Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Piperazines”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,549 records · Page 86Linked to original sources
PubMed1996

Evaluation of phenylpiperazines as targeting agents for neuroblastoma.

The potential of radiolabelled phenylpiperazines as agents for the detection and therapy of tumours of neural crest origin was evaluated by in vitro pharmacological studies with human neuroblastoma cell lines [SK-N-SH and SK-N-BE(2C)], and in vivo by biodistribution measurements. The ability of phenylpiperazines: 4-phenyl-piperazine (PP), 1-carboxamidino-4-phenyl-piperazine (CAPP), [4-(3-chlorophenyl)-piperazine (mCPP), 4-(3-trifluoro methyl phenyl)-piperazine (TFMPP), and (1,1-dimethyl-4-phenyl)-piperazinium hydrochloride (DMPP) and chlorophenyl hydroxypiperidine [CP(OH)P], to inhibit MIBG uptake by neuroblastoma cells was determined by incubation with [125I]MIBG (0.1 microM) for 2 h in the presence of varying concentrations (10(-8)-10(-3) M) of ligand. For measuring uptake, cells were incubated with [125I]IPP (0.1 microM) and cell-associated radioactivity was measured at various times. Retention was studied by incubating cells in the presence of [125I]IPP (0.1 microM) for 2 h, followed by replacement with drug-free medium and determination of cell-bound radioactivity. Selectivity of [125I]IPP uptake was studied by inhibition studies with MIBG, DMI, 5HT and phenylpiperazines. The biodistribution of [125I]IPP was measured in normal rats at 0.083, 0.5, 1, 2 and 24 h (six animals per group). The IC50S (microM) for inhibition of [125I]MIBG uptake were: PP, 1.5; CPP, 2.5; CAPP, 2.5; DMPP, 5; CP(OH)P, 30 and TFMPP, 65. The rate of cellular uptake of [125I]IPP was greatest between 0 and 60 min and decreased after 60 min, similar to MIBG. After an initial rapid washout of approximately 50% of the radioactivity, retention remained constant for 3 h. The IC50S (microM) for inhibition of [125I]IPP uptake were: MIBG, 18-25; DMI, 0.6-1.5; 5HT, > 100; IPP, 1.8-2.5; CPP, 7.0-9.0 and TFMPP, > or = 20. The in vivo studies demonstrated a pattern of distribution similar to MIBG. The results demonstrate that phenylpiperazines display significant affinity for neuroblastoma with uptake and retention characteristics similar to MIBG.

3-Iodobenzylguanidine↗
PubMed1994

[3H]GBR-12935 binding to cytochrome P450 in the human brain.

The presence of multiple [3H]GBR-12935 binding sites in the human brain has been revealed in several recent studies. One site represents the dopamine uptake site. In rat brain it was demonstrated that [3H]GBR-12935 also binds to nondopaminergic "piperazine acceptor sites." One of these sites has been identified as cytochrome P450IID1 in canine brain. [3H]GBR-12935 binding to the piperazine acceptor sites in the human brain was investigated in the present study. A pharmacological definition of the piperazine acceptor sites is presented: the [3H]GBR-12935 binding fraction that could be discriminated by 10 microM GBR-12909 in the presence of 0.3 microM mazindol. This binding fraction was saturable, with binding affinity in the range of 3-8 nM. It was also demonstrated that the piperazine acceptor or cytochrome P450-sensitive drugs cis-flupentixol and proadifen (SKF 525 A) compete for the same binding sites, suggesting the cytochrome P450 nature of the binding. The findings presented support the proposal that at least part of this fraction represents cytochrome P450IID6, the human form of P450IID1. The distribution of [3H]GBR-12935 binding to the suggested P450IID6-site in 12 brain regions was examined, without significant differences in binding densities between the regions. The significance of the present findings on the cytochrome P450 system in brain is discussed.

Aged↗
PubMed1970

Aspects of the pharmacology of a new anthelmintic: pyrantel.

