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At least 523 records · Page 29Linked to original sources

PubMed2006

SAR study of 1-aryl-4-(phenylarylmethyl)piperazines as ligands for both dopamine D2 and serotonin 5-HT1A receptors showing varying degrees of (Ant)agonism. Selection of a potential atypical antipsychotic.

The syntheses of several 1-aryl-4-(arylpyridylmethyl)piperazines (4) and their affinities for dopamine D(2) and serotonin 5-HT(1A) receptors are described. The compounds were evaluated both in vitro and in vivo, resulting in the identification of the drug candidate SLV313 (4e) with equipotent and full D(2) receptor antagonism and 5-HT(1A) receptor agonism. Minor structural modifications in SLV313 revealed the possibility of designing compounds possessing varying degrees of partial agonism on one or both target receptors.

Administration, Oral↗

PubMed1991

[Pharmacological effects of the novel dopamine uptake inhibitor 1-[2-[bis(4-fluorophenyl)-methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system].

The effects of 1-[2-[bis (4-fluorophenyl)methoxy]ethyl]-4-(3- phenylpropyl) piperazine dihydrochloride (I-893) on the central nervous system were behaviorally and electroencephalographically investigated. Intraperitoneally injected I-893 (5-10 mg/kg) dose-dependently increased spontaneous motor activity in mice, but repeated injections did not affect the increase in the locomotor activity. In reserpinized mice, spontaneous motor activity was not increased by oral I-893. In alpha-MPT-treated mice, the motor activity was lower than that in vehicle-treated animals with intermediate doses (10-40 mg/kg, p.o.) of I-893, but there was no difference between the two groups with high doses. In rats with unilaterally 6-OHDA-induced lesion of the nigrostriatal pathway, I-893 induced circling behavior toward the lesioned side. Haloperidol-induced catalepsy in rats was reduced by I-893. Tremorine-induced tremor in mice was inhibited by I-893. The effect was not altered in the mice treated with I-893 for 10 days. Oral I-893 induced stereotypy in rats, but it did not affect methamphetamine-induced stereotypy. Hypnosis induced by barbiturates was antagonized by I-893. In rats treated with I-893 for 6 days, pentobarbital-induced sleep was not different from that in vehicle-treated animals on the day after the final treatment. Intravenous I-893 altered EEGs in the cerebral cortex and amygdala nucleus to low voltage and fast waves and altered hippocampal EEG to theta waves in immobilized rabbits. These results suggest that I-893 inhibits re-uptake of dopamine released by exocytosis and indirectly has dopaminergic effects.

Animals↗

PubMed1998

Reduction of 4-cyclohexyl-1-[(1R)-1,2-diphenylethyl]-piperazine-induced memory impairment of passive avoidance performance by sigma 1 receptor agonists in mice.

Intraperitoneal administration of 4-cyclohexyl-1-[(1R)-1,2-diphenylethyl]-piperazine (CDEP) immediately after the training session produced significant memory impairment in the mouse passive avoidance performance. Interestingly, this memory impairment was alleviated by subcutaneous administrations of sigma receptor agonists, (+)-N-allylnormetazocine ((+)-SKF-10,047), (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP) and 1,3-di(2-tolyl)guanidine (DTG) immediately after the training session. In particular, the remarked recovery for this memory impairment was produced by (+)-SKF-10,047. A receptor binding study showed that CDEP possessed high affinities for both sigma 1 and sigma 2 receptor subtypes (IC50 1.4 +/- 0.3 nM for sigma 1 receptor subtype, 1.8 +/- 0.3 nM for sigma 2 receptor subtype), while (+)-SKF-10,047 had a high selectivity for the sigma 1 receptor subtype. These findings suggest that the sigma receptor, particularly sigma 1 receptor subtype, may play an important role in the CDEP-induced impairment of learning and memory processes.

Animals↗

PubMed2002

1-(1-naphthyl)-piperazine, a mixed 5-HT1A and 5-HT2A/2C receptor ligand, elicits an anxiolytic-like effect in the open-field test without changes in 5-HT metabolism.

