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PubMed2002

Novel soluble cationic trans-diaminedichloroplatinum(II) complexes that are active against cisplatin resistant ovarian cancer cell lines.

Positively charged, water soluble cis/trans-[PtCl(2)(piperazine)(Am1)] (where Am1 = NH(3), n-butylamine, isopropylamine, 4-picoline, piperidine, and piperazine) has significant cytotoxic activity against cisplatin resistant ovarian cancer cells. The charged complexes are taken up by cancer cells much more rapidly than cisplatin and bind to cellular DNA and to calf thymus DNA much faster than cisplatin or transplatin. The platinum-piperazine complexes bind proteins (ubiquitin and myoglobin) very slowly as compared to cisplatin and to their neutral piperidine analogues. Altogether, the results reported here suggest that combination of positively charged ligands with a trans-Pt(II)Cl(2) center may lead to the discovery of platinum complexes that are able to circumvent cisplatin resistance.

Antineoplastic Agents↗
PubMed2002

Synthesis and pharmacological evaluation of 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-phenylpiperazines with clozapine-like mixed activities at dopamine D(2), serotonin, and GABA(A) receptors.

A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a-r) were designed and synthesized as possible ligands with mixed dopamine (DA) D(2)/serotonin 5-HT(1A) affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D(2) like, 5-HT(1A), and 5-HT(2A) receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D(2) like, serotonin 5-HT(1A), and 5-HT(2A) receptors, with IC(50) values ranging from 25 to >10,000 nM. As for the modification of the piperazine N(4)-phenyl ring, the affinities for both D(2) like and 5-HT(1A) receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D(2) like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT(1A) receptors. A quantitative structure-affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D(2) like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a-r to 5-HT(1A) receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT(2A) receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D(2)/5-HT(1A) IC(50) ratio of approximately 1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl(-) currents at recombinant GABA(A) receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.

Animals↗
PubMedDate not supplied

Pharmacokinetics and metabolism of a selective PDE5 inhibitor (UK-343,664) in rat and dog.

1. UK-343,664 is a novel potent and selective PDE5 inhibitor. Plasma clearances in the male and female rat were high (120 and 54 ml min(-1) kg(-1)), giving rise to short elimination half-lives (0.2 and 0.3h respectively). Lower clearance in dog (14 ml min(-1) kg(-1)) was the primary factor resulting in a longer elimination half-life (3.7 h). The higher clearance in rat than dog was in agreement with in vitro metabolism rates in hepatic microsomes. 2. The volume of distribution was lower in rat (1.3-2.11 kg(-1)) compared with dog (4.61 kg(-1)) probably due to increased plasma protein binding in rat (96 versus 81% in dog). 3. Oral bioavailabilities were 2, 12 and 70% in the male and female rat and dog respectively. Tmax < or = 0.5 h in all animals. 4. In multiple oral dose studies, increased systemic exposure was seen with increasing dose up to doses of 200 mg kg(-1) in rat and 150 mg kg(-1) in dog. A marked super-proportional increase in the male rat indicated a capacity-limited clearance at high doses. 5. At the maximal dose of 200 mg kg(-1) in the female rat, no clinical signs were observed after 14 days of treatment. Only minimal signs were recorded in the male rat and dog at the highest dose levels investigated. 6. After single oral or intravenous doses of [14C]-UK-343,664, the majority of radioactivity was excreted in the faeces of both species. 7. UK-343,664 was extensively metabolized in both rat and dog. The major primary pathways in dog involved piperazine N-deethylation and loss of a two carbon fragment from the piperazine ring (N,N'-de-ethylation). More extensive metabolism in the rat included additional notable metalbolites arising from hydroxylation and lactamization of the piperazine ring, which were only minor metabolites in the dog.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1978

An evaluation of levamisole for treatment of ascariasis.

Levamisole (Decaris, Belgium) was tested in Iran, Brazil, and in Mississippi and Louisiana for its efficacy as a single-dose oral treatment for Ascaris infections. Subjects were children ages 2 to 15 years, and numbers treated with levamisole and comparative anthelmintics are as follows: 453 with levamisole; 461 with piperazine citrate; 17 with pyrantel pamoate; and 19 with a placebo. Cure rates and total reduction in mean egg counts observed were 92% and 98% respectively for levamisole and 66% and 90% for piperazine. Sixteen of 17 treated with pyrantel pamoate were cured. In none of the drugs were there notable side reactions, but in all four studies side effects were more frequent with piperazine than with levamisole. Levamisole was found to be a well-tolerated, highly effective single-dose ascaricide. It should prove to be particularly useful for mass chemotherapy in Ascaris control programs.

