alcohol Dehydrogenase↗
Evidence for inhibition of dopamine-beta-hydroxylase in vivo after sub-acute pyrazole treatment in rats.
Pyrazole, a widely used inhibitor of alcohol dehydrogenase, has been shown to cause a decrease of brain and heart noradrenaline (NA). An attempt to explain the mechanism of this effect is now described. L-DOPA (50-200 mg/kg, s.c.) was unable to restore brain or heart noradrenaline levels in pyrazole pre-treated rats. After monoamine oxidase inhibition with tranylcypromine or pargyline there was a slight increase in brain NA in these rats but no further increase was observed in response to L-DOPA (30 mg/kg). Brain dopamine levels were relatively higher in pyrazole pre-treated rats. This difference was particularly clear in the hypothalamus but not present at all in striatum. It was impossible to duplicate the above results using nialamide as the monoamine oxidase inhibitor. After depletion of monoamine stores by reserpine (2 x 2 mg/kg) or oxypertine (75 mg/kg) and treatment with tranylcypromine and L-DOPA it is possible to get an indication of the maximal rate of synthesis of NA. In pyrazole treated rats synthesis of NA in brain was 70% reduced and about 50% reduced in heart. Synthesis of dopamine from L-DOPA was unimpaired. Dopamine-beta-hydroxylase activity in the hypothalamus of rats treated for four days with pyrazole (100 mg/kg i.p.) was more than 40% reduced. This inhibition could not be obtained by addition of pyrazole to samples of purified dopamine-beta-hydroxylase. The results strongly suggest that the reason for the decrease in brain and peripheral NA seen after pyrazole administration in rats is due to inhibition of dopamine-beta-hydroxylase.
Animals↗
Ethanol, disulfiram, and pyrazole: effects on interferon production in mice.
The effects of ethanol alone or combined with pyrazole or disulfiram were studied in reference to interferon production. Saline, ethanol (2 g/kg), pyrazole (2 mg/kg), or disulfiram (2 mg/kg) were injected, intraperitoneally, 3 hr after poly I:C, an interferon inducer. Drugs were administered either by a single injection, or twice daily for 7 days, and the mice were sacrificed 6 hr after poly I:C. Sera from mice were pooled, dialyzed, and assayed for interferon by the microplaque reduction method. Administration of ethanol alone reduced interferon production 76% and 66% after the single and the multiple injections, respectively. A similar inhibition of interferon occurred after either pyrazole or disulfiram, with a greater potency for pyrazole. Treatment with pyrazole prior to ethanol reduced interferon production further, but only after the 7-day schedule. All drugs tested affected cellular immunity as measured by interferon production. Moreover, reduced interferon production by these agents was associated with a loss of splenic lymphoid tissue, suggesting that ethanol, pyrazole, and disulfiram could affect susceptibility to viral infection.
Animals↗
Histochemical and morphological evaluation of cerebral cortex of newborn rat in the course of joint ethanol and pyrazole administration.
The object of the study was the cerebral cortex of newborn rat. Tissue material was collected from the 2-nd to the 8-th hour after birth both from control animals and newborns whose mothers had been given both ethanol and pyrazole throughout gestation period, and also either ethanol alone or pyrazole. The drug were administered by gastric tube, in doses: ethanol 8.0 g/kg body weight, pyrazole 36 mg/kg body weight. Histochemical studies revealed variation in the intensity of reaction of the respiratory enzymes during examination of the cortex of newborns whose mothers had been fed with ethanol alone, or pyrazole alone. A strong inhibition of enzymatic reaction was observed in the examined cerebral cortex of newborns after a joint ethanol and pyrazole administration. Morphological studies showed an inhibition of maturing process of the cerebral cortex cells of animals treated with ethanol alone, whereas the cerebral cortex of animals whose mothers had been given both ethanol and pyrazole, presented symptoms allowing to diagnose encephalitis congenita symptomatica.
Animals↗
Alkylating nucleosides. 2. Synthesis and cytostatic activity of bromomethylpyrazole and pyrazole nitrogen mustard nucleosides.
