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PubMed2005

N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy').

3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') is an illicit drug that stimulates the release of serotonin (5-HT) and dopamine (DA) from neurons. Recent evidence reveals that drug users are ingesting piperazine analogs, like 1-benzylpiperazine (BZP, or 'A2') and 1-(m-trifluoromethylphenyl)piperazine (TFMPP, or 'Molly'), to mimic psychoactive effects of MDMA. In the present study, we compared the neurochemistry of MDMA, BZP, and TFMPP in rats. The effects of MDMA, BZP, and TFMPP on transporter-mediated efflux of [3H]5-HT and [3H]MPP+ (DA transporter substrate) were determined in synaptosomes. The effects of drugs on extracellular levels of 5-HT and DA were examined using in vivo microdialysis in conscious rats. MDMA evoked transporter-mediated release of [3H]5-HT and [3H]MPP+. BZP released [3H]MPP+, whereas TFMPP was a selective releaser of [3H]5-HT. MDMA (1-3 mg/kg, i.v.) increased dialysate 5-HT and DA in a dose-related fashion, with actions on 5-HT being predominant. BZP (3-10 mg/kg, i.v.) elevated dialysate DA and 5-HT, while TFMPP (3-10 mg/kg, i.v.) elevated 5-HT. Administration of BZP plus TFMPP at a 1:1 ratio (BZP/TFMPP) produced parallel increases in dialysate 5-HT and DA; a 3 mg/kg dose of BZP/TFMPP mirrored the effects of MDMA. At a 10 mg/kg dose, BZP/TFMPP increased dialysate DA more than the summed effects of each drug alone, and some rats developed seizures. Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug-drug synergism may occur when piperazines are coadministered at high doses.

Animals↗

PubMed2004

In vivo metabolism of the new designer drug 1-(4-methoxyphenyl)piperazine (MeOPP) in rat and identification of the human cytochrome P450 enzymes responsible for the major metabolic step.

1. The in vivo metabolism of 1-(4-methoxyphenyl)piperazine (MeOPP), a novel designer drug, was studied in male Wistar rats. 2. MeOPP was mainly O-demethylated to 1-(4-hydroxyphenyl)piperazine (4-HO-PP) in addition to degradation of the piperazine moiety. 3. O-demethylation, the major metabolic step, was studied with cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes in pooled human liver microsomes (pHLM) and in single donor human liver microsomes with CYP2D6 poor metabolizer genotype (PM HLM). 4. CYP2D6 catalysed O-demethylation with apparent Km and Vmax values of 48.34 +/- 14.48 microM and 5.44 +/- 0.47 pmol min(-1) pmol(-1) CYP, respectively. pHLM catalysed the monitored reaction with an apparent Km = 204.80 +/- 51.81 microM and Vmax = 127.50 +/- 13.25 pmol min(-1) mg(-1) protein. 5. The CYP2D6-specific chemical inhibitor quinidine (1 and 3 microM) significantly inhibited 4-HO-PP formation by 71.9 +/- 4.8% and by 98.5% +/- 0.5%, respectively, in incubation mixtures with pHLM and 200 microM MeOPP. 6. O-demethylation was significantly lower in PM HLM compared with pHLM (70.6% +/- 7.2%). 7. These data suggest that polymorphically expressed CYP2D6 is the enzyme mainly responsible for MeOPP O-demethylation.

Algorithms↗

PubMed1997

Preliminary evaluation of a fixed dose of zwitterionic piperazine (TVZ-7) in clinical cancer.

One of the zwitterion buffers that has shown significant therapeutic value in the treatment of pain due to cancer, immunologically mediated diseases, and the pain associated with these conditions is in the class of N-substituted amino-sulfonic acids known as "Good Buffers." Zwitterion molecules have neither a negative nor a positive charge; thus, they are neutral. 4-(2 Hydroxyethyl)-1-piperazine ethane sulfonic acid has been used for several decades in artificial biological systems (tissue culture) as a buffer. We have been exploring the therapeutic value of these zwitterionic buffers. Pilot animal studies have demonstrated that zwitterionic piperazine increases bone marrow hypercellularity and induces extramedullary hematopoiesis. We report the initial human use to explore dose toxic and physiologic effects of a fixed dose of the zwitterionic piperazine molecule. There appears to be potential therapeutic value in the treatment of pain due to cancer, and there are preliminary indications that tumor activity and tumor size are reduced. Immunologically mediated diseases may also be affected. Toxicity is low and there appear to be minimal side effects.

