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Results for “Piperazines”

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PubMed1979

Induction of cataracts in the rat by derivatives of (4' -pyridyl) - 1 piperazine.

A structure ocular toxicity study in the rat of (4' - pyridyl) - 1 piperazine and of some derivatives with psychopharmacological profile, allows some interesting conclusions. (4' - pyridyl) - 1 piperazine does not lead to crystalline lens opacity, though some aryloxypropanol or aryloxypropyl derivatives do. At least, (2' - pyridyl) - 1 piperazine and one aryloxpropanol derivative do not improve cataract. So the appearance of cataracts is probably due to substitution of an alkylaryl side chain on the N-4 position of (4' - pyridyl) - piperazine.

Animals↗

PubMed1978

Anthelmintic efficacy of thenium closylate-piperazine phosphate combination tablets against Toxocara canis in pups and young dogs.

Thenium closylate-piperazine phosphate combination tablets, tablets containing either thenium or piperazine, and control tablets (excipients only) were administered in 2 doses 5 to 7.5 hours apart to weaned pups and young dogs, in critical controlled trials to test efficacy against naturally acquired infections of Toxocara canis. In the 1st trial, the combination tablets produced a mean clearance of 94% from 18 pups. Tablets containing thenium alone showed a mean clearance of 9% from 25 pups, and tablets containing piperazine alone caused a mean clearance of 56% from 16 pups. Clearances, corrected for spontaneous worm losses observed in pups treated with the control tablets, were 90% (combination), 5% (thenium alone), and 52% (piperazine alone). In the 2nd and 3rd trials, efficacy of the combination tablet in 15 pups was 78% when corrected for worm losses in pups which had received placebo (excipient) tablets. Each component in the combination tablet contributed its full single-entity efficacy and, if in combination, synergistic effect between the components.

Animals↗

PubMed1997

Synthesis and biodistribution of two potential PET radioligands for dopamine reuptake sites: no-carrier-added 4-(2-[18F]fluoroethyl) and 4-[11C]methyl BTCP-piperazine.

Radioligands that specifically target dopamine uptake sites can provide a means of determining dopamine fiber loss at intrastriatal mesencephalic grafts in Parkinsonian patients, using Positron Emission Tomography (PET). The BTCP derivative, 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-(2-hydroxyethyl)-piperazine, shows in vitro high affinity and selectivity for the dopamine transporter. To evaluate the potential of such a compound as a potential dopaminergic PET tracer the positron-emitting analogues, 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-(2-[18F]fluoroethyl)-piperazine and 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-[11C]methylpiperazine, were synthesized. Radiofluorination was carried out by the reaction of 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-4-(2-chloroethyl)-piperazine with cyclotron-produced n.c.a. 18F-(half life 109.9 min) obtained by the (p,n) reaction on 18O-enriched water. Labelling with carbon-11 (half life 20.4 min) was achieved by 11C methylation of 1-[1-(2-benzo(b)thiophenyl)cyclohexyl]-piperazine with [11C]methyl iodide. After intravenous administration to rats these two compounds enter the brain, but despite their high in vitro affinity they display a high non specific binding in vivo which greatly limits their use as PET radioligands.

Animals↗

PubMed2004

Piperazine derivatives of [1,2,4]triazolo[1,5-a][1,3,5]triazine as potent and selective adenosine A2a receptor antagonists.

The [1,2,4]triazolo[1,5-a]triazine derivative 3, more commonly known in the field of adenosine research as ZM-241385, has previously been demonstrated to be a potent and selective adenosine A2a receptor antagonist, although with limited oral bioavailability. This [1,2,4]triazolo[1,5-a]triazine core structure has now been improved by incorporating various piperazine derivatives. With some preliminary optimization, the A2a binding affinity of some of the best piperazine derivatives is almost as good as that of compound 3. The selectivity level over the adenosine A1 receptor subtype for some of the more active analogues is also fairly high, > 400-fold in some cases. Many compounds within this piperazine series of [1,2,4]triazolo[1,5-a]triazine have now been shown to have good oral bioavailability in the rat, with some as high as 89% (compound 35). More significantly, some piperazines derivatives of [1,2,4]triazolo[1,5-a]triazine also possessed good oral efficacy in rodent models of Parkinson's disease. For instance, compound 34 was orally active in the rat catalepsy model at 3 mg/kg. In the 6-hydroxydopamine-lesioned rat model, this compound was also quite effective, with a minimum effective dose of 3 mg/kg po.

Adenosine A2 Receptor Antagonists↗

PubMed1984

Piperazine-induced airway symptoms: exposure-response relationships and selection in an occupational setting.