Glycosylation of ethyl 3(5)-(bromomethyl)pyrazole-5(3)-carboxylate (3) and 3(5)-(bromomethyl)pyrazole-5(3)-carboxamide (4) with poly-O-acetylated sugars via an acid-catalyzed fusion method afforded the corresponding ethyl 3-(bromomethyl)pyrazole-5-carboxylate and 3-(bromomethyl)pyrazole-5-carboxamide substituted nucleosides 5 and 7, respectively. In some cases, the positional isomers 6 and 8 were also obtained. Treatment of 5 and 7 with methanolic ammonia gave the deprotected 3-(aminomethyl)pyrazole-5-carboxamide nucleosides 9. Reaction of 3--5 and 7 with bis(2-chloroethyl)amine led to the corresponding pyrazole nitrogen mustards 10--13. All the bromomethylpyrazole nucleosides described showed significant cytostatic activity against HeLa cell cultures.
Antineoplastic Agents↗
Effect of pyrazole, 4-methylpyrazole, 4-bromopyrazole and 4-iodopyrazole on brain noradrenaline levels of mice and rats.
Four daily doses of pyrazole (50 mg/kg), caused a reduction in rat brain noradrenaline (NA) of over 20% when determined 24 hrs after the final injection. Neither 4-methylpyrazole (10-50 mg/kg), nor 4-iodopyrazole (10-50 mg/kg) had any effect. In mice treated similarly, pyrazole (50-400 mg/kg) caused a dose-dependent decrease in brain NA. Neither 4-methylpyrazole, 4-bromopyrazole nor 4-iodopyrazole caused any significant change in the levels. However if the brain NA levels were examined 6 hrs after a single dose, then in addition to pyrazole, 4-methylpyrazole showed a dose-dependent ability to lower brain NA. 4-bromopyrazole and 4-iodopyrazole, given acutely, caused a dose-dependent decrease in rectal temperature and exploratory behaviour. 4-methylpyrazole in high doses (200-400 mg/kg) showed similar properties but they did not correlate with the decrease in brain NA. Pyrazole, after acute treatment, showed little ability to change rectal temperature of exploratory behaviour. It is concluded that the NA-depleting effect of pyrazole is not related to inhibition of alcohol dehydrogenase, since other 4-substituted pyrazoles which are more potent inhibitors of the enzyme have little or no effect on brain NA levels.
Animals↗
Metabolism of pyrazole. Structure elucidation of urinary metabolites.
Pyrazole has been widely used as an inhibitor of alcohol dehydrogenase both in vivo and in vitro. Very little attention has been paid to the metabolism of this agent and possible biological activity of any metabolites. Several isotopic variants of pyrazole, both stable and radioactive, were used in a study of its metabolic fate by gas chromatography-mass spectrometry. Seven metabolites were structurally identified and included hydroxylated and conjugated derivatives of pyrazole. Two metabolites were conjugated with a pentose, perhaps indicating that pyrazole serves as a substrate in the salvage pathway of purines and pyrimidines forming pyrazole ribosides. The use of d3-pyrazole greatly enhanced structural assignment of the metabolites by revealing the metabolism at or next to a labeled carbon atom.
Animals↗
Effects of pyrazole treatment of physical status and brain biogenic amines in rats.
The recovery of brain noradrenaline (NA) from a single dose of 100 mg/kg pyrazole was rapid, but after 500 mg/kg brain NA levels were still maximally reduced 3 days later and did not return to normal until 7 days after injection. The consumption of water followed a similar time course at this dose. Sub-acute experiments were carried out in two sets of animals: those with free access to food and water throughout the experiment and those which during the latter half of the experiment received a known, restricted quantity of food and fluid by gastric intubation. Diet restriction did not alter the pyrazole induced decrease in brain NA and potentiated the decrease observed in the heart. A significant increase in brain 5-hydroxyindoleacetic acid was observed with pyrazole 100 mg/kg in both diet schedules. In addition to the disturbances in food and water consumption, pyrazole also caused a decrease in locomotor activity which was only partly due to the starvation. Rectal temperature did not change. At the higher pyrazole dose in the rats fed by intubation there was incomplete emptying of the stomach. It is concluded that these many changes demonstrate the non-specificity of pyrazole and caution is advocated in its use combined with ethanol in research on experimental alcoholism.
Animals↗
3-Substituted pyrazole derivatives as inhibitors and inactivators of liver alcohol dehydrogenase.