Adolescent↗
PubMed1997

Structure and serotonin 5-HT2C receptor activity of ortho- and meta-substituted phenylpiperazines.

The structural characteristics of ortho- and meta-substituted phenylpiperazines have been investigated in order to understand their actions at the serotonin 5-HT2C receptor. The crystal structures of the 4-methylated analogues of two phenylpiperazines that are already known as 5-HT2C ligands, 1-(1-naphthyl)-4-methylpiperazine (1NMP) and 1-[(3-trifluoromethyl)phenyl]-4-methylpiperazine (TFMPMP), and those of two novel 5-HT2C ligands, 1-(2-methoxyphenyl)piperazine (oMPP) and 1-(3-methoxyphenyl)piperazine (mMPP), are determined. Molecular mechanics calculations are performed to calculate the energy profiles of six phenylpiperazines for rotation about the central phenyl-nitrogen bond. The activities of several phenylpiperazines, in combination with their crystal structures and conformational characteristics, lead to the hypothesis that the conformation for which the piperazine ring and the phenyl ring are approximately co-planar should be the 5-HT2C receptor 'activating' conformation. This hypothesis is then used to predict the activities of the two novel 5-HT2C ligands oMPP and mMPP. oMPP is predicted to be an antagonist at this receptor, whereas mMPP is predicted to be an agonist. As this prediction was confirmed by in vitro and in vivo tests, the proposed conformation is very likely to be responsible for the activation of the 5-HT2C receptor.

Piperazines↗
PubMed1987

Biochemical and pharmacological characterization of [3H]GBR 12935 binding in vitro to rat striatal membranes: labeling of the dopamine uptake complex.

Binding of the selective dopamine (DA) uptake inhibitor [3H]GBR 12935 to rat striatal membranes was characterized biochemically and pharmacologically. [3H]GBR 12935 binding at 0 degree C was reversible and saturable and Scatchard analysis indicated a single binding site with a KD of 5.5 nM and a Bmax of 760 pmol/mg tissue. [3H]GBR 12935 labeled two binding sites. One binding site was identified as the classic DA uptake site, since methylphenidate, cocaine, diclofensine, and Lu 19-005 potently inhibited [3H]GBR 12935 binding to it. Binding to the second site was inhibited by high concentrations of the above compounds. IC50 values for inhibition of [3H]GBR 12935 binding to the DA uptake site were proportional to IC50 values for inhibition of DA uptake. However, substrates of DA uptake, e.g., DA and 1-methyl-4-phenylpyridine, and DA releasers, e.g., the amphetamines, inhibited [3H]GBR 12935 binding less than DA uptake. Rate experiments excluded the possibility that these "weak" inhibitors affected the binding by allosteric coupled binding sites. The second binding site was not a noradrenergic, serotonergic, or GABAergic uptake site. Neither was it a dopaminergic, acetylcholinergic, histaminic, serotonergic, or adrenergic receptor. However, [3H]GBR 12935 was potently displaced from it by disubstituted piperazine derivatives, i.e., flupentixol and piflutixol. DA uptake and the DA uptake binding site of [3H]GBR 12935 were located primarily in the striatum, but the piperazine acceptor site was distributed uniformly throughout the brain. Also only the DA uptake binding site was destroyed by 6-OH-DA. Thus, [3H]GBR 12935 labels the classic DA uptake site in rat striatum and also a piperazine acceptor site. Substrates for DA uptake and releasers of DA inhibited [3H]GBR 12935 binding with low potency, but did not alter the rate constants for [3H]GBR 12935 binding. Therefore inhibitors of DA uptake label the carrier site and prevent the carrier process.

Animals↗
PubMed1986

A sensitive high performance liquid chromatographic assay of a new metabolite of ampicillin in man.

A sensitive, high-performance liquid chromatographic method has been developed for the determination of piperazine-2,5-dione, a new metabolite of ampicillin, in human urine. Piperazine-2,5-dione was separated from human urine on a C18-column using phosphate buffer-methanol (pH 3.5) as eluent. Subsequently, the effluent underwent a postcolumn reaction with mercurous chloride and was then detected at 305 nm. It was found that piperazine-2,5-dione was also excreted in the urine of a volunteer dosed with ampicillin.

Ampicillin↗
PubMed2004

Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent.

