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Tetramisole, a new synthetic anthelmintic, was compared with piperazine in the treatment of ascariasis in African children. Of 100 children receiving tetramisole 94 were cured, and of 100 given piperazine 85 were cured (0.05>P>0.02). Tetramisole was free of side-effects.
We have obtained a series of non-symmetrical 1,4-disubstituted derivatives of piperazine, with the structure of organic nitrates, as potential NO donors. These compounds were obtained from respective hydroxyl derivatives of piperazine in an esterification reaction by fuming nitric acid. The obtained nitrates were tested in-vitro by reaction with a sulfhydryl compound. The structure of the most active nitrate and its hydroxyl analogue was used for the calculation of geometrical optimization with the determination of 3D-QSAR by a semi-empirical method PM3 using HyperChem 4.5.
The metabolic stability of the acyl-CoA: cholesterol O-acyltransferase (ACAT) inhibitor N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(2, 4-dimethylphenyl)piperazine (YIC-708-424) and its n-alkoxy derivatives containing an alkyl chain of 3 or 7 to 10 carbons, which exhibited different hypocholesterolemic activities, was investigated in vivo and in vitro in rats. After the oral administration of YIC-708-424 to rats at a dose of 5 mg/kg/d for 7 d, the parent compound was not detected in the blood. On the other hand, when the n-alkoxy derivatives were administered to rats, an increase in the alkyl chain length produced a progressive increase in the blood concentration of the parent compound. Both in the blood of rats administered YIC-708-424 and in the reaction mixture after the incubation of YIC-708-424 with rat hepatic 9000 x g supernatants, an inactive major metabolite, N-(4-benzyloxy-3, 5-dimethoxycinnamoyl)-N'-(4-carboxyl-2-methylphenyl)piperazine, was observed. The ratio of the maximum velocity to the apparent Michaelis-Menten constant (V(max)/K(m)) for the degradation of the n-propyloxy derivative in rat hepatic and intestinal microsomes was almost equivalent to that of YIC-708-424. On the other hand, an increase in the alkyl chain length of n-alkoxy derivatives produced a progressive decrease in V(max)/K(m) for the degradation of these compounds. Additionally, the in vivo hypocholesterolemic activities of YIC-708-424 and its n-alkoxy derivatives were positively correlated with the blood concentration of the parent compound and were negatively correlated with their V(max)/K(m). These results suggest that the metabolic stability of ACAT inhibitors in the liver and intestinal epithelium, which are the major target organs of these compounds, has a strong influence on their pharmacological activities in vivo.
New series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(2-iodophenyl)propyl]piperazine (o-BON) and 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-[3-(3-iodophenyl)propyl]piperazine (m-BON) were evaluated as single photon emission computed tomography (SPECT) radiopharmaceuticals for mapping sigma receptors in the central nervous system (CNS) and peripheral organs. In vivo biodistribution studies of [125I] o- and m-BON in mice demonstrated high initial uptakes and prolonged retention in the brain. In contrast to high brain uptake and retention, the blood accumulations were low, resulting in good brain-blood ratios (7.9-9.2). In the other tissues, high uptake of [125I] o- and m-BON were observed in the liver, kidney, heart, lung, and pancreas. Moreover, selective interactions of [125I] o- and m-BON with sigma receptors were confirmed by pretreatment experiments with various sigma and other receptor ligands. Haloperidol posttreatment induced decreases in the accumulation of [125I] o- and m-BON. These data suggest that [125I] o- and m-BON binding to sigma receptors is reversible and competitive. Furthermore, ex vivo autoradiograms of [125I] o- and m-BON in rats showed high uptake in the parietal cortex, vestibular nucleus, and pons nucleus and moderate uptake in the thalamus, inferior colliculus, hippocampus, hypothalamus, and temporal cortex. These ex vivo autoradiograms were comparable with the histochemical distribution of sigma receptors. Furthermore, the uptake of [125I] o- and m-BON reflected quantitative amounts of sigma receptor in the brain. These results demonstrated that radiolabeled o- and m-BON have good characteristics for mapping sigma receptors in the CNS and the peripheral organs with SPECT.
The metabolites of 1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride (KB-2796) in the bile, urine and feces in rats were investigated after oral administration of [methine-14C], [benzyl-14C] and unlabelled KB-2796. Their structures were characterized by thin-layer chromatography, mass spectrometry, proton nuclear magnetic resonance and comparison with synthesized authentic compounds. The main pathways of biotransformation of KB-2796 in rats were: (a) O-demethylation at each methoxy group of the trimethoxybenzyl moiety, (b) N-dealkylation at 1 and 4-position of the piperazine ring and (c) hydroxylation at 5-position of the 2,3,4-trimethoxyphenyl ring.