The effects of acute 1-(1-naphthyl)-piperazine (1-NP, 2 mg/kg i.p.) on rat open-field and social interaction behaviors were studied followed by postmortem and in vivo microdialysis measurement of serotonin (5-HT) and 5-hydroxyidolacetic acid (5-HIAA) content. 1-NP treatment elicited an anxiolytic-like effect in the open-field test, which was not modified by citalopram (5 mg/kg i.p.) challenge. A statistically insignificant tendency toward prolongation of the social interaction time was also found. The only significant change in the postmortem experiment was found in the striatum: 5-HIAA content was reduced after combined 1-NP plus citalopram treatment. Using the in vivo microdialysis technique, no difference in the 5-HT or 5-HIAA output between the treatment groups was found in the frontal cortex of anaesthetized rats. Our present study demonstrates the anxiolytic-like properties of 1-NP in the open-field test, but this effect is irrelevant to changes in 5-HT metabolism.

Analysis of Variance↗

PubMed1977

Effect of piperazine oestrone sulphate on serum lipids and lipoproteins in menopausal women.

Twenty menopausal women and 2 women with gonadal dysgenesis were treated with piperazine oestrone sulphate 1.5-3 mg dialy on a cyclical basis for a period of 6 months. Fasting serum lipids and lipoprotein esterified fatty acid indices (EFI) were estimated before starting treatment and after 3 and 6 months. There were small falls in serum cholesterol (significant at 3 months) and beta-lipoprotein EFI (significant at 6 months). Serum triglyceride and pre-beta-lipoprotein EFI rose significantly at both 3 and 6 months. Serum total phospholipid levels were reduced (significant at 6 months) with most marked changes in the sphingomyelin fraction. Other parameters were not significantly altered.

Cholesterol↗

PubMed1988

Negative chronotropic and positive inotropic effects of a unique cardioactive agent, N,N'-dicyclopropyl methyl piperazine (bis) hydrochloride (INO 2628), in isolated, blood-perfused dog atria.

The effects of a novel piperazine derivative (INO 2628) on sinus node pacemaker activity and atrial contractile force were investigated in isolated, blood-perfused dog atrium. Injections of INO 2628 (0.03-100 mumol) into the sinus node artery of the isolated atrium induced a dose-dependent decrease in sinus rate and an increase in contractile force. The positive inotropic effects at more than 10 mumol were accompanied by a transient negative inotropism. Propranolol did not affect the positive inotropic response to INO 2628, but it significantly suppressed positive chronotropic and inotropic responses to norepinephrine. Atropine at a dose which completely blocked negative chronotropic and inotropic responses to carbachol, produced a slight but significant depression of INO 2628-induced negative chronotropic responses; inotropic responses were unaffected. These results suggest that INO 2628 induces noncholinergic negative chronotropic and nonadrenergic positive inotropic responses in isolated dog atria.

Animals↗

PubMed1983

Disposition and metabolism of buspirone and its metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

After i.v. injection (10 mg/kg) to rats, buspirone is rapidly cleared from blood with a t1/2 (beta) or 30 min. After the same dose is given orally, the drug is not detectable in blood or brain within the limits of sensitivity of the method. The metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) has a longer t1/2 than buspirone. It is present to about the same extent in rat plasma and brain after either i.v. or p.o. buspirone. Unlike buspirone, 1-PP accumulates in the brain reaching concentrations between four-and five times those in plasma. Its brain AUC is higher than that of buspirone even when buspirone is given i.v. The results suggest that 1-PP may contribute to the pharmacological effect of the parent drug.

Animals↗

PubMed1983

Terminal N-sulphoconjugation of an alicyclic amine (piperazine), identified as a new metabolite of tiaramide in mouse and rat.

A new metabolite of tiaramide, 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazineethanol, found in mouse urine was identified as potassium 4-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-1-piperazinesulphonate (M-I). Sex differences in the excretion of M-I were noted in the mouse following oral administration of tiaramide and female mice excreted about 4.6-fold more M-I in urine than males. M-I could not be detected in the urine of male or female rats treated orally with tiaramide. After oral dosing with 1-[(5-chloro-2-oxo-3(2H)-benzothiazolyl)acetyl]-piperazine (DETR), M-I was detected in the urine, and the urinary excretion by male and female rats was similar to that in mice.