The heterocyclic secondary amine piperazine is known to cause asthma. In a cohort of 602 workers, employed during the period 1942-1979, at a chemical industry where piperazine is handled, a study conducted by means of a mailed questionnaire showed a strong exposure-response relationship as to frequency of work-related airway symptoms indicating asthma. In the most exposed group about a third of the workers had experienced such symptoms. Age, length of employment, smoking habits, and previous work-related asthmatic symptoms, but not atopy, modified the response. Further, there was an association between piperazine exposure and chronic bronchitis. In the most exposed group every fourth subject had chronic bronchitis. The frequency was modified by smoking habits; atopy was a confounder. Although many subjects, especially high-exposed ones, left work because of airway symptoms, there was no difference in occurrence of airway symptoms between former and present employees, ie, no "healthy worker selection" ("survivor population effect").

Asthma↗

PubMed1988

Excretion of N-mononitrosopiperazine in urine in workers manufacturing piperazine.

Piperazine has been shown to nitrosate in vivo to N-mononitrosopiperazine (MNPZ) by oral intake. Urine from workers exposed to piperazine in a chemical plant was analysed for nitrosamines by gas chromatography-thermal energy analysis. In five out of 11 exposed cases, MNPZ excretion in urine was 0.3 to 4.7 micrograms/24 h (during and after a work shift). In four cases, MNPZ was detected in some urine samples, and in two cases MNPZ was not detected (less than 0.1 ng/ml). The individual excretion was strongly dependent on piperazine exposure, which ranged from 0.06 to 1.7 mg/m3 (time-weighted average; Spearman's rank correlation 0.78, P = 0.01). The MNPZ excretion showed no significant correlation with nitrite or nitrate in saliva (both: r = 0.50, P = 0.10).

Adult↗

PubMed2000

Synergistic action of a cyclic depsipeptide and piperazine on nematodes.

The present study describes the synergistic effects of the cyclic depsipeptide BAY 44-4400 and piperazine in the treatment against the nematodes Trichinella spiralis, Heligmosomoides polygyrus, and Heterakis spumosa. The in vitro anthelmintic activity of a combination of the two compounds (1.7 motility units) against T. spiralis larvae was significantly higher than the sum of the individual drug effects (1.3 motility units). With regard to the rate of expulsion of H. polygyrus worms from the intestine of infected mice, an additive effect was observed; piperazine alone exerted an efficacy of 54.4% and BAY 44-4400 alone, one of 44.4%, whereas the combination of these compounds had an efficacy of 97.5%. With regard to the expulsion of H. spumosa worms, the effect of the combination was more than 5 orders of magnitude greater than the sum of the effects of the single compounds, i.e., there was a considerable potentiation of the actions of BAY 44-4400 and piperazine. Moreover, the combination exerted a significantly higher degree of degenerative effects on the intestine and on the nerve chords of H. spumosa as compared with the single compounds.

Animals↗

PubMed1988

Excretion of N-mononitrosopiperazine after low level exposure to piperazine in air: effects of dietary nitrate and ascorbate.

The secondary amine piperazine may be nitrosated in vivo, following oral intake or occupational exposure by inhalation. The suspected carcinogen N-mononitrosopiperazine could be formed in the human stomach, and in part excreted in the urine. In this study, 0.4 microgram N-mononitrosopiperazine, determined by gas chromatography-Thermal Energy Analysis, was observed in the urine in one of four volunteers, at an experimental exposure by inhalation of 0.3 mg piperazine/m3. The intake of spinach and beetroot caused an increased nitrosation of piperazine, and up to 1.7 microgram N-mononitrosopiperazine was excreted in the urine in the four individuals. This excretion indicates that about 5% of the absorbed piperazine dose was converted to N-mononitrosopiperazine. With the same nitrate-rich diet, but with the addition of citrus fruits and fresh vegetables, the highest excretion was 0.6 microgram N-mononitrosopiperazine. The excretion was significantly correlated with the ratio between the maximum level of nitrite in saliva and the ascorbate level in plasma. There was also a significant interindividual variation. N,N'-Dinitrosopiperazine was not found in any sample of urine.

Administration, Inhalation↗

PubMed1992

Effect of dietary nitrate on endogenous nitrosation of piperazine in humans.