1. The pharmacological properties of an anthelmintic, pyrantel, and some of its analogues have been described and compared with piperazine in a variety of vertebrate and helminth preparations.2. Pyrantel and its analogues in common with nicotine and decamethonium cause spastic paralysis in chicks and contracture of the chick semispinalis and toad rectus abdominis muscles.3. In the soleus and anterior tibialis muscles of the cat, pyrantel in large amounts caused a short-lived neuromuscular block that was preceded by initial depolarization.4. In preparations from cat and rat, pyrantel showed properties common to both competitive and depolarizing neuromuscular blocking drugs.5. Pyrantel blocked the contracture evoked by transmural stimulation and caused a marked contracture of the worm. Piperazine caused a gradually developing reduction in the responses to transmural stimulation and no contracture.6. Pyrantel and its analogues caused a slowly developing contracture of strip preparations of Ascaris, being more than 100 times more active than acetylcholine in this respect. Piperazine caused a relaxation of Ascaris strip preparations and in common with (+)-tubocurarine blocked the responses to acetylcholine and pyrantel analogues on this preparation.7. Pyrantel caused depolarization and increased spike discharge frequency in single muscle cells of Ascaris, these changes being accompanied by increase in tension. Piperazine, on the other hand, caused hyperpolarization and reduction in spike discharge frequency and relaxation, and antagonized the effects of pyrantel.

Animals↗
PubMed1990

Distribution of radioactively labelled eltoprazine in rat and dog.

Eltoprazine labelled with 14C either in the phenyl or the piperazine ring was administered orally to rats and dogs. While distribution of radioactivity was not affected by the position of label during the first hours after dosing, from six hours onward concentrations of radioactivity in the organs of rats were higher after [14C]piperazine-labelled eltoprazine. In most organs, radioactivity originating from the [14C]phenyl-labelled compound was detectable up to 72 hours, while [14C]piperazine-labelled material could still be detected 384 hours after dosing. These results suggest that the piperazine ring may be broken down to aliphatic amines which are retained in the body. Quantitatively, however, this is of minor importance, representing about 1% of the dose. With either label, the highest concentrations of the radiolabel were found in liver and kidney. Excretion of radioactivity in rat and dog urine and faeces was not influenced by the position of the radiolabel.

Animals↗
PubMed1992

Oxidative metabolism of flunarizine in rat liver microsomes.

The oxidative metabolism of flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to 1-[bis-(4-fluorophenyl)methyl]piperazine (M-1), 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'-hydroxyphenyl)-2- propenyl]piperazine (M-2) and 4,4'-difluorobenzophenone (M-3) has been studied in liver microsomes of Wistar and Dark Agouti (DA) rats. Kinetic analysis demonstrated a sex difference (male > female) in the formation of M-1 and M-3, but not in that of M-2 in Wistar rats. Comparison of the kinetic data of FZ with those of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ], a prototypic and unfluorinated drug (Kariya et al., Biochem. Pharmacol., in press) revealed that the formation clearances (Clfs) estimated by Vmax/km for the ring hydroxylated metabolites of FZ and CZ are higher than those for the N-dealkylated metabolites of these drugs in female rats. Furthermore, the introduction of two fluorine atoms to CZ (forming FZ) decreased the Clfs for most of metabolites, especially for the N-dealkylated product, M-3. The formation of the metabolites from FZ was suppressed by carbon monoxide and SKF 525-A, and only the ring hydroxylation forming M-2 was significantly lower in female DA than in female Wistar rats. These results suggest that the microsomal oxidation of FZ is mediated by cytochrome P450, and that a cytochrome P450 isozyme(s) belonging to the CYP2D subfamily is involved in the ring hydroxylation of FZ forming M-2.

Animals↗
PubMed1988

Properties of some 1-arylpiperazines as antagonists of stereotyped behaviors mediated by central serotonergic receptors in rodents.