Analgesics↗

PubMed1985

Disposition of the psychotropic drugs buspirone, MJ-13805 and piribedil, and of their common active metabolite 1-(2-pyrimidinyl)-piperazine in the rat.

1-(2-Pyrimidinyl)-piperazine (PmP) is a common metabolite of the structurally related drugs buspirone, MJ-13805 and piribedil. After i.v. injection (25 mumol/kg) to rats, all three parent drugs are rapidly cleared with a t 1/2 (beta) of about 30 min. The metabolite t 1/2 is about four times that of its parent drugs. About 25, 23 and 2% of buspirone, MJ-13805 and piribedil, respectively, reaches the systemic circulation as PmP. The metabolite concentrates in the brain where its A.U.C. is about twice those of buspirone and MJ-13805. Results indicate that PmP formation is a pharmacologically significant process for both buspirone and MJ-13805 but it is probably less important for piribedil.

Animals↗

PubMedDate not supplied

Relationships between the lipophilicity of some 1,4-piperazine derivatives of aryloxyaminopropanols and their beta-andrenolytic activity.

Nineteen 1,4-piperazine derivatives of aryloxyaminopropanol were evaluated with respect to beta-adrenolytic activity. The retention factors obtained from HPLC, RM values obtained from partition TLC and the lipophilic Hansch's (4) constants pi were determined and the compounds were studied with respect to their lipophilicity based on chromatographic properties. The study of the influence of different substituents introduced at the para position on the phenyl ring on the retention factor indicated the log k vs. the number of carbon atoms in R1 substituent to be a linear relationship. Attempts have been made to relate the beta-adrenolytic activity to the lipohydrophilic parameters by deriving a quantitative relationship between them. Significant parabolic correlation was observed between the beta-adrenolytic activity and the logarithm of the retention factor, log k. An analogous relationship was obtained between the beta-adrenolytic activity of the compounds and the RM values obtained from partition TLC as well as Hansch's lipophilic constants pi.

Adrenergic beta-Antagonists↗

PubMed2000

Nigrostriatal lesions alter oral dyskinesia and c-Fos expression induced by the serotonin agonist 1-(m-chlorophenyl)piperazine in adult rats.

The loss of dopaminergic innervation of the basal ganglia, a group of subcortical regions involved in motor control, is the hallmark of Parkinson's disease. The resulting molecular and cellular alterations mediate behavioral deficits and may modify neuronal responses to other neurotransmitters. In the present study, we sought to determine the effects of chronic dopamine (DA) depletion on responses mediated by stimulation of serotonergic 2C (5-HT(2C)) receptors, a serotonergic receptor subtype present in discrete regions of the basal ganglia. Specifically, the effects of unilateral lesions of nigrostriatal DA neurons on oral dyskinesia and Fos protein expression induced by the non-selective 5-HT(2C) agonist 1-(m-chlorophenyl)piperazine (m-CPP) were examined. Confirming previous findings, both peripheral and local injections of m-CPP into the subthalamic nucleus elicited oral dyskinesia. Nigrostriatal lesions markedly enhanced oral bouts induced by peripheral but not intrasubthalamic administration of m-CPP. In intact rats, Fos expression was increased by m-CPP (1 mg/kg, i.p.) in the striatum and the subthalamic nucleus. After nigrostriatal lesions, m-CPP-induced Fos expression remained unchanged in the subthalamic nucleus but was reduced in the medial quadrants of the striatum and was markedly enhanced in the entopeduncular nucleus. These data demonstrate regionally specific alterations in behavioral and cellular responses to a serotonergic agonist in an animal model of Parkinson's disease.

Animals↗

PubMed2000

[Effects of a (fluorophenyl) piperazine derivative (substance IIIv) on cardiovascular function].