3-Substituted pyrazoles, HOCH2 (1), HOCH2CH2 (2), HOCH2CH2CH2 (3), ClCH2 (4), ClCH2CH2 (5), ClCH2CH2CH2 (6), and CH3CO (7), were synthesized and evaluated in vitro on horse liver alcohol dehydrogenase for their potential as inhibitors of ethanol metabolism. 1 to 6 bound to the enzyme-NAD+ complex with dissociation constants of 40 to 200 microM, much higher than the constants for the corresponding 4-substituted pyrazoles, but with the same absorption maximum at 295 nm. 4 inactivated the enzyme within a few minutes, but NAD+ protected against reaction, and 4 nonspecifically alkylated many sulfur atoms in the protein. The isomer, 4-(chloromethyl)pyrazole, behaved similarly, 5 and 6 strongly inhibited the enzyme in the presence of NAD+, due to formation of the slowly dissociable (10(-3)s-1) enzyme-NAD+-pyrazole complex, but did not irreversibly inactivate the enzyme. 7 inhibits the enzyme weakly (Kp = 5 mM). It appears that the 3-substituted pyrazoles bind to the enzyme-NAD+ complex with the reactive functional group improperly positioned for specific irreversible reaction.
Alcohol Oxidoreductases↗
Effects of pyrazole and 3-amino-1,2,4-triazole on the metabolism and toxicity of dimethylnitrosamine in the rat.
Pretreatment of rats with pyrazole or 3-amino-1,2,4-triazole (3-AT) known inhibitors of alcohol metabolism, profoundly inhibited the metabolism of dimethylnitrosamine (DMN), both in terms of [14C]CO2 excretion and of the decline in the blood concentration. Additionally, 4-methylpyrazole, tetraethylthiuram disulfide (disulfiram), methanol, and ethanol inhibited the metabolism of DMN in the whole animal. In parallel experiments with [14C]aminopyrine, no substantial inhibitory effect was found with pyrazole, 3-AT, or disulfiram pretreatment. Investigations into the effects of pyrazole and 3-AT pretreatment on the acute toxicity and hepatotoxicity of DMN showed that pyrazole significantly increased the median lethal dose (LD50) of DMN and provided substantial protection against the hepatotoxicity of DMN, in that centriblobular necrosis was not seen at dose levels of DMN up to 25 mg/kg and early histochemical changes indicative of liver injury were not observed at a dose level of 15 mg DMN/kg. In contrast, 3-AT pretreatment did not affect the LD50 of DMN or provide any protection against the hepatotoxicity of DMN. Further, although both inhibitors delayed the incorporation of radioactivity from [14C]DMN into hepatic subcellular organelles, pyrazole was significantly more effective than was 3-AT.
Amitrole↗
Inhibition of dopamine beta-hydroxylase by 4-hydroxypyrazole: ethanol-pyrazole effects on serum dopamine beta-hydroxylase in vivo.
Chronic pyrazole treatment caused a 40% decrease in rat serum dopamine beta-hydroxylase (DBH) activity. Ethanol given simultaneously with pyrazole prevented the inhibition. 4-Hydroxypyrazole, the major metabolite of pyrazole, competitively inhibited both rat serum DBH and partially purified bovine adrenal DBH in vitro. In vivo, 4-hydroxypyrazole caused large decreases in rat serum (53-84%) and adrenal (97%) DBH activity but had no effect on brain enzyme. The decrease in rat serum DBH after chronic pyrazole treatment and the pyrazole-induced changes in physiological parameters, such as body weight and temperature, may be due to the formation of 4-hydroxypyrazole.
Adrenal Glands↗
Combined action of pyrazole and ethanol on a rat liver: histochemical and ultrastructural study.
The effect on a rat liver of combined administration of pyrazole and ethanol was studied histochemically and by electron microscopy. The study revealed strong hepatotoxic action of pyrazole combined with ethanol. Feeding with ethanol alone induces slight alterations in the liver, pyrazole alone affects the liver but slightly, whereas a combined administration of pyrazole and ethanol both by light and electron microscopy examination revealed a strong toxic action leading to severe damage of the liver cells including necrosis.
Acid Phosphatase↗
Heterocyclic tricycles as potential CNS agents I: 4-aminoalkylindeno[1,2-c]pyrazoles.
Series of 4-(3-dimethylaminopropyl)-4-hydroxyindeno[1,2-c]pyrazoles and 4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c-]pyrazoles were synthesized and identified. The compounds were evaluated as potential CNS agents using spontaneous and forced motor activity in mice as an initial test. 2-Ethyl-3-methyl-4-(1-methyl-4-piperidyl)-4-hydroxyindeno[1,2-c]pyrazole possessed significant biological activity.
Animals↗