This investigation evaluated the effects of the 1-arylpiperazines (1-(1-naphthyl)piperazine (1-NP), 1-(2-[4-aminophenylethyl]-4-[3-trifluoromethylphenyl]piperazine (PAPP), 1-(3-trifluoromethylphenyl)piperazine (TFMPP) and 1-(3-chlorophenyl)piperazine (mCPP) on head-twitching elicited by central 5-hydroxytryptamine2, (5-HT2) agonists and on the 5-HT motor syndrome associated with stimulating 5-HT1A receptors in rodents. 1-NP (0.25-16.0 mumol/kg i.p.) dose-dependently inhibited head twitching produced by carbidopa (100 mumol/kg i.p.) plus 5-hydroxy-L-tryptophan (1000 mumol/kg i.p.) in mice. Pretreatment with 4 mumol/kg of 1-NP shifted the entire dose-response curve for head-twitching induced by quipazine (0.33-46.7 mumol/kg i.p.) to the right without reducing locomotor stimulation produced by quipazine (8 mumol/kg) in mice placed in novel photocell cages. 1-NP, PAPP, TFMPP and mCPP (8 mumol/kg) antagonized twitching after 5-methoxy-N,N-dimethyltryptamine (100 mumol/kg i.p.) or 5-hydroxy-L-tryptophan. In rats, these arylpiperazines (1-32 mumol/kg) dose-dependently antagonized twitching elicited by quipazine (10 mumol/kg) without producing correlated alterations in locomotion. 1-NP, PAPP, and mCPP were equipotent and 6-fold more potent than TFMPP against twitching. None of these arylpiperazines caused twitching. 1-NP (4 mumol/kg) also antagonized twitching following the direct 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (6 mumol/kg i.p.) but not after the thyrotropin releasing hormone analog MK-771 (20 mumol/kg i.p.) in rats. Larger doses of 1-NP (4-32 mumol/kg) and PAPP (64 mumol/kg) but not TFMPP or mCPP (16-128 mumol/kg), also reduced the incidence of the 5-HT syndrome produced by 5-methoxy-N,N-dimethyltryptamine (30 mumol/kg) in rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2005

Structural characterization and DNA interactions of new cytotoxic transplatin analogues containing one planar and one nonplanar heterocyclic amine ligand.

trans-Diaminedicholoroplatinum(II) complexes with one planar and one non-planar heterocyclic amine ligand were designed as new potential antitumor drugs. The X-ray crystallographic structures of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl revealed that the piperidine and piperazine ligands bind to the platinum through the equatorial position and that the ligands adopt the chair conformation. The nonplatinated amine of the piperazine can form hydrogen bonds with atoms that are approximately 7.5 A away from the Pt binding site. DNA is considered a major pharmacological target of platinum compounds. Hence, to expand the database correlating structural features of platinum compounds and DNA distortions induced by these compounds, which may facilitate identification of more effective anticancer platinum drugs, we describe the DNA binding mode in a cell-free medium of trans-[PtCl2(4-picoline)(piperidine)] and trans-[PtCl2(4-picoline)(piperazine)].HCl. Interestingly, the overall impact of the replacement of the second ammine group in transplatin by the heterocyclic ligands appears to change the character of the global conformational changes induced in DNA towards that induced by cisplatin. The clinical ineffectiveness of the parent transplatin has been proposed to be also associated with its reduced capability to form bifunctional adducts in double-helical DNA. The results of the present work support the view that replacement of both ammine groups of transplatin by heterocyclic ligands enhances cytotoxicity probably due to the marked enhancement of the stability of intrastrand cross-links in double-helical DNA.

Antineoplastic Agents↗
PubMed1992

Oxidative metabolism of cinnarizine in rat liver microsomes.

The oxidative metabolism of cinnarizine (CZ) [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)-piperazine] to 1-(diphenylmethyl)piperazine (M-1), 1-(diphenylmethyl)-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine (M-2), benzophenone (M-3) and 1-[4'-hydroxyphenyl)-phenylmethyl]-4-(3- phenyl-2-propenyl)piperazine (M-4) has been studied in rat liver microsomes. In Wistar rats, kinetic analysis revealed sex differences (male > female) in the Km values for formation of all the metabolites and the Vmax values for the formation of M-1, M-3 and M-4. The reactions required NADPH, and were inhibited by carbon monoxide and SKF 525-A. Only M-2 formation was suppressed by sparteine or metoprolol, and was significantly lower in female Dark Agouti rats than in Wistar rats of both sexes. The results suggest that CZ is oxidized by cytochrome P450, and M-2 formation is related to debrisoquine/sparteine-type polymorphic drug oxidation.