Glucuronides of piperazine hydroxylamines are rarely reported in the literature, and even more rarely are their structures unambiguously identified. One major metabolite was detected by liquid chromatography/mass spectrometry-radioactivity in urine from monkeys treated with the aryl piperazine oral hypoglycemic agent 9-[(1S,2R)-2-fluoro-1-methylpropyl]-2-methoxy-6-(1-piperazinyl) purine hydrochloride (1). The mass spectrum of this metabolite indicated that it was both monooxygenated and glucuronidated on the piperazine ring. Possible structures included the N- or O-glucuronic acid conjugates of a carbinolamine, hydroxylamine, or N-oxide. Treatment with beta-glucuronidase gave a monooxygenated derivative of the parent compound. 1H NMR analysis of either the glucuronic acid conjugate or the monooxygenated product provided insufficient evidence to unambiguously determine their structures. Incubation of 1 with pig liver microsomes resulted in formation of the same monooxygenated derivative derived from beta-glucuronidase treatment of the glucuronide metabolite. This in vitro system was used to generate sufficient material for analysis by 13C NMR, and the metabolite was identified as a hydroxylamine derivative 2. Incubation of the hydroxylamine with monkey liver microsomes and uridine diphospho-5'-glucuronic acid gave the same glucuronic acid conjugate as that observed in monkey urine. 13C NMR analysis of this biosynthetic product led to its unequivocal structure assignment as the O-glucuronic acid conjugate of the hydroxylamine 3.

Administration, Oral↗
PubMed1969

Levamisole in the treatment of ascariasis in children.

Levamisole (the laevorotatory isomer of tetramisole) is a new synthetic anthelmintic. A cure rate of 91% was obtained in a series of 111 ascariasis-infected children treated with a single oral dose of the drug. The failures, who were treated with the drug a second time one week later, were all cured. In a comparative study of levamisole and piperazine citrate in a series of 100 children with ascariasis a cure rate of 92% and 90% was obtained with a single dose of levamisole and piperazine respectively, indicating equal efficacy. Levamisole is better tolerated than piperazine citrate and is virtually free of toxic effects.

Anthelmintics↗
PubMed2004

Studies on 1-arylpiperazine derivatives with affinity for rat 5-HT7 and 5-HT1A receptors.

Several 1-aryl-4-(2-arylethyl)piperazine derivatives were synthesized and tested in-vitro for their binding affinity for 5-HT(7) and 5-HT(1A) receptors. These compounds displayed 5-HT(7 )receptor affinity ranging between K(i) = 474 nM and K(i) = 8.2 nM, besides high affinity for the 5-HT(1A) receptor. Intrinsic activity of the most potent compounds was assessed. 4-[2-(3-Methoxyphenyl)ethyl]-1-(2-methoxyphenyl)piperazine (16) and 1-(1,2-benzisoxazol-3-yl)-4-[2-(3-methoxyphenyl)ethyl]piperazine (20) (K(i) = 24.5 and 8.2 nM, respectively) behaved as partial agonist and full agonist, respectively, when tested for 5-HT(7) receptor-mediated relaxation of substance P-induced guinea-pig ileum contraction.

Animals↗
PubMed1998

Synthesis of substituted chiral piperazones resembling aza-sugars.

(6R)-6-(Hydroxymethyl)piperazin-2-one (1), (6S)-6-(hydroxymethyl)piperazin-2-one (2) and (6S)-6-[(1R, 2S, 3R)-1,2,3,4-tetrahydroxybutyl]piperazin-2-one (3) have been prepared in optically pure forms starting from D-glucosamine hydrochloride (4). The compounds (1-3) were tested for glycosidase inhibition.

Aza Compounds↗
PubMed1978

Levamisole in ascariasis. A multicenter controlled evaluation.

An analysis is presented of 10 clinical studies from various countries where levamisole 50--150 mg was compared to pyrantel, piperazine, and placebo in a total of 1,734 patients, mostly children (levamisole: 830, controls: 904), suffering from ascariasis either as a single infection or usually mixed with other nematode infections. Degree of infection and efficacy of treatment were determined by quantitative coproparasitological methods. Levamisole produced higher cure rates (91%) and egg reduction rates (98%) than pyrantel, piperazine, or placebo. The efficacy of levamisole was unrelated to the patients' sex and age, the severity of infection, the presence of another worm infection, the type of associated worm infections, or the egg-counting technique. The overall incidence of reported adverse reactions was lower after levamisole than after piperazine, pyrantel or placebo; abdominal pain and headache, the most frequent complaints after levamisole, were related to the initial severity of ascariasis. Follow-up examinations 6 months after treatment suggested that levamisole might delay reinfection.