The present paper links up with the study of principal pharmacological effects of newly synthesized aryloxyaminopropanols substituted with 1,4-piperazine derivatives in the hydrophilic moiety of the molecule. The substance with the working name IIIv showing the highest beta-adrenolytical and vasodilating effect underwent further pharmacological evaluations with the aim of contributing to the elucidation of the mechanism of its action. After 7-day administration of the substance in two doses (5 and 50 mg.kg-1), the changes in the reactibility of arterial preparations were investigated on three models of the contraction of the isolated rat aorta (KCl, noradrenaline, and PGF2 alpha) from both qualitative and quantitative views. The results were also supplemented with organometric studies of the effect of the substance in rats.

Adrenergic beta-Antagonists↗

PubMedDate not supplied

Anticancer activity of genistein-piperazine complex. In vitro study with HL-60 cells.

Genistein, a principal soy isoflavone, has recently aroused interest in medical research owning to its numerous biochemical properties such as: inhibition of the activity of tyrosine-specific protein kinases and topoisomerase II, estrogenic and antioxidant activity as well as antiproliferative and antiangiogenic effects. Therefore, genistein is extensively investigated as a novel anticancer drug. To improve physicochemical properties of genistein (e.g., water solubility) we have synthesized its complexes with amines. Genistein-piperazine complex (GP) has been then examined whether it exhibits anticancer action against human promyelocytic leukemia cell line (HL-60) cultured in vitro. The parallel study with pure genistein has also been undertaken. Cell proliferation, viability, apoptosis and cell cycle kinetics have been assayed for various drugs concentrations (10-40 microM) and periods of exposure (1-6 days). GP reduced proliferation rate, decreased cell viability and induced apoptotic cell death, in a dose- and time-dependent manner. Flow-cytometric analysis of cell cycle distribution revealed a progressive and sustained accumulation of cells in the G2/M phase that was accompanied by unperturbed protein synthesis. The measured anticancer effects of GP and genistein were qualitatively and quantitatively similar, indicating that genistein-amine complex does not loose the activity of the parent compound.

Antineoplastic Agents, Phytogenic↗

PubMed2000

Effects of 2-[3-estrone-N-ethyl-piperazine-methyl]tetracycline (XW630) on osteoporosis in ovariectomized rats.

AIM: To study the effects of 2-[3-estrone-N-ethyl-piperazine-methyl]tetracycline (XW630) on experimental osteoporosis in ovariectomized (OVX) rats. METHODS: Serum estradiol (E2) content and bone 1-carboxyglutamic acid-containing protein (BGP) content were measured by radioimmunoassay. With undecalcified bone section and tetracycline intraperitoneal labeling, the bone static and dynamic data were studied in right femur samples. RESULTS: After treatment with XW630 2.5 mg.kg-1, serum BGP content increased by 75.7% but there was no change in serum E2 content and uterus weight compared with OVX rats. Compared with OVX rats, the static data of trabecular bone volume/total tissue volume, trabecular bone volume/sponge bone volume, and mean trabecular plate density were enhanced after treatment with XW630 for 13 wk. The dynamic data of single-labeled surface, double-labeled surface, trabecular osteoid surface, and bone formation rate in tissue level in XW630 group were increased and osteoid maturation period was shortened. CONCLUSION: XW630 enhanced bone activation frequency and increased trabecular connectivity, stability, and strength. XW630 stimulated bone formation and inhibited bone resorption with no effect on reproductive system.

Animals↗

PubMedDate not supplied

The analysis of the hypotensive action of new piperazine derivatives in the experimental hypertension in rats.

The correlation of hypotensive action and chemical structure of some new piperazine derivatives was studied in normotensive rats and those with experimental hypertension. In the latter, all the tested derivatives, administered both once and repeatedly, appeared to have hypotensive action of various degree. In normotensive animals, there was no evidence of such action.

Animals↗

PubMedDate not supplied

Conformational analysis and pharmacophore design for selected 1-(2-pyrimidinyl)piperazine derivatives with sedative-hypnotic activity.

