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PubMed1998

S 18126 ([2-[4-(2,3-dihydrobenzo[1,4]dioxin-6-yl)piperazin-1-yl methyl]indan-2-yl]), a potent, selective and competitive antagonist at dopamine D4 receptors: an in vitro and in vivo comparison with L 745,870 (3-(4-[4-chlorophenyl]piperazin-1-yl)methyl-1H-pyrrolo[2, 3b]pyridine) and raclopride.

The novel benzoindane S 18126 possessed > 100-fold higher affinity at cloned, human (h) D4 (Ki = 2.4 nM) vs. hD2 (738 nM), hD3 (2840 nM), hD1 (> 3000 nM) and hD5 (> 3000 nM) receptors and about 50 other sites, except sigma1 receptors (1.6 nM). L 745,870 similarly showed selectivity for hD4 (2.5 nM) vs. hD2 (905 nM) and hD3 (> 3000 nM) receptors. In contrast, raclopride displayed low affinity at hD4 (> 3000 nM) vs. hD2 (1.1 nM) and hD3 receptors (1.4 nM). Stimulation of [35S]-GTPgammaS binding at hD4 receptors by dopamine (DA) was blocked by S 18126 and L 745,870 with Kb values of 2.2 and 1.0 nM, respectively, whereas raclopride (> 1000 nM) was inactive. In contrast, raclopride inhibited stimulation of [35S]-GTPgammaS binding at hD2 sites by DA with a Kb of 1.4 nM, whereas S 18126 (> 1000 nM) and L 745,870 (> 1000 nM) were inactive. As concerns presynaptic dopaminergic receptors, raclopride (0.01-0.05 mg/kg s.c. ) markedly enhanced DA synthesis in mesocortical, mesolimbic and nigrostriatal dopaminergic pathways. In contrast, even high doses (2. 5-40.0 mg/kg s.c.) of S 18126 and L 745,870 were only weakly active. Similarly, raclopride (0.016 mg/kg i.v.) abolished inhibition of the firing rate of ventrotegmental dopaminergic neurons by apomorphine, whereas even high doses (0.5 mg/kg i.v.) of S 18126 and L 745,870 were only weakly active. As regards postsynaptic dopaminergic receptors, raclopride potently (0.01-0.3 mg/kg s.c.) reduced rotation elicited by quinpirole in rats with unilateral lesions of the substantia nigra, antagonized induction of hypothermia by PD 128, 907, blocked amphetamine-induced hyperlocomotion and was effective in six further models of potential antipsychotic activity. In contrast, S 18126 and L 745,870 were only weakly active in these models (5.0-> 40.0 mg/kg s.c.). In six models of extrapyramidal and motor symptoms, such as induction of catalepsy, raclopride was likewise potently active (0.01-2.0 mg/kg s.c.) whereas S 18126 and L 745,870 were only weakly active (10.0-80.0 mg/kg s.c.). In freely moving rats, raclopride (0.16 mg/kg s.c.) increased levels of DA by + 55% in dialysates of the frontal cortex. However, it also increased levels of DA in the accumbens and striatum by 70% and 75%, respectively. In contrast to raclopride, at a dose of 0.16 mg/kg s.c. , neither S 18126 nor L 745,870 modified frontal cortex levels of DA. However, at a high dose (40.0 mg/kg s.c.), S 18126 increased dialysate levels of DA (+ 85%) and noradrenaline (+ 100%), but not serotonin (+ 10%), in frontal cortex without affecting DA levels in accumbens (+ 10%) and striatum (+ 10%). In conclusion, S 18126 and L 745,870 behave as potent and selective antagonists of cloned, hD4 vs. other dopaminergic receptor types in vitro. However, their in vivo effects at high doses probably reflect residual antagonist actions at D2 (or D3) receptors. Selective blockade of D4 receptors was thus associated neither with a modification of dopaminergic transmission nor with antipsychotic (antiproductive) or extrapyramidal properties. The functional effects of selective D4 receptor blockade remain to be established.

Animals↗
PubMed1993

Mono N-aryl ethylenediamine and piperazine derivatives are GABAA receptor blockers: implications for psychiatry.