Adolescent↗
PubMedDate not supplied

Application of the isotope technique in pharmacodynamic analysis of penetration of drugs into parasites.

Penetration of piperazine adipate into Ascaris lumbricoides var. suum L. was studied by scintigraphy andautoradiography. The results indicate that anthelminthic drugs, including piperazine, penetrate into the parasite mainly through the mouth or other natural orifices, and only slightly through the cuticle, and that the amount of piperazine that penetrates depende on its concentration in the solution.

Animals↗
PubMedDate not supplied

Pharmacological analysis of the hypothermic effects of NAN-190 and its analogs, postsynaptic 5-HT1A receptor antagonists, in mice.

In this study, we examined the role of 5-hydroxytryptamine (5-HT)1A and alpha1-adrenergic receptors in the hypothermia induced by 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]-piperazine (NAN-190) and its analogs, 1-(2-methoxyphenyl)-4-[(4-succinimido)butyl]piperazine (MM77) and trans-1(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]piperazine (MP245), which--like NAN-190--showed a high affinity for 5-HT1A and alpha1-adrenoceptors. Administration of NAN-190 (a partial agonist of presynaptic and an antagonist of postsynaptic 5-HT1A receptors and alpha1-adrenoceptors), MM77 and MP245 (antagonists of postsynaptic 5-HT1A receptors), as well as 8-OH-DPAT (a 5-HT1A agonist) and prazosin (an alpha1-adrenoceptor antagonist) induced a dose-dependent hypothermia in mice. The silent antagonist of 5-HT1A receptors, WAY 100635, which abolished the hypothermic effect of 8-OH-DPAT, inhibited the hypothermia induced by NAN-190 administered at a dose of 1 mg/kg (but not 2 mg/kg) and by MP245 (0.5 and 1 mg/kg), but failed to change the MM77 (1 and 4 mg/kg)-induced decrease in body temperature in mice. The alpha1-adrenoceptor agonist St 587, which reduced the hypothermic effect of prazosin, inhibited the decrease in body temperature evoked by NAN-190 at the higher dose and by MP245 at both the doses used, but did not affect the MM77-induced hypothermia in mice. The obtained results suggest that the hypothermia in mice induced by NAN-190 and its constrained analog MP245 is connected with stimulation of 5-HT1A receptors and with blockade of alpha1-adrenoceptors, participation of these receptors not being equivalent, though. The origin of the hypothermia evoked by MM77 is still unknown.

Adrenergic alpha-1 Receptor Agonists↗
PubMedDate not supplied

Synthesis, anticonvulsant properties and 5-HT1A/5-HT2A receptor affinity of new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane and [4.5]decane-1,3-dione derivatives.

A series of twenty new N-[(4-arylpiperazin-1-yl)-propyl]-2-aza-spiro[4.4]nonane- and [4.5]decane-1,3-dione derivatives were synthesized and their anticonvulsant activity was evaluated in maximal electroshock (MES) and sc pentertazole (sc PTZ) tests. Their neurotoxicity was examined as well. Although no antiseizure properties of the investigated compounds were found in the MES model, eight of them were active in the sc PTZ test and three, namely 2-{3-[4-(2-fluorophenyl)-piperazin-1yl]-propyl}-2-aza-spiro[4.4]nonane-1,3-dione (7), 2-{3-[4-(2-fluorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3- dione (22) and 2-{3-[4-(3-chlorophenyl)-piperazin-1-yl]-propyl}-7-methyl-2-aza-spiro[4.5]-decane-1,3-dione (23) were classified to the Anticonvulsant Screening Program (ASP) 1 class. In addition, since the investigated compounds belong to a class of long-chain arylpiperazines, their serotonin 5-HT1A and 5-HT2A receptor affinity was determined. All the 2-OCH3 and 3-Cl derivatives were the most potent 5-HT1A receptor ligands (Ki = 24-143 and 70-107 nM, respectively), whereas the highest 5-HT2A affinity was observed for the unsubstituted and 3-Cl derivatives (Ki = 8-66 nM). No correlation between anticonvulsant and serotonergic activity was observed.

Animals↗
PubMed1991

Comparison of serotonin agonistic and antagonistic activities of a new antidepressant agent Trelibet (EGYT-475) and its metabolite EGYT-2760 on isolated rat fundus.