Animals↗
PubMed1995

Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine.

Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 mumol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'- hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout the experiments. The concentrations obtained after the 30 doses were in the order of FZ > F-2 > CZ > C-2 for the plasma and of F-2 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations of C-2 and F-2 were 2.4 and 3 times higher than those of the parent drugs. Binding affinities of CZ, FZ, and their 10 metabolites for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-met hoxy- 4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 < C-2 < FZ < CZ < C-4 << F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results suggest some important roles of C-2 and F-2 in the development of parkinsonism as active metabolites during chronic medication with CZ and FZ, respectively.

Animals↗
PubMed1995

Novel 5-HT2-like receptor mediates neurogenic relaxation of the guinea-pig proximal colon.

The aim of the current investigation was to characterize the 5-HT receptors that mediate neurogenic relaxation of the guinea-pig proximal colon. After blockade of 5-HT2A, 5-HT3 and 5-HT4 receptor-mediated contractions, 5-hydroxytryptamine (5-HT) induced relaxations yielding a biphasic concentration-response curve. Other tryptamines were also agonists with the following rank order of potency: 5-HT > 5-carboxamidotryptamine = 5-methoxytryptamine > or = alpha-methyl-5-HT (partial agonist) > tryptamine (partial agonist). 5-Hydroxytryptophan, 2-methyl-5-HT and N-methyltryptamine were virtually inactive as agonists. The curve to 5-HT was not affected by pargyline, citalopram, phentolamine, or by the 5-HT4 receptor antagonists 2-methoxy-4-amino-5-chloro-benzoic acid 2-(diethylamino)ethyl ester (SDZ 205-557) and (1-butyl-4-piperidinylmethyl)-8-amino-7-chloro-1,4-benzodioxan+ ++-5-carboxylate (SB 204070). 8-Hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT), 5-methoxy-3[1,2,3,6-tetrahydroxypyridin-4-yl]-1H-indole (RU 24969), 2-(2,6-dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxane (WB 4101), 1-(3-chlorophenyl)piperazine (mCPP), 1-(m-trifluoromethylphenyl)-piperazine (TFMPP), flesinoxan, sumatriptan and 6-chloro-2-(piperazinyl)-pyrazine (MK212) were inactive as 5-HT receptor agonists. The first phase of the curve to 5-HT was inhibited by: metergoline (pA2 = 8.8 +/- 0.3, against 5-methoxytryptamine 9.3 +/- 0.3), methysergide (non-surmountable), methiothepin (non-surmountable), spiroxatrine (non-surmountable), MK212 (non-surmountable), mesulergine (7.8 +/- 0.3), mCPP (7.1 +/- 0.1), mianserin (7.0 +/- 0.4), ritanserin (8.9 +/- 0.2), rauwolscine (7.0 +/- 0.2), yohimbine (6.2 +/- 0.2), 1-(1-naphthyl)-piperazine (7.7 +/- 0.2) and RU 24969 (6.4 +/- 0.1), but not by 1-(2-methoxyphenyl)4-[4-(2-phthalimidobtyl]-piperazine (NAN-190), spiperone, sumatriptan, 8-OH-DPAT and flesinoxan. It is suggested that the 5-HT receptor under study could be considered an unknown 5-HT2-like receptor.

Animals↗
PubMed1987

Binding of Hoechst 33258 to the minor groove of B-DNA.