Ethylenediamine (EDA) and piperazine are known GABA-A receptor agonists and this activity appears to reside in their carbamate adducts. In CO2-free incubation medium EDA and piperazine weakly reverse the inhibitory action of 1 microM GABA on specific [35S]t-butylbicyclophosphorothionate (35S-TBPS) binding to rat brain membranes in vitro. In 25 mM sodium bicarbonate buffer, EDA and piperazine much more potently inhibit 35S-TBPS binding in a way reversible by the GABA-A receptor blocker R5135. Thus, native EDA and piperazine are weak GABA-A receptor blockers, while their presumed carbamate adducts, formed by reaction with bicarbonate, are more potent GABA-A receptor agonists. Virtually all structural modifications of EDA or piperazine result in GABA-A receptor blockers, even in the presence of bicarbonate, judging from their abilities to fully or partially reverse the inhibitory effect of GABA on 35S-TBPS binding. Of 12 non-aromatic piperazine or EDA derivatives, the piperazine derivatives are the more potent GABA antagonists, although all are weak compared to the mono N-aryl derivatives. Nineteen mono N-aryl EDA derivatives are moderately potent GABA antagonists, including 10 with demonstrated or potential antidepressant activity. Most of the N-aryl piperazines are moderately to highly potent GABA antagonists, one (pitrazepin) being 4 to 5 times more potent than bicuculline. There are several clinically effective antidepressants (e.g. Amoxapine, Mianserine) and antipsychotics (Clothiapine, Loxapine, Metiapine, Clozapine and Fluperlapine) among the more potent N-aryl piperazine GABA antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstanes↗
PubMed1977

Anticonvulsant activity and selective inhibition of NAD-dependent oxidations by 1,4-disubstituted piperazines.

Several 1-(1-aryl-3-ethylthiocarbamido)-4-(arylaminothiocarbonyl)piperazines were synthesized, characterized by their sharp melting points and elemental analyses and evaluated for anticonvulsant activity. All disubstituted piperazines at a dose of 100 mg/kg i.p. provided 10-90% protection against pentylenetetrazol-induced convulsions in mice. These disubstituted piperazines selectively inhibited the in vitro oxidation of nicotinamide adenine dinucleotide (NAD)-dependent oxidation of pyruvate, alpha-ketoglutarate, beta-hydroxybutyrate and NADH by rat brain homogenates. The NAD-independent oxidation of succinate remained unaltered. The anticonvulsant activity possessed by disubstituted piperazines was unrelated with their ability to selectively inhibit respiratory activity of rat brain homogenates. Amongst 1-(substituted benzyl)-4-(substituted benzoyl)piperazines exhibiting central nervous system (1, 2) depressant activity it was found that 1-(2-chlorobenzyl)-4-(2-chlorobenzoyl)piperazine possessed maximum activity (2). The ability of piperazine carbamides (3) and piperazinothiocarbamides to possess anticonvulsant activity (4) prompted synthesis of 1-(1-aryl-3-ethylthiocarbamido)-4-(arylaminothiocarbonyl)piperazines and evaluation of their anticonvulsant activity. The effects of these disubstituted piperazines were also investigated on the in vitro respiratory activity of rat brain homogenates in an attempt to elucidate the biochemical mechanism of action for their anticonvulsant activity.

Animals↗
PubMed1999

Interactions of buspirone with itraconazole and rifampicin: effects on the pharmacokinetics of the active 1-(2-pyrimidinyl)-piperazine metabolite of buspirone.

The effects of inhibition and induction of the metabolism of buspirone on the plasma concentrations of 1-(2-pyrimidinyl)-piperazine (a piperazine metabolite), the principal active metabolite of buspirone, were investigated. Two separate randomized, placebo-controlled cross-over studies with two phases were carried out in healthy volunteers. In Study I, six subjects took itraconazole 200 mg daily or matched placebo orally for 4 days. On day 4, 10 mg buspirone was administered orally. In study II, six subjects took rifampicin 600 mg daily or matched placebo orally for 5 days. On day 6, 30 mg buspirone was administered orally. Buspirone and piperazine metabolite concentrations in plasma were determined by gas chromatography. Itraconazole decreased the mean AUC of the piperazine metabolite by 50% (P<0.05) and the Cmax by 57% (P<0.05) compared with placebo, whereas the mean AUC and Cmax of unchanged buspirone were increased 14.5-fold (P<0.05) and 10.5-fold (P<0.05), respectively, by itraconazole. Rifampicin had no significant effect on the AUC of the piperazine metabolite, but it increased the mean Cmax of the piperazine metabolite by 35% (P=0.08). The mean AUC and Cmax of parent buspirone were reduced by 91% (P<0.05) and 85% (P<0.05), respectively, by rifampicin. The mean ratio of the AUC of the piperazine metabolite to that of buspirone was decreased 34-fold (P<0.05) by itraconazole and increased 7.6-fold (P<0.05) by rifampicin. In conclusion, itraconazole and rifampicin caused only relatively minor changes in the plasma concentrations of the active piperazine metabolite of buspirone, although they had drastic effects on the concentrations of parent buspirone.