The conformational of selected 1-(2-pyrimidinyl)piperazine derivatives with high sedative-hypnotic activity was analysed and the model bioactive conformations were suggested. Subsequently, the pharmacophores of analysed compounds were designed. It was suggested that the pharmacophore of bioactive derivatives should be composed of 11 features that characterise the binding model of pyrimidinylpiperazine ligands to the binding site at the hypothetic receptor. This 11 feature pharmacophore was compared to three other pharmacophores designed for the selected anxiolytics (benzodiazepines and buspirone analogues) and the sedative-hypnotic agents (benzodiazepines and barbiturates). Several substantial differences between the pharmacophores were found: the number of pharmacophoric features and their distribution in 3-D space were unique for selected groups of compounds that exhibit sedative-hypnotic or anxiolytic activity.

Hypnotics and Sedatives↗

PubMed2001

Metabolism of vanoxerine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine, by human cytochrome P450 enzymes.

Vanoxerine (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine; GBR12909) is a promising agent for the treatment of cocaine dependence. Knowledge of the major pathway for GBR12909 metabolism is important for prediction of the likelihood of drug-drug interactions, which may affect the therapeutic clinical outcome, when this agent is used in cocaine-dependent individuals receiving multiple drug therapy. We studied biotransformation of GBR12909 in human liver microsomes (n = 4), human hepatocytes, and microsomes containing cDNA-expressed human P450 isoforms with GBR12909 concentrations within the range of steady-state plasma concentrations detected in healthy volunteers. A high-pressure liquid chromatography assay was used to measure parent GBR12909 and its primary metabolite. GBR12909 was metabolized by human liver microsomes, hepatocytes, and cDNA-expressed human P450s to a single metabolite. Ketoconazole, a selective inhibitor of CYP3A, reduced GBR12909 biotransformation in human liver microsomes and primary hepatocytes by 92 +/- 2 and 92.4 +/- 0.4%, respectively. Quercetin (an inhibitor of CYP2C8/3A4) was a less effective inhibitor producing 62 +/- 22% inhibition in human liver microsomes and 54 +/- 35% in hepatocytes. Other P450 selective inhibitors did not decrease GBR12909 biotransformation more than 29% in either human liver microsomes or hepatocytes with the exception of chlorzoxazone (CYP2E1), which inhibited GBR12909 biotransformation by 71.4 +/- 18.5% in primary human hepatocytes. Ciprofloxacin (CYP1A2), sulfaphenazole (CYP2C9), quinidine (CYP2D6), chlorzoxazone (CYP2E1), and mephenytoin (CYP2C19) did not demonstrate statistically significant inhibition (p > 0.05) of GBR12909 biotransformation in liver microsomes. cDNA-expressed P450 3A4 metabolized GBR12909 to a greater extent than 2C8 and 2E1. These data suggest the possibility that multiple P450 isoforms may be involved in human GBR12909 metabolism but that CYP3A appears to be the major enzyme responsible for human GBR12909 biotransformation.

Biotransformation↗

PubMedDate not supplied

Novel N-[omega-[4-(2-methoxyphenyl)piperazin-1-yl]-ethyl]pyrid-2(1H)-ones with diversified 5-HT1A receptor activity.

Novel omega-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl derivatives 1-6 containing 4-, 5- and/or 6-arylsubstituted pyrid-2(1H)-one moiety were synthesized. All the new compounds were examined in vitro to assess their 5-HT1A and 5-HT2A receptor affinities. Compounds 3 and 4 with a 5- or a 6-phenylsubstituted pyridone ring demonstrated high 5-HT1A receptor affinity (Ki = 17 and 38 nM, respectively) and were tested in behavioral functional models. Derivative 3 can be regarded as a weak 5-HT1A postsynaptic antagonist, whereas 4 showed features of a weak partial agonist of 5-HT1A receptors (an agonist of pre- and an antagonist of postsynaptic ones). Binding affinities and in vivo results were discussed in comparison with those for the previously described tetramethylene analogs. The obtained results showed that the shortening of the aliphatic chain to two methylene groups exposed the intrinsic activity of the ligand 4 at 5-HT1A receptor sites.

Animals↗