The effects of Trelibet (EGYT-475, N-benzyl-piperazine-picolinyl-fumarate) and its active metabolite (EGYT-2760, N-benzyl-piperazine) on the serotoninergic responses of rat stomach fundus were investigated and compared with those of MCPP (m-chlorophenyl-piperazine) which is the common metabolite of the arylpiperazine antidepressants Trazodone and Etoperidone. The contraction inhibitory potencies of the agents were determined on the equipotent contractions (EC50) to serotonin (5-HT) and prostaglandin F2 alpha (PGF2 alpha). Isotonic contractile responses to 5-HT were not affected by EGYT-475, however, both EGYT-2760 and MCPP produced concentration related and reversible inhibition of the serotoninergic responses. The IC50 values for EGYT-2760 and MCPP were 40.5 +/- 7.5 mumol/l and 125 +/- 35 nmol/l, respectively. The inhibition was selective for the serotoninergic responses, as the equipotent responses to PGF2 alpha were not affected. EGYT-2760 and MCPP displayed not only 5-HT antagonistic, but also partial agonistic activities on the rat fundus preparation. Maximum contractile response of the fundus preparation to MCPP was approximately 25%, to EGYT-2760 was 10% of the maximum response to 5-HT.

Animals↗
PubMed1990

Characterization of serotonergic receptors mediating contraction of ovine umbilical artery.

Responses to serotonergic agonists were studied in isolated umbilical arteries obtained from fetal lambs within 2 weeks of term. The order of potency of the agonists was determined to be 2,5-dimethoxy-4-methyl-amphetamine (DOM) greater than 5-hydroxytryptamine (5-HT) greater than alpha-methyl-5-HT greater than 1-(3-chlorophenyl) piperazine = m-trifluoromethyl-phenylpiperazine greater than 8-hydroxy-dipropylaminotetralin greater than 2-methyl-5-HT greater than 1-(2-methoxyphenyl) piperazine. Variations in the sensitivity and potency of the agonists results primarily from the variation in the affinity for the 5-HT2 receptor and less so in the efficacy, alpha-Methyl-5-HT was a full agonist compared to 5-HT. The others were partial agonists. The mean KA values for 5-HT and DOM were 4.71 +/- 0.62 x 10(-7) and 0.36 +/- 0.04 x 10(-7) M, respectively. Contractions to 5-HT and DOM were antagonized by ketanserin with pA2 values being 9.4 and 9.1, respectively, suggesting that they act on the same receptor and that their responses are mediated by 5-HT2 receptors. Contractile responses to 8-hydroxy-dipropylaminotetralin, 2-methyl-5-HT and the phenylpiperazines [m-trifluoromethyl-phenylpiperazine and 1-(3-chlorophenyl) piperazine] were also blocked by ketanserin (10(-8) M), indicating that contractions produced by these agonists were mediated by 5-HT2 receptors. No antagonism by MDL 72222 (3-tropanyl-3,5-dichlorobenzoate) of responses to 5-HT indicates that 5-HT3 receptors are not present in this tissue.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1984

[The almitrine dimesylate molecule. Various structure-activity relationship aspects].

The improvement in PaO2 induced by almitrine bismesylate is due to better adjustment between alveolar ventilation and lung perfusion (VA/Q ratio). Experimental studies and clinical pharmacology suggest that this improvement involves changes in both alveolar ventilation and pulmonary circulation. By synthesizing and testing compounds with different structures in a series of trisubstituted triazines, it has been possible to determine qualitative structure-activity relationships and to select almitrine bismesylate is due to better adjustment between the greatest, most rapid and longest lasting increase in PaO2. Almitrine bismesylate is a molecule with three components: a di-allylamino-triazine group, a piperazine ring and a bis-parafluoro-benzhydryl fraction. The di-allylamino-triazine group may be regarded as responsible for the effects on blood gases and ventilation. The presence of two allyl-amino substituents is an absolute prerequisite, and the triazine ring can possibly be replaced by a very similar pyrimidine ring. The piperazine ring is mainly responsible for dissociation between the effects on blood gases and on ventilation as well as for the general kinetics of the biological action of the drug. Molecules of this series which have a pyrrolidine ring or an azetidine ring instead of a piperazine ring do increase PaO2 but much more slowly than almitrine bismesilate. Finally, the bis-parafluoro-benzhydryl group modulates the intensity and duration of the effects on blood gases. Other constituents, such as the cinnamylamino, alpha-cyclohexyl-parafluorobenzyl, beta-naphthyl methyl or 5-fluoro-benzofluranyl-methyl groups also exert favourable biological activities comparable to those of the bis-parafluorobenzhydryl group characteristic of almitrine bismesylate.

Almitrine↗