The effect of dietary nitrate on endogenous nitrosation of a therapeutic dose of piperazine has been described in five human volunteers who acted as their own controls. The urinary excretion of endogenously formed N-nitro-somonopiperazine (MNPz) ranged between 9.2 and 80.1 micrograms/24 h on a normal uncontrolled diet which increased from 25.7 to 163.7 micrograms/24 h when the diet was supplemented with 250 mg nitrate. The corresponding urinary nitrate was 63.0-122.7 mg/24 h and 119.2-322.0 mg/24 h, respectively. The dinitroso derivative of piperazine was detected only in trace amounts and no detectable increase in its excretion was observed during high nitrate exposure. The unchanged piperazine (range 294-784 mg/24 h) in urine showed a decrease under high nitrate regimen (range 185-399 mg/24 h).

Carcinogens↗

PubMedDate not supplied

Absence and atonic seizures induced by piperazine.

A previously healthy 2-year-old girl, who presented with transient neurologic dysfunction manifested mainly by absence and atonic seizures, was treated with large doses of the antihelminthic piperazine hexahydrate. The role of piperazine salts and piperazine-containing compounds in producing neurotoxic side effects is discussed. We suggest that these drugs be considered as a possible cause of transient encephalopathy and nonepileptic seizures in previously healthy individuals.

Child, Preschool↗

PubMed2006

Effect of piperazine (diethylenediamine) on the moulting, proteome expression and pyrophosphatase activity of Ascaris suum lung-stage larvae.

Piperazine (diethylenediamine) is an anthelmintic widely used against animal and bird ascariasis. In this study, we show that treatment with piperazine blocks Ascaris suum larval moulting and development processes and affects larval proteome expression profiles. A. suum lung-stage L3 (LL3) obtained from an infected rabbit's lungs were cultured in RPMI medium in the presence of increasing concentrations of piperazine sulfate (Pzes). Our results showed that Pzes potently inhibited moulting of A. suum LL3 in a dose-dependent manner and that moulting was completely blocked (100%) at 50mM concentrations. We then examined the changes in A. suum LL3 proteome expression patterns following Pzes exposure using two-dimensional (2D) electrophoresis. Pzes exposure inhibited expression of at least 16 major protein spots in unmoulted LL3 out of more than 200 visible protein spots resolved on 2D gels prepared from moulted larvae (i.e., lung-stage L4). Pzes exposure also inhibited expression of 13 immunogenic protein spots in unmoulted LL3. More importantly, Pzes exposure inhibited activity of a moulting-specific enzyme, inorganic pyrophosphatase of A. suum (AsPPase), by 26%. Expression of native AsPPase was also reduced following Pzes exposure as detected by immunoblotting and immunofluorescent staining. Transmission electron microscopy showed that Pzes interfered with growth and ecdysis of the cuticle and caused damage to gut tissues of the larvae. Our results suggest that A. suum LL3 may become a suitable model to screening new-class anthelmintics with antimoulting functions and that A. suum LL3-Pzes may serve as a useful tool for identification of moulting-specific potential proteins in Ascaris roundworms.

Animals↗

PubMed2004

Chiral, nonracemic (piperazin-2-yl)methanol derivatives with sigma-receptor affinity.

Starting with the proteinogenic amino acid (S)-serine a series of chiral nonracemic (piperazin-2-yl)methanols 3 with various N-4 substituents is described. The key step in the synthesis of 3 is the reaction of the chloroacetamide 5 with various primary amines to yield the diastereomeric bicyclic piperazinediones cis-6 and trans-6. The scope and limitation of this transformation is thoroughly investigated. The alpha1- and sigma2-receptor affinities of the piperazines 3 are determined in receptor binding studies with guinea pig brain and rat liver membrane preparations using [3H]-labeled (+)-pentazocine and ditolylguanidine, respectively. It was found, that an additional phenyl residue in the N-4 substituent is favorable to high sigma1-receptor affinity. In this series the p-methoxybenzyl substituted piperazine 3d reveals the highest sigma1-receptor affinity (Ki=12.4 nM) with selectivity toward sigma2-, NMDA-, kappa-opioid, and mu-opioid receptors.

Animals↗

PubMed2005

Privileged structure based ligands for melanocortin receptors--substituted benzylic piperazine derivatives.

Replacement of the aryl piperazine moiety in compound 1 with a variety of substituted benzylic piperazines (6) yields compounds that afford melanocortin receptor 4 (MCR4) activity. Analogs with ortho substitution on the aromatic ring afforded the highest affinity. Resolution of the stereocenter of the benzylic piperazine based privileged structure revealed that the R-enantiomer was more active.

Benzene Derivatives↗

PubMed2005

Enhanced FTase activity achieved via piperazine interaction with catalytic zinc.