Adult↗

PubMed1974

Interaction between piperazine and chlorpromazine.

The interaction between piperazine and chlorpromazine has been studied in rats and mice. Piperazine administered a few hours previously potentiated the action of chlorpromazine on the central nervous system. No such interaction was found between piperazine and prochlorperazine.

Animals↗

PubMed2005

In-vivo effects of the 1,2,4-piperazine derivatives MM5 and MC1, putative 5-HT agonists, on dopamine and serotonin release in rat prefrontal cortex.

Two 1,2,4-substituted derivatives of piperazine were tested for their effect on dopamine and serotonin (5-HT) release in rat prefrontal cortex. Both compounds, 1-[4-(4-chinolin-2-yl-piperazin-1yl)-butyl]piperidin-2-on (MM5) and 1-[4-(2-methyl-4-chinolin-2-yl-piperazin-1-yl)-butyl]-8-azaspiro [4.5]decano-7,9-dion (MC1), produced hypothermia in mice and showed affinity for 5-HT1A receptors in-vitro. Like the selective 5-HT1A agonist 8-OH-DPAT (0.1 mg kg(-1)), MM5 given peripherally (30 mg kg(-1)) decreased the extracellular 5-HT level in rat prefrontal cortex, while MC1 suppressed 5-HT release at a higher dose (40 mg kg(-1)), but not at a lower one (30 mg kg(-1)). The effect of both compounds on 5-HT release was abolished by WAY 100635 (0.3 mg kg(-1)). MC1 (30 and 40 mg kg(-1)), but not MM5, raised cortical dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and extracellular homovanillic acid (HVA) levels. The effect of MC1 on dopamine release was reversed by neither WAY 100635 nor the non-selective 5-HT2 antagonist ritanserin (2 mg kg(-1)). However, ritanserin prevented the effect of the higher dose of MC1 on 5-HT release. The results of this study suggest that MM5 exhibits the profile of a 5-HT1A agonist devoid of dopaminergic activity. MC1 seems to possess moderate agonist activity at 5-HT1A and 5-HT2A receptors, while acting on 5-HT release in the rat prefrontal cortex. However, the facilitation of dopamine release by this compound does not seem to be related to its affinity for 5-HT1A and 5-HT2A receptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1982

The effect of serotonin agonist 1-(trifluoromethylphenyl)-piperazine on corticotropin releasing factor and arginine vasopressin in rat hypothalamic nuclei.

Effects of 1-(m-trifluoromethylphenyl)-piperazine, a serotonin agonist, were examined on rat plasma levels of adrenocorticotropin (ACTH) and arginine vasopressin (AVP), and on hypothalamic contents of corticotropin releasing factor (CRF) and AVP, to investigate the role of brain serotonin in ACTH regulation. Both plasma ACTH and AVP levels increased markedly 30 min after injection of the compound and were still elevated at 80 min. CRF and AVP contents in the median eminence decreased 30 min after injection but returned to the basal levels by 80 min. The AVP content in the supraoptic nucleus was elevated 80 min after injection. The CRF and aVP content did not significantly change in the paraventricular, suprachiasmatic and arcuate nuclei. Serotonin or 1-(m-trifluoromethylphenyl)-piperazine did not stimulate the release of ACTH in pituitary cell cultures. These results suggest that both CRF and AVP were secreted into the portal vessels by 1-(m-trifluoromethylphenyl)-piperazine to release ACTH from the anterior pituitary and that both the ACTH and AVP release were stimulated via the brain serotonergic mechanism.

Adrenocorticotropic Hormone↗

PubMed2005

1,4-bis(3-aminopropyl)piperazine libraries: from the discovery of classical chloroquine-like antimalarials to the identification of new targets.