New mu-opioid receptor (MOR) agonists containing piperazine and homopiperazine moieties in the structures were synthesized and their affinities to and agonist potencies on MOR were evaluated. Among the synthesized compounds, 4-[4-(2-methoxyphenyl)piperazin-1-yl]-N,N-dimethyl-2,2-diphenylbutanamide (20 Aa) showed the highest affinity to the human MOR expressed in Chinese hamster ovary (CHO)-K1 cells, and the highest agonist potency on the MOR in isolated guinea-pig ileum preparation.
A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.
Studies were performed to elucidate the effects of 1-[2-[bis (fluorophenyl) methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride (I-893), a newly synthesized aryl-1,4-dialkyl-piperazine derivative, on turnover of dopamine and norepinephrine in the rat brain. The contents of both monoamines were not affected by I-893 at an oral dose of 10 mg/kg. The oral administration of 50-250 mg/kg produced a transient increase in dopamine content of the caudate nucleus and hypothalamus, and thereafter, the content dose-dependently decreased. Norepinephrine levels in the hypothalamus and frontal cortex were slightly decreased by I-893. I-893 potentiated the rate of alpha-methyl-p-tyrosine-induced depletion of dopamine and norepinephrine. The 3-methoxytyramine content in animals treated with pargyline was increased by I-893 in the caudate nucleus and olfactory tubercle. NSD-1015-induced accumulation of DOPA was suppressed by larger doses of I-893. Oral administration of I-893 (10-50 mg/kg/day) for 14 days slightly attenuated the inhibitory effects of the drug on the norepinephrine level, while it did not affect the inhibitory effect on the dopamine level. These results suggest that I-893 facilitates the release of dopamine and norepinephrine and/or inhibits the uptake of the monoamines in the presynaptic nerve terminals.
The effects of a piperazine derivative, trimetazidine (1-(2, 3, 4-trimethoxybenzyl) piperazine dihydrochloride) on the frog end-plate membrane were studied. Action and resting membrane potentials and the input resistance of muscle fibers were not affected by trimetazidine (82-165 muM). Under these conditions, the frequency of the miniature endplate potentials was unchanged while its amplitude was slightly decreased. The amplitude of acetylcholine (ACh) potentials were markedly and reversibly decreased after application of trimetazine (82-165 muM). The dose response curve of the end-plate membrane to ACh showed a non-competitive type of blockade. Trimetazidine (165 muM) not only decreased the amplitude of the end-plate currents (EPC) recorded from the glycerinated muscles using a voltage clamp technique, but also drastically shortened its time course. Under these conditions, the falling phase of the EPC became completely voltage insensitive. The equilibrium potential for the EPC slightly shifted to a more negative value in the presence of trimetazine (165 muM). Coefficient of variation of EPC was increased by Trimetazidine (165 mum), indicating a decrease in the quantal content of the EPC. The rate of desensitization of the end-plate to ACh was facilitated and the rate of decrease in EPC amplitude during tetanic stimulation became voltage sensitive by the action of trimetazidine (133 muM). It is concluded that trimetazidine mainly acts on the postsynaptic membrane with a weak presynaptic action. The agent seems to block a step subsequent to the interaction of ACh with its receptor, which presumably involves changes in the ion conductance of the membrane and is responsible for the voltage sensitivity of the response.
1. An oral dose of the coronary vasodilator 4-(3,4,5-trimethoxy[14C]cinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was well absorbed and more than 60% of the dose was excreted within 24 h. In 5 days, rats, dogs, and man excreted in the urine and faeces respectively 36.7% and 58.3%, 33.4% and 68.6%, and 61.3% and 38.1% dose. Faecal radioactivity was probably excreted via the bile. 2. Plasma concentrations of radioactivity reached a maximum within about 1 h in all three species and declined fairly rapidly (t0.5 less than 3 h). For several hours, more than 50% of the plasma radioactivity was due to unchanged drug. After correction for dose and body weight (normalization), peak plasma concentrations of unchanged drug in man, rat and dog were in the approximate ratio 100 :30:1. 3. Similar metabolites were excreted by the three species, but the relative proportions differed. Rats and man excreted 17.2% and 15.9% respectively as unchanged drug in the urine whereas dogs excreted only 3.6%. Rat bile and urine contained 4.3% and 9.8% dose respectively as glucuronides of the mono-O-demethylated compounds and dog and human urine contained 9.0% and 2.6% respectively of these metabolites. The corresponding pyrrolidone accounted for 2.5%, 5.5% and 5.1% respectively in rat, dog and human urine. Complete O-demethylation also occurred since 4-(3,4,5-trihydroxycinnamoyl)-1-(N-pyrrolidinocarbonylmethyl)piperazine was present in rat faeces (22.1% dose).