Adolescent↗
PubMed2006

Photoaddition of N-substituted piperazines to C60: an efficient approach to the synthesis of water-soluble fullerene derivatives.

An oxidative radical photoaddition of mono N-substituted piperazines to [60]fullerene was systematically investigated. Reactions of C60 with piperazines bearing bulky electron-withdrawing groups (2-pyridyl, 2-pyrimidinyl) were found to be the most selective and yielded C60(amine)4O as major products along with small amounts of C60(amine)2. In contrast, interactions of fullerene with N-methylpiperazine and N-(tert-butoxycarbonyl)piperazine were found to have low selectivity due to different side reactions. Tetraaminofullerene derivative C60(N-(2-pyridyl)piperazine)4O was found to react readily with organic and inorganic acids to yield highly water-soluble salts (solubility approximately 150 mg mL(-1)). In contrast, C60(N-(2-pyrimidinyl)piperazine)4O undergoes hydrolysis under the same conditions and results in a complex mixture of compounds with an average composition of C60(N-(2-pyrimidinyl)piperazine)2(OH)2O. Radical photoaddition of N-(2-pyridyl)piperazine to fullerene derivatives can be used as a facile route for their transformation into water-soluble compounds. Two model fullerene cycloadducts (a methanofullerene and a pyrrolidinofullerene) were easily converted into mixtures of regioisomers of A=C60(N-(2-pyridyl)piperazine)4O (A=cyclic addend) that give highly water-soluble salts under acid treatment.

Amines↗
PubMed1985

Comparative antiarrhythmic and local anaesthetic effects of piperazine citrate and lignocaine hydrochloride.

The effect of pretreatment with lignocaine hydrochloride (0.1 mg/g body weight) and piperazine citrate (1 mg/g body weight) on the number of deaths due to ouabain (0.02-0.12 mg/g body weight) was determined in the toad. Lignocaine was at least 10 times more potent than piperazine. Considering the doses that gave 50% protection from the 100% deaths due to ouabain (0.09 mg/g), lignocaine was 14.8 times more potent, but it was 56-60 times more toxic than piperazine as shown by the LD50s in the mouse and toad. Lignocaine was also about 10 times more potent than piperazine in preventing electrically-induced arrhythmia in the isolated guinea-pig atrium suspended in low potassium Ringer-Locke solution. With regard to infiltration anaesthesia, lignocaine was about 158 times more potent than piperazine. Therefore the relative potencies of the antiarrhythmic activities of piperazine and lignocaine do not correlate with the relative local anaesthetic potencies. It was concluded that, although lignocaine is 10-15 times more potent than piperazine as an antiarrhythmic agent, piperazine should be a much safer drug and could have potential utility as a substitute for lignocaine as an antiarrhythmic agent.

Anesthetics, Local↗
PubMed1999

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 2. Syntheses and biological activities of 1,4-dialkyl-, 1,4-dibenzyl, and 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines and isosteric analogues of imidazoline.

Piperazine derivatives have been identified as new antidiabetic compounds. Structure-activity relationship studies in a series of 1-benzyl-4-alkyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazines resulted in the identification of 1-methyl-4-(2', 4'-dichlorobenzyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine, PMS 812 (S-21663), as a highly potent antidiabetic agent on a rat model of diabetes, mediated by an important increase of insulin secretion independently of alpha2 adrenoceptor blockage. These studies were extended to find additional compounds in these series with improved properties. In such a way, substitution of both piperazine N atoms was first optimized by using various alkyl, branched or not, and benzyl groups. Second, some modifications of the imidazoline ring and its replacement by isosteric heterocycles were carried out, proceeding from PMS 812, to evaluate their influence on the antidiabetic activity. The importance of the distance between the imidazoline ring and the piperazine skeleton was studied third. Finally, the influence of the N-benzyl moiety was also analyzed compared to a direct N-phenyl substitution. The pharmacological evaluation was performed in vivo using glucose tolerance tests on a rat model of type II diabetes. The most active compounds were 1,4-diisopropyl-2-(4', 5'-dihydro-1'H-imidazol-2'-yl)piperazine (41a), PMS 847 (S-22068), and 1,4-diisobutyl-2-(4',5'-dihydro-1'H-imidazol-2'-yl)piperazine (41b), PMS 889 (S-22575), which strongly improved glucose tolerance without any side event or hypoglycemic effect. More particularly, PMS 847 proved to be as potent after po (100 micromol/kg) as after ip administration and appears as a good candidate for clinical investigations.