The purpose of this review is to provide an update on our work based on the 1,4-bis(3-aminopropyl)piperazine skeleton and how it allowed our group to validate a new target. After a brief introduction where we will relate the way this substructure was introduced in our 4-aminoquinolinyl derivatives, we will present first the different libraries synthesized around this moiety: (1) libraries of sulfonamides, amides and amines derived from 4-aminoquinolines and, (2) libraries where the 4-aminoquinoline nucleus is replaced. High throughput evaluation of biological activity and physicochemical parameters will be presented. The evaluation of the anti-malarial activity of the compounds will be discussed in the light of a chloroquine-like mechanism (accumulation in the acidic food vacuole and inhibition of beta-hematin formation). In a second part we will present active 1,4-bis(3-aminopropyl)piperazine as tools for identification and/or validation of new antimalarial targets. Fluorescence assays on some derivatives show that they are surprisingly localized outside the food vacuole, suggesting the existence of other target(s). Secondly, we will present a library of 1,4-bis(3-aminopropyl)piperazine as inhibitors of the cytosolic aminopeptidase Pfa-M1, a new potential target for antimalarials.

Antimalarials↗

PubMed1993

Some properties of new DNA-specific bisbenzimidazole fluorochromes without a piperazine ring.

Three new bisbenzimidazole (BBI) compounds, which differ from Hoechst 33258 mainly by substitution of a N-dimethylaminopropylcarboxamide group in place of the N-methylpiperazine ring, were studied for their DNA- and AT-base pair specificity as well as for their ability to be quenched by incorporated 5-bromodeoxyuridine (BrdU). Each of them had DNA binding specificity comparable to or greater than that of Hoechst 33258 and each had a greater specificity for AT-rich regions than did Hoechst 33258. The dependence of fluorescence of new dyes on the BrdU-incorporation into DNA is different from that of Hoechst 33258 and related compounds with piperazine ring. The quenching effect is much weaker, and two of the new compounds (BBI-1 and BBI-2) even show somewhat enhanced binding (fluorescence) at lower concentrations. Certain BBI dyes without piperazine ring may have some advantage over Hoechst for accurate DNA (AT-specific) measurements. The piperazine ring appears to play an important role in the yet unknown mechanism of Hoechst quenching by incorporated BrdU.

Adenine↗

PubMedDate not supplied

Synthesis and antiaggregatory activity of RGD-peptidomimetics based on 4-oxo-4-(piperazine-1-yl)butyric acid as Arg-mimetic.

A scheme of synthesis of previously obtained RGDF-peptidomimetic-4-oxo-4-(piperazine-1-yl)butyrylglycyl-D,L-beta-phenyl-beta-alanine (I), was simplified. The novel RGDF-peptidomimetic -4-oxo-4-piperazine-1-yl)butyryl-glycyl-L-aspartyl-L-phenylalanine (II) was synthesized with the use of 4-oxo-4-(piperazine-1-yl)butyric acid as arginyl mimetic. The obtained pseudopeptides were able to inhibit both platelet aggregation in human blood and binding of fibrinogen to its receptor.

Blood Platelets↗

PubMed2004

New 3-[4-(2,3-dihydro-14-benzodioxin-5-yl)piperazin-1-yl]-1-(5-substituted benzo[b]thiophen-3-yl)propanol derivatives with dual action at 5-HT(1A) serotonin receptors and serotonin transporter as a new class of antidepressants.

Compounds derived from 2,3-dihydro-(1,4-benzodioxin-5-yl)piperazine and benzo[b]thiophene with different substituents in 5 position (H, F, NO2, NH2, CH3 and OH) have been synthesized in order to obtain new dual antidepressant drugs. The final compounds were evaluated for in vitro 5-HT(1A) receptor affinity and serotonin reuptake inhibition by radioligand assays. Compounds 1-(5-nitrobenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl]propan-1-ol (4c) (Ki = 6.8 for 5-HT(1A) receptor and Ki = 14 for 5-HT transporter) and 1-(5-hydroxybenzo[b]thiophen-3-yl)-3-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazin-1-yl] propan-1-ol (4f) (Ki = 6.2 for 5-HT(1A) receptor and Ki = 18.2 for 5-HT transporter) showed the best results for both activities.