An X-ray crystallographic structure analysis has been carried out on the complex between the antibiotic and DNA fluorochrome Hoechst 33258 and a synthetic B-DNA dodecamer of sequence C-G-C-G-A-A-T-T-C-G-C-G. The drug molecule, which can be schematized as: phenol-benzimidazole-benzimidazole-piperazine, sits within the minor groove in the A-T-T-C region of the DNA double helix, displacing the spine of hydration that is found in drug-free DNA. The NH groups of the benzimidazoles make bridging three-center hydrogen bonds between adenine N-3 and thymine O-2 atoms on the edges of base-pairs, in a manner both mimicking the spine of hydration and calling to mind the binding of the auti-tumor drug netropsin. Two conformers of Hoechst are seen in roughly equal populations, related by 180 degrees rotation about the central benzimidazole-benzimidazole bond: one form in which the piperazine ring extends out from the surface of the double helix, and another in which it is buried deep within the minor groove. Steric clash between the drug and DNA dictates that the phenol-benzimidazole-benzimidazole portion of Hoechst 33258 binds only to A.T regions of DNA, whereas the piperazine ring demands the wider groove characteristic of G.C regions. Hence, the piperazine ring suggests a possible G.C-reading element for synthetic DNA sequence-reading drug analogs.

Base Sequence↗
PubMed2005

Oxidative transformation of fluoroquinolone antibacterial agents and structurally related amines by manganese oxide.

Various members of the popular fluoroquinolone antibacterial agents (FQs) have been frequently detected in municipal wastewater and surface water bodies in recent years. This study was conducted to gain a better understanding of the fate of FQs in the sediment-water environment. Seven FQs were examined for adsorptive and oxidative interactions with delta-MnO2 under environmental conditions and exhibited reactivity in the order of ciprofloxacin approximately enrofloxacin approximately norfloxacin approximately ofloxacin > lomefloxacin > pipemidic acid >> flumequine. Four amines that are structurally related to the aniline and piperazine functional groups of FQs showed reactivity to oxidation by delta-MnO2 in the order of 1-phenylpiperazine > aniline > N-phenylmorpholine > 4-phenylpiperidine. Comparison among the above compounds clearly indicates thatthe piperazine moiety of FQs is the predominant adsorptive and oxidative site to MnO2. Product analyses showed that oxidation by MnO2 results in dealkylation and hydroxylation at the piperazine moiety of FQs, with the quinolone ring essentially intact. The reaction kinetics, reactivity comparison, and product characterization point to a surface reaction mechanism that likely begins with formation of a surface complex between FQ and the surface-bound MnIV, followed by oxidation at the aromatic N1 atom of FQ's piperazine moietyto generate an anilinyl radical intermediate. The radical intermediates subsequently undergo N-dealkylation, C-hydroxylation, and possibly coupling to yield a range of products. Even though the quinolone ring appears to be stable with respect to MnO2, it affects the overall reactivity and potentially product distribution of FQs via substituent effects. Results of this study strongly suggest that manganese oxides commonly present in soils will likely play an important role in the abiotic degradation of fluoroquinolone antibacterial agents in the environment.

Absorption↗
PubMed2000

Secondary amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid as inhibitors of pyruvate dehydrogenase kinase.

N'-methyl-N-(4-tert-butyl-1,2,5,6-tetrahydropyridine)thiourea, SDZ048-619 (1), is a modest inhibitor (IC(50) = 180 microM) of pyruvate dehydrogenase kinase (PDHK). In an optimization of the N-methylcarbothioamide moiety of 1, it was discovered that amides with a small acyl group, in particular appropriately substituted amides of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid, are inhibitors of PDHK. Utilizing this acyl moiety, herein is reported the rationale leading to the optimization of a series of acylated piperazine derivatives. Methyl substitution of the piperazine at the 2- and 5-positions (with S and R absolute stereochemistry) markedly increased the potency of the lead compound (>1,000-fold). Oral bioavailability of the compounds in this series is good and is optimal (as measured by AUC) when the 4-position of the piperazine is substituted with an electron-poor benzoyl moiety. (+)-1-N-[2,5-(S, R)-Dimethyl-4-N-(4-cyanobenzoyl)piperazine]-(R)-3,3, 3-trifluoro-2-hydroxy-2-methylpropanamide (14e) inhibits PDHK in the primary enzymatic assay with an IC(50) of 16 +/- 2 nM, enhances the oxidation of [(14)C]lactate into (14)CO(2) in human fibroblasts with an EC(50) of 57 +/- 13 nM, diminishes lactate significantly 2.5 h post-oral-dose at doses as low as 1 micromol/kg, and increases the ex vivo activity of PDH in muscle, liver, and fat tissues in normal Sprague-Dawley rats. These PDHK inhibitors, however, do not lower glucose in diabetic animal models.