Animals↗
PubMedDate not supplied

Electrocardiographic profile of oral piperazine citrate in healthy volunteers.

The electrocardiographic (ECG) profile of oral piperazine citrate was determined in healthy volunteers. Piperazine caused reduction in heart rate in all the subjects. The highest percentage of change was 15.7. The average pretreatment (73.6+/-6.59 beats/min) when compared with the heart rate 1 hour after piperazine was administered (64.6+/-5.21 beats/min) was statistically significant (P=0.0054). The QT and JT intervals had average increases of 9.7% and 11.1%, respectively. In contrast, piperazine did not have any effect on the QRS complex following its administration. However, the average PR interval 1 hour after ingesting oral piperazine 2 g was significantly prolonged, 0.18+/-0.0063 seconds compared with a pretreatment average of 0.16+/-0.0098 seconds. The difference between the 2 values was statistically significant (P=0.0161). No dysrhythmic phenomena were seen. Sinus rhythm was maintained in all the volunteers, with every QRS-T complex preceded by a P wave. The direction and magnitude of the mean electric axis of QRS complex and T wave were not altered by piperazine. It is concluded that oral piperazine citrate induced some changes on the ECG profile of healthy human volunteers, typical of many potent antiarrhythmic agents.

Adult↗
PubMed2004

S-stereoselective piperazine-2-tert-butylcarboxamide hydrolase from Pseudomonas azotoformans IAM 1603 is a novel L-amino acid amidase.

An amidase acting on (R,S)-piperazine-2-tert-butylcarboxamide was purified from Pseudomonas azotoformans IAM 1603 and characterized. The enzyme acted S-stereoselectively on (R,S)-piperazine-2-tert-butylcarboxamide to yield (S)-piperazine-2-carboxylic acid. N-terminal and internal amino acid sequences of the enzyme were determined. The gene encoding the S-stereoselective piperazine-2-tert-butylcarboxamide amidase was cloned from the chromosomal DNA of the strain and sequenced. Analysis of 2.1 kb of genomic DNA revealed the presence of two ORFs, one of which (laaA) encodes the amidase. This enzyme, LaaA is composed of 310 amino acid residues (molecular mass 34 514 Da), and the deduced amino acid sequence exhibits significant similarity to hypothetical and functionally characterized proline iminopeptidases from several bacteria. The laaA gene modified in the nucleotide sequence upstream from its start codon was overexpressed in Escherichia coli. The activity of the recombinant LaaA enzyme in cell-free extracts of E. coli was 13.1 units.mg(-1) with l-prolinamide as substrate. This enzyme was purified to electrophoretic homogeneity by ammonium sulfate fractionation and two column chromatography steps. On gel-filtration chromatography, the enzyme appeared to be a monomer with a molecular mass of 32 kDa. It had maximal activity at 45 degrees C and pH 9.0, and was completely inactivated in the presence of phenylhydrazine, Zn2+, Ag+, Cd2+ or Hg2+. LaaA had hydrolyzing activity toward L-amino acid amides such as L-prolinamide, L-proline-p-nitroanilide, L-alaninamide and L-methioninamide, but did not act on the peptide substrates for the proline iminopeptidases despite their sequence similarity to LaaA. The enzyme also acted S-stereoselectively on (R,S)-piperidine-2-carboxamide, (R,S)-piperazine-2-carboxamide and (R,S)-piperazine-2-tert-butylcarboxamide. Based on its specificity towards L-amino acid amides, the enzyme was named L-amino acid amidase. E. coli transformants overexpressing the laaA gene could be used for the S-stereoselective hydrolysis of (R,S)-piperazine-2-tert-butylcarboxamide.

Amides↗
PubMed1976

A comparative study of the action of gamma-aminobutyric acid and piperazine on the lobster muscle fibre and the frog spinal cord.

1 The effects of gamma-aminobutyric acid (GABA) and piperazine were compared on two in vitro preparations, the lobster muscle fibre and the frog spinal cord. 2 Both GABA and piperazine increased the membrane conductance of single lobster muscle fibres without changing the membrane potential; sigmoidal log dose-conductance curves for these agents were obtained and a similar model expressed the receptor interaction of both substances. 3 The actions of GABA and piperazine on lobster muscle were antagonized by picrotoxin and were Cl-dependent. 4 In the frog spinal cord GABA depolarized the dorsal roots presumably by mimicking the activity of the transmitter depolarizing the primary afferents; sigmoidal log dose-response curves for GABA were obtained. 5 On the dorsal roots piperazine produced either depolarizations or biphasic responses; these were mainly indirect effects as was shown by experiments in the presence of tetrodotoxin (TTX). 6 The effects of GABA on the dorsal root (in TTX-treated cords) were antagonized by picrotoxin whereas those of piperazine were more resistant to this alkaloid. The GABA-induced responses appeared to be largely Na+-dependent while both Na+ and Cl- seemed to mediate the effects of piperazine. 7 It is proposed that piperazine has GABA-agonist activity on lobster muscle but little GABA-like activity on the frog spinal cord.