Animals↗

PubMed2004

Synthesis and anticonvulsant activity of some piperazine derivatives.

Various 1,4-substituted derivatives of piperazine (I-XII) were synthesized and evaluated for their anticonvulsant activity in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (ScMet)--induced seizures and for neurotoxicity (TOX) in the rotorod test in mice and rats. The most promising compounds seem to be 1-[(2,4,6-trimethyl)-phenoxyethyl]-4-(2-hydroxyethyl)-piperazine dihydrochloride (II) and 1,4-bis-[(4-chloro-3-methyl)-phenoxyethyl]-piperazine dihydrochloride (X) which displayed anti-MES activity with their protective index (PI) higher than that for valproate II (rats), X(mice)).

Animals↗

PubMed1991

[Immunomodulation in patients with cavernous kidney tuberculosis using piperazine adipinate and amniocene].

Findings of a complex immunologic examination of 138 patients with active cavernous tuberculosis of the kidneys concurrent with secondary immunodeficiency are presented. Biostimulators and immunomodulating drugs were administered as conservative treatment in this case. Changes in cellular and humoral immunity indices as well as those of the mononuclear-phagocyte system before and after treatment were traced in the groups of patients receiving biogenic stimulators (such, as aloe extract, vitreous body, plasmol, Fibs) and immunoregulating drugs (like piperazine adipinate and injected amniocene). It was found that the biogenic stimulators fail to have a pronounced effect on the immunologic indices. The inclusion of piperazine adipinate and injected amniocene into a complex of antibiotic and chemotherapy brings about a significant improvement of the cellular immunity indices and the mononuclear-phagocyte system function which are inhibited to a greater extent in patients with active destructive nephrophthisis. A recommended use of piperazine adipinate and amniocene as adjuncts to a complex treatment has been proved in patients of this category by means of clinicoimmunologic correlations.

Adjuvants, Immunologic↗

PubMed1987

The effect of piperazine adipate and parbendazole on the carbohydrate metabolism of Ascaridia galli and Heterakis gallinae.

Carbohydrate metabolism of Ascardia galli and Heterakis gallinae was studied after their exposure in vitro to 10(-2) to 10(-5) M piperazine adipate and parbendazole for 10 to 60 min. Following treatment with 10(-2) M piperazine adipate O2 uptake was reduced by 87% in A. galli and 70% in H. gallinae, while parbendazole (10(-2) M) reduced O2 uptake by 70% and 86%, respectively. Glycogen contents were reduced significantly by 10(-2) M piperazine adipate in both the worms, while lactic acid level was enhanced. Parbendazole, however, did not cause any significant change in glycogen contents and lactic acid level in either parasite.

Animals↗

PubMed1979

Anticonvulsant effects of benzhydryl piperazines on maximal electroshock seizures in rats.

The anticonvulsant effects of four benzhydryl piperazines, SC-13504 (ropizine, an anticonvulsant), hydroxyzine (HDX, an anxiolytic), chlorcyclizine (CCZ, an antihistaminic) and buclizine (BUC, an antihistaminic), were investigated utilizing a modified maximal electroshock seizure test in rats. In addition to detecting the presence or absence of tonic hindlimb extension, the modified method quantified various phases of the seizure. All four benzhydryl piperazines exhibited anticonvulsant activity in maximal electroshock seizure, but SC-13504 was similar in efficacy to phenobarbital and phenytoin, and much more effective than HDX, CCZ or BUC. Additionally, SC-13504 possessed a therapeutic index much greater than any of the compounds tested. The duration of action of the benzhydryl piperazines, in hours was: SC-13504, 0.5 to 8; HDX, 0.5 to 2; CCZ, 0.5 to 16; and BUC, 2 to 8. Buc and CCZ are postulated to be converted to active anticonvulsant metabolites.