Benzyl-14C-1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl) piperazine dihydrochloride (14C-KB-2796), a new cerebral vasodilator, was synthesized in order to investigate the metabolic fate. The synthesis of carboxy-14C-2,3,4-trimethoxybenzoic acid (IV) was accomplished by the reaction of 2,3,4-trimethoxybromobenzene (II) with ter-butyllithium followed by carboxylation with 14C-carbon dioxide generated from 14C-barium carbonate. Formyl-14C-2,3,4-trimethoxybenzaldehyde (VI) was prepared by the reduction of the methyl ester of IV. The free base of 14C-KB-2796 was obtained by the condensation of VI with bis(4-fluorophenyl)methyl-piperazine, and converted to I. An overall radiochemical yield from 14C-barium carbonate was 39%, the specific activity was 1,816.7 MBq/mmol (49.1 mCi/mmol) and its radiochemical purity was 99% in reverse isotope dilution analysis and thin layer chromatographic method.
New chiral epoxysuccinic acid derivatives 5 approximately 23 bearing various amino acids and N-substituted piperazines were synthesized to evaluate their inhibitory activities against mu-calpain and cathepsin B. After screening these compounds, 1-[(2S,3S)-epoxysuccinyl-L-leucyl]-4-(2-chlorophenyl)piperazine 9 proved to exhibit fairly strong inhibitory activity against both cysteine proteases. L-Valyl derivative 19 exhibited selective inhibitory activity against cathepsin B in comparison with that against mu-calpain.
1-Beta-Chloroethyltheobromine (CETb) heated with piperazine in the medium of 2-methoxyethanol yields N,N'-bis-(theobrominyl-1-ethyl)-piperazine dihydrochloride (IIb) or 1-piperazinoethyltheobromine (I). The use of N-methyl, N-beta-hydroxyethyl, N-ethoxycarbonyl and N-phenylpiperazine for exchange of chlorine in CETb lead to corresponding 1-N-alkyl or N-arylpiperazinoethyltheobromines (III--VIa) isolated in the form of salts. The preliminary investigations for diuretic and cardiovascular activity of the obtained compounds were performed.
Enantiomerically pure (S)-piperazine-2-carboxylic acid was synthesized by kinetic resolution of methyl-4-(tert-butyroxycarbonyl)-piperazine-2-carboxylate using a low cost enzyme alcalase.
2-[3-Estrone-N-ethyl-piperazine-methyl] tetracycline (XW630) showing anti-osteoporosis activity is a new compound with piperazine-tetracycline in the steroid structure of estrone. The affinity of XW630 with uterine estrogen receptor and its estrogenic activity were studied in this paper. The relative affinities of estrone, estradiol and XW630 with estrogen receptor (ER) of the uterine myoma tissues were found to be 0.325, 1.000 and 0.011, respectively, by the competitive assay. The estrogenic activity index of estrone, estradiol and XW630 were shown to be 9.70, 10.30 and 6.90, respectively, by the uterine weight assay using immature mice. These indexes indicate that: the estrogenic activity of XW630 is about 1/1960 that of estrone and 1/7742 that of estradiol. The vaginal smear assay of oophorectomized mice also showed that the estrogenic activity of XW630 is less than that of estrone and estradiol.
The first reported case of piperazine toxicity resembling viral hepatitis is described in a 25-year-old woman. The illness, which was severe, occurred after administration of the drug on two separate occasions. The evidence favors a hypersensitivity mechanism rather than a direct toxic effect of piperazine or its metabolites on the liver. The humoral or cellular immune basis for such hypersensitivity has not been elucidated.
The effect of a steric hindrance around the protonation center of the model 4-substituted 1-(3-chlorophenyl)-piperazines 1-9 and 11-14 on their affinity for 5-HT1A and 5-HT2 receptor sites was investigated. Additional evidence for hydrophobic interactions between the N-4 hydrocarbon substituents and 5-HT1A receptors has been presented. However, the hydrophobic forces play a minor role in stabilization of the bioactive complex with 5-HT2 receptors. It has also been found that even bulky substituents around the protonation center of 1-aryl-piperazines are well tolerated at both 5-HT1A and 5-HT2 sites.
The 1-(2-pyrimidinyl)-piperazine derivatives campirone, campironine, levopironine) evoked hyperpolarizing responses of rat dorsal root ganglion neurons mediated by 5-hydroxytryptamine(1A) receptor activation and, like chlordiazepoxide, potentiated neuronal responses evoked by GABA-depolarizing receptor activation. The drugs studied in the lighted space and threatening situation avoidance tests showed an anxiolytic effect. Picrotoxin was found to be effective in inhibiting the anxiolytic effect of chlordiazepoxide, levopironine and campironine, but it failed to affect the antianxious action of campirone. Whether the GABA-ergic mechanisms may contribute to the anxiolytic action of 1-(2-pyrimidinyl)-piperazine derivatives.