Aminobutyrates↗
PubMed1982

Electrophysiological effects of piperazine and diethylcarbamazine on Ascaris suum somatic muscle.

1 Electrophysiological recordings were made from the bag region of Ascaris suum muscle. Membrane potential and input conductance or membrane current under voltage clamp were measured. 2 In high-Cl- Ringer, bath-applied piperazine, at concentrations greater than 10(-4)M, produced a dose-dependent and reversible increase in input conductance associated with a hyperpolarizing potential. The increase in input conductance was reduced when the preparations were bathed in low-Cl- Ringer. Gamma-Aminobutyric acid (GABA) and piperazine reversal potentials were measured with a voltage clamp on the same cells using iontophoretic application of the agonists. The reversal potentials were the same and close to the predicted Nernst Cl- potential (-65 mV). When GABA and piperazine were applied simultaneously piperazine reversibly reduced the amplitude of the control outward GABA current response. It was concluded that piperazine acts as a GABA agonist of low potency on the extra-synaptic GABA receptors of the bag, mediating an increase in Cl- conductance. 3 Acetylcholine was applied iontophoretically within 100 micron of the bag region while the preparation was bathed in a low-Ca2+, low-Cl- Ringer. The response under voltage clamp was a dose-dependent inward current associated with an increase in input conductance. This response was reversibly antagonized by 3 X 10(-5)M tubocurarine, high concentrations of diethylcarbamazine (10(-3) to 10(-2)M) but not high concentrations of piperazine (10(-3) to 10(-2)M). It was concluded that there are extra-synaptic acetylcholine receptors on the bag region of Ascaris muscle and that diethylcarbamazine but not piperazine acts as an antagonist. 4 Bath-applied diethylcarbamazine (10(-4) to 2 X 10(-3)M) produced a reversible dose-dependent depolarization of the membrane potential which was associated with an increase in the amplitude and frequency of spontaneous depolarizing potentials in active preparations at 32 degrees C to 35 degrees C in high-Cl- Ringer. The excitatory action of diethylcarbamazine was not blocked by 3 X 10(-5)M tubocurarine. Diethylcarbamazine (10(-4) to 10(-3)M) had no effect on the outward current response to GABA iontophoresis. Diethylcarbamazine (10(-4) to 10(-2)M) reversibly antagonized in a dose-dependent manner the delayed rectification of the bag membrane. In a low-Ca2+, low-Cl- Ringer, diethylcarbamazine (10(-4) to 2 X 10(-3)M) reversibly antagonized the voltage-sensitive outward current of the bag. This effect was mimicked by high-K+ Ringer or perfusion with 4-aminopyridine (10(-3) to 2 X 10(-3)M). It was concluded that diethylcarbamazine did not react with the GABA receptor but antagonized a voltage-sensitive K+ conductance.

Acetylcholine↗
PubMed1987

Vascular and cellular responses to guanidino propyl piperazine CK0569A, a new anti-plaque agent.

Guanidino propyl piperazine CK0569A (abbreviation piperazine) used as a 0.1% mouthrinse has been shown to be effective against plaque bacteria. In addition to its efficacy as an antibacterial agent, its safety should be taken into consideration. In this study the effect of piperazine on the microcirculation of the hamster cheek pouch was studied. The effect of this drug was also investigated on rat leukocytes in vivo and on macrophages and erythrocytes in vitro. Piperazine caused a distinct retardation in the microcirculation of the hamster cheeck pouch even at a low concentration (0.01%), but the effect was abolished in 5 min. The number of leukocytes decreased markedly in the experimentally induced inflammatory exudate in the presence of 0.05% piperazine as compared to the controls. The macrophages in vitro released their lysosomal and cytoplasmic enzymes and lost their viability. The erythrocytes in vitro were destroyed in the presence of 0.005% piperazine as well. Based on these results it can be suggested that 0.005-0.05% piperazine under experimental conditions causes changes that indicate loss of cell viability.

Animals↗