Benzocycloheptapyridine tricyclic compounds with piperazine or substituted piperidine moieties extending either from the 5- or 6-position of the tricyclic bridgehead exhibited enhanced FTase activity: this resulted from favorable binding of the ligand nitrogen with the catalytic zinc found in the FTase. A single isomer at C-11 with piperazine adduct extending from the 6-position, compound 24, exhibited excellent FTase activity with IC50 = 0.007 microM, soft agar IC50 = 72 nM, and Rat AUC(PO, 10 mpk) = 4.0 microM x h. X-ray of (-)-[8-chloro-6-(1-piperazinyl)-1H-benzo[5,6]]cyclohepta[1,2-b]pyridine-11-yl]-1-(methylsulfonyl)piperidine 24 bound to Ftase revealed favorable interaction between piperazine nitrogen and catalytic zinc atom.

Alkyl and Aryl Transferases↗

PubMed2006

Determination of piperazine in pharmaceutical drug substances using capillary electrophoresis with indirect UV detection.

A fast, selective capillary electrophoresis (CE) method was developed for piperazine counter-ion analysis and applied to the analysis of an active pharmaceutical ingredient (API) that exists as a hemipiperazine salt. Due to the poor chromophore, the detection method chosen was indirect UV detection using benzylamine as the UV absorbing probe. Piperazine quantitation was performed using diethylamine as an internal standard and the method was validated for specificity, linearity, precision, and accuracy. The results indicate the method is suitable for piperazine counter-ion analysis in support of salt form characterization.

Antinematodal Agents↗

PubMed1998

Embryonation and infectivity of Ascaris suum eggs isolated from worms expelled by pigs treated with albendazole , pyrantel pamoate, ivermectin or piperazine dihydrochloride.

The effect of anthelmintic treatment of pigs on the embryonation and infectivity of Ascaris suum eggs isolated from expelled worms was investigated. Four groups of two naturally infected pigs were dosed with albendazole, pyrantel pamoate, ivermectin or piperazine dihydrochloride, respectively. Following worm expulsion, the eggs were removed from the uteri of female worms and embryonated in sulphuric acid. The infectivity of the embryonated eggs was tested through mouse inoculation. Egg development appeared normal in cultures from worms of the piperazine. pyrantel and ivermectin treated groups. In the albendazole cultures, egg development was largely arrested at the one-cell stage (81%). Where development occurred, irregular cell division was observed and only 7% of the eggs in the culture developed into fullgrown larvae. Following mouse inoculation with 2500 embryonated eggs, significantly lower lung larval counts on day 8 post inoculation (p.i.) were observed for mice in the piperazine and pyrantel treated groups (P < 0.01) compared to untreated controls. The larvae that developed in the eggs from ivermectin and albendazole treated groups appeared fully infective for mice. It was concluded that ovicidal activity of albendazole in vivo inhibits subsequent A. suum egg development in vitro; albendazole is, therefore, not suitable to obtain worms for egg embryonation to produce experimental inoculums. The anthelmintic treatment of pigs with ivermectin had only a limited effect on both embryonation and infectivity of A. suum eggs isolated from expelled worms.

Albendazole↗

PubMed2003

Formation of p-cresol:piperazine complex in solution monitored by spin-lattice relaxation times and pulsed field gradient NMR diffusion measurements.

A study of the nature of the anthelmintic p-cresol:piperazine complex in chloroform solution has been conducted using different NMR techniques: self-diffusion coefficients using DOSY; NOE, NULL, and double-selective T1 measurements to determine inter-molecular distances; and selective and non-selective T1 measurements to determine correlation times. The experimental results in solution and CP-MAS were compared to literature X-ray diffraction data using molecular modeling. It was shown that the p-cresol:piperazine complex exists in solution in a very similar manner as it does in the solid state, with one p-cresol molecule hydrogen bonded through the hydroxyl hydrogen to each nitrogen atom of piperazine. The close correspondence between the X-ray diffraction data and the inter-proton distances obtained by NULL and double selective excitation techniques indicate that those methodologies can be used to determine inter-molecular distances in solution.

Binding Sites↗

PubMed1959

The effect of piperazine on succinate production by Ascaris lumbricoides.

Piperazine reduced the production of succinate by Ascaris lumbricoides. This effect was reversible. There was a close parallelism between the concentrations of piperazine which paralysed the worm and those which inhibited the formation of succinate. Piperazine did not affect the incorporation of [2-(14)C]lactate into succinate by strips of Ascaris muscle. It was concluded that production of succinate supplies energy for the contraction of Ascaris muscle.

Animals↗