Amides↗
PubMed1987

Photoaffinity labeling of adenylate cyclase-linked serotonin receptors in Aplysia neurons.

Serotonin stimulated adenylate cyclase in Aplysia neurons with a Kact of 0.7 microM. Under the same conditions, 1-[2-(4-aminophenyl)ethyl]4-(3-trifluoromethylphenyl)piperazine stimulated adenylate cyclase with a Kact of 20 microM. The azido derivative of this compound, 1-[2-(4-azidophenyl)ethyl]4-(3-trifluoromethylphenyl)piperazine, or of serotonin, (4-amino, 3-nitrophenylazido-serotonin), also stimulated the cyclase in the dark, but with lower efficiency (Kact greater than 10(-4) M). Irradiation of the membranes in the presence of 100 microM 1-[2-(4-azidophenyl)ethyl]4-(3-trifluoromethylphenyl)piperazine abolished 75% of the cyclase activity stimulated by 5 microM serotonin. Under the same conditions, 100 microM 4-amino, 3-nitrophenylazido-serotonin did not inhibit serotonin-stimulated adenylate cyclase activity. When [3H]1-[2-(4-azidophenyl)ethyl]4-(3-trifluoromethylphenyl)piperazine (20 microM) was irradiated with membranes for 5 min at 4 degrees C, a dozen peptides were labeled, as revealed by a fluorogram of sodium dodecyl sulfate-polyacrylamide gels. Among them, the labeling of five polypeptides (molecular weights of 45,000, 55,000, 63,000, 80,000, and 94,000) was protected by the presence of 0.2 mM serotonin during photolysis. These peptides may be related to serotonin receptors.

Adenylyl Cyclases↗
PubMed1989

Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites.

The relationship between the chemical structure and epileptogenic activity of quinolones was investigated. When the quinolones were administered intravenously to mice concomitantly with oral biphenylacetic acid, a major metabolite of the nonsteroidal antiinflammatory drug fenbufen, enoxacin, norfloxacin, ciprofloxacin, and pipemidic acid, which have an unsubstituted piperazine moiety at the 7 position of their parent nuclei, provoked clonic convulsions and subsequent death at doses of 6.25 mg/kg or more in a dose-dependent manner. AM-1091 and T-3262, which have an unsubstituted aminopyrrolidine moiety at their 7 positions, were less epileptogenic than the compounds listed above were. In contrast, ofloxacin, AT-4140, and nalidixic acid, which have piperazine substituted with methyl group(s) or no piperazine moiety at their 7 positions, never induced convulsions, even at doses of 100 mg/kg. Lomefloxacin, which has a 3-methyl piperazine, however, provoked convulsions at doses of 6.25 mg/kg or more. In the presence of biphenylacetic acid, all the test quinolones except nalidixic acid competitively inhibited [3H]muscimol binding to receptor sites for gamma-aminobutyric acid (GABA) in vitro. Nalidixic acid did not inhibit the binding at all, even at the highest concentration tested, i.e., 10(-4) M. The 50% inhibition doses for [3H]muscimol binding varied within 4 orders of magnitude or more, between 10(-8) to more than 10(-4) M for various compounds, and there was a close correlation between the epileptogenic activities of quinolones and their inhibitory potencies for [3H]muscimol binding to GABA receptor sites. These results indicate that the epileptogenic activity of quinolones possibly relates to the GABA-like structures of substituents at their 7 positions, which act as antagonists of GABA receptors.