Animals↗

PubMed1978

[Piperazine intoxication in long-term hemodialysis].

A 35-year-old patient with terminal renal failure who had received 30 mg piperazine hexahydrate/kg body weight daily for 10 days for oxyuriasis was subsequently admitted to hospital in precoma with severe clinical symptoms not unlike those observed in so-called dialysis dementia: loss of consciousness, dysarthria, apraxia, clonic spasms, tremor, muscular weakness, dropping of objects, inability to think clearly and/or hallucinations. The EEG showed disturbances with diffuse, multifocal delta waves. Under maintenance hemodialysis the patient became asymptomatic one week after discontinuation of the piperazine therapy. Piperazine is contraindicated in patients with renal failure.

Adult↗

PubMed1982

Piperazine-induced occupational asthma.

Asthmatic reactions were studied among some 130 factory workers who handled amines and other chemicals. Among present employees, we found 15 cases of asthma associated with occupational exposure to chemicals; among former employees there were at least 18. The inducing agent was judged to be piperazine in 29 persons and ethylenediamine (EDA) in three. The asthma was of the late or dual type; immediate reactions alone were to seen. No one had attacks of asthma before employment, and atopic subjects were not preferentially affected. Routine spirometry revealed airway obstruction in fewer than half of the recent cases. Tests of nonspecific bronchial reactivity with methacholine in six subjects with recent asthma showed hyperactivity in five, while tow subjects with earlier asthma did not have hyperactivity. Bronchial provocation tests with piperazine in one subject were positive both in the factory and in the laboratory. The level of piperazine was 1.2 mg/m3 time-weighted average (TWA) in a work place associated with induction of the asthmatic state, and 0.3 mg/m3 in a place connected with attacks in "sensitized" subjects.

Adult↗

PubMed1976

[Tetramisol, piperazine, and metrifonate treatment of experimental invasion by Ascaridia galli in chickens of differents ages].

The authors studied the anthelminthic effectiveness of a single peroral application of tetramisol (40 mg per 1 kg 1. w.), piperazine (500 mg per 1 kg 1. w.) and metriphonate (50 mg per 1 kg 1.w.) in the artificial invasion by Ascaridia galli. A set of 118 chickens of the White Leghorn breed were subjected to a single invasion by 3000 or 1500 invasive eggs at the age of 6, 36, and 48 days. The inteseffectiveness and extenseffectiveness of the treatment with the tested preparations were examined on the fifteenth day after invasion; the examination was based on the findings of ascarids in the helminthological dissection performed 48 hours on the findings of ascarids in the melminthological dissection performed 48 hours after therapy. The numbers of ascarids in the tested animals were compared with those in the controls. A histological examination was carried out to study the tissue reaction in the intestine, liver, spleen, kidneys, heart, and brain. Tetramisol showed the highest effectiveness. The intenseffectiveness of this substance reached 89-100% in young as well as older chickens. Piperazine had a good effectiveness in older chickens (61-83%); in young chickens it was entirely ineffective. The intenseffectiveness percentage of metriphonate was almost at a zero level. The extenseffectiveness of tetramisol ranged between 20 and 100% (the low values are characteristic of a severe course of invasion). Piperazine showed an extenseffectiveness ranging from 17 to 67% only in older chickens in cases of a mild invasion; otherwise it was equal to zero. Metriphonate was entirely ineffective. The reflection of ascaridiasis in the tissue reaction of the host manifested itself as granulomatous changes in intestinal mucous membrane, as multiplied histiocytic elements and plasma cells, and inflammatory lymphocytic infiltrates in the liver parenchyma.

Age Factors↗

PubMedDate not supplied

Colorimetric determination of piperazine.

A sensitive method for the quantitative determination of piperazine is described. The method is precise and responds linearly from 25 g to 500 mug and above of the material. The procedure is based on the formation of a complex of piperazine with reineckate in neutral or acid medium. The complex can be separated by centrifugation. It is then dissolved in acetone and estimated at 530 nm in a colorimeter. Piperazine present in trichloroacetic acid extractrs of biological samples can also be estimated by this method.

Animals↗