4-Quinolones↗
PubMed1988

Neihumicin, a new cytotoxic antibiotic from Micromonospora neihuensis. III. Structure-activity relationships.

Structure-cytotoxicity relationships studies have indicated that the C-3 and C-6 disubstituted piperazine-2,5-diones are structurally required for significant cytotoxicity, and the neihumicin-like C-3 and C-6 disubstituted unsymmetrical piperazine derivatives are, in general, more cytotoxic than the corresponding symmetrical piperazine-2,5-diones. Several synthetic analogs including 3,6-di-(2,4,5-trimethoxybenzylidene)piperazine-2,5- dione, 3,6-dibenzylidene-2-ethoxy-3,6-dihydropyrazine-5-one, 3-benzylidene-6-(m-chlorobenzylidene)-2-methoxy-3,6-dihydropyrazine++ +-5-one, have been shown to be more cytotoxic than neihumicin.

Antibiotics, Antineoplastic↗
PubMedDate not supplied

Some aspects of the pharmacology and physiology of the Ascaris suum muscle.

Out of 11 agonists, including such agents as bradykinin, prostaglandin E2, eledoisin, only acetylcholine (Ach) caused the isolated exposed ascaris muscle to contract during treatment for 30 sec and at 10(-7) g/ml (or lower concentrations). The possibility of using this preparation for the identification and quantification of Ach in biological tissues and fluids was highlighted. Neostigmine, but not physostigmine, augmented Ach activity. This suggests that cholinesterases present in the ascaris muscle may be structurally dissimilar to those in the mammalian gut muscle. Several chemically unrelated antagonists showed anti-Ach activity in this preparation in a descending order: d-tubocurarine (dtc) greater than mepyramine greater than atropine, decamethonium, succinylcholine greater than hexamethonium greater than piperazine. Neither adrenaline nor noradrenaline relaxed the ascaris muscle but gamma-aminobutyric acid (GABA) and, occasionally, piperazine caused immediate relaxation of the muscle. GABA was about 150 times more potent than piperazine in this regard. GABA also showed anti-Ach activity which was 0.8-3 times that of dtc. It is suggested that GABA is the inhibitory transmitter in the ascaris suum and that the anti-Ach activity of piperazine is due either to stimulation of GABA receptors and/or to nonspecific blockade of Ach receptors.

Acetylcholine↗
PubMed1988

[Biotransformation of meclozine in the human body].

After oral administration of 1-[(4-chlorophenyl)-phenylmethyl]-4-[3-methylphenyl)-methyl]-piperazine (1, Meclozine) eleven compounds were isolated from human urine and faeces. The structural elucidation of the metabolites was accomplished by comparison of their spectral data with those of the synthetic reference compounds. The metabolites were identified as: Meclozine (1), N-[(4-chlorophenyl)-phenylmethyl]-piperazine (2), 3-(4-[(4-chlorophenyl)-phenylmethyl]-piperazino)-methyl-benzoic acid (3), 3-(4-[(4-chlorophenyl)-phenylmethyl]-piperazino)-methyl-benzamide] (4), 2-[3-(4-[(4-chlorophenyl)-phenylmethyl]-piperazino)-methyl-benzoyl ]-amino- ethanesulphonic acid (5), 3-(4-[(4-chlorophenyl)-3'-hydroxy-4'-methoxyphenylmethyl]-piper azino)- methyl-benzoic acid (6), 1-[(4-chlorophenyl)-phenylmethyl]-4-[(3-methylphenyl)-methyl]- piperazine-N4-oxide (7), 1-[(4-chlorophenyl)-phenylmethyl]-4-[(3-methylphenyl)-methyl]- piperazine-N,N'-dioxide (8), 3-methyl-benzoic acid (9), 3-methyl-hippuric acid (10) and 3-methyl-benzoic acid-glucuronide (11). The structure of compound 11 was confirmed after enzymatic cleavage and identification of the aglycon. A further metabolite was detected, but not identified.

Biotransformation↗