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At least 1,009 records · Page 56Linked to original sources
PubMed1991

Tandospirone and its metabolite, 1-(2-pyrimidinyl)-piperazine--I. Effects of acute and long-term administration of tandospirone on serotonin neurotransmission.

The acute and long-term effects of the antidepressant/anxiolytic selective 5-HT1A receptor ligand, tandospirone (SM-3997) on 5-HT neurotransmission were assessed using single-cell extracellular recording in chloral hydrate-anaesthetized rats. The acute intravenous administration of tandospirone decreased the firing rate of 5-HT neurones of the dorsal raphe (ED50 = 9.1 +/- 1.1 micrograms/kg). A treatment with tandospirone for 2 days (10 mg/kg/day, s.c.), markedly reduced the firing activity of 5-HT neurones of the dorsal raphe; this was followed by a partial recovery after 7 days and by complete recovery after 14 days of administration of tandospirone. After treatment with tandospirone for 14 days (10 mg/kg/day, s.c.), the responsiveness of 5-HT neurones to the intravenous administration of LSD was reduced, suggesting that somatodendritic 5-HT autoreceptors had desensitized. The depressant effects of microiontophoretically-applied tandospirone and 5-HT, on the firing activity of CA3 pyramidal neurones in the hippocampus were blocked by the intravenous injection of the 5-HT1A receptor antagonist, BMY-7378. The depressant effect of microiontophoretically-applied 5-HT onto these same neurones was markedly reduced during concurrent background application of tandospirone, suggesting that the latter acted as a partial agonist at postsynaptic 5-HT1A receptors. The sustained administration of tandospirone for 14 days (10 mg/kg/day, s.c.) altered neither the effectiveness of microiontophoretically-applied 5-HT and tandospirone nor that of endogenous 5-HT, released by the electrical simulation of the afferent 5-HT pathway, in suppressing the firing activity of pyramidal neurones in the hippocampus, suggesting that postsynaptic 5-HT1A receptors had not desensitized. Furthermore, long-term treatment with tandospirone did not alter the sensitivity of the terminal 5-HT autoreceptor. It is thus concluded that desensitization of somatodendritic 5-HT autoreceptors permits 5-HT neurones to regain their physiological rate of firing during long-term treatment with tandospirone and, consequently, to release a normal amount of 5-HT into the synaptic cleft. This, combined with the sustained activation of normosensitive postsynaptic 5-HT1A receptors by tandospirone, during such a treatment, should result in an enhanced tonic activation of postsynaptic 5-HT1A receptors.

Animals↗
PubMed1988

Psychopharmacological profile of 1-(m-(trifluoromethyl) phenyl) piperazine (TFMPP).

The effect of TFMPP, an agonist of the 5-HT1b receptors, was studied in mice on several psychopharmacological parameters. In contrast to imipramine-like drugs, TFMPP neither antagonized reserpine-induced hypothermia nor increased yohimbine-induced toxicity. Similarly to imipramine-like drugs, TFMPP antagonized oxotremorine-induced hypothermia and was active in the behavioural despair test. In addition, TFMPP normalized a social behavioural deficit induced by isolation. The effects of TFMPP on oxotremorine-induced hypothermia in the behavioural despair test and in the isolation-induced social behavioural deficit are all antagonized by d-1 propranolol. It is concluded that TFMPP seems to possess psychotropic activity resembling only in part that of imipramine-like drugs and that these actions may be mediated through 5-HT1b receptors.

Animals↗
PubMed1989

Apparent antinociceptive properties of piperazine-type serotonin agonists: trifluoromethylphenylpiperazine, chlorophenylpiperazine, and MK-212.

Squirrel monkeys were studied under a titration procedure in which responding adjusted the intensity of an electrical stimulus delivered to the tail (0.1-3.3 mA range in 15 steps). The 5-HT agonists trifluoromethylphenylpiperazine (TFMPP), chlorophenylpiperazine (mCPP), and 6-chloro-2(1-piperazinyl)pyrazine (MK-212) increased the intensity at which shock was maintained. The order of potency was: MK-212 greater than mCPP greater than TFMPP. Reductions in absolute rates of responding were small, and not related systematically to increases in shock intensity. Pretreatment with the nonselective 5-HT antagonist methysergide (0.1-1.0 mg/kg) resulted in a 3- to 10-fold shift to the right of the dose-effect curves for the 5-HT agonists. In contrast, the selective 5-HT2 antagonists ketanserin (0.3-1.7 mg/kg) and pirenperone (0.001-0.1 mg/kg) did not alter the effects of these agonists. This suggests that the apparent antinociceptive actions of these 5-HT agonists are probably mediated by effects at the 5-HT1 receptor subtype.

Animals↗
PubMed1996

Reduction in number of dopamine uptake sites but unchanged number of piperazine-acceptor/CYP450IID6 binding sites in the human caudate nucleus in aging.

A substantial decrease in number of striatal dopamine uptake sites is a characteristic finding in aging. This decrease resembles the dopaminergic nigro-striatal degeneration in Parkinson's disease (PD). A dysfunction of cytochrome P450IID6 (debrisoquine-4-hydroxylase) is suggested to be involved in the pathogenesis of PD. In this study, binding sites associated with the neuronal form of P450IID6 were studied in the caudate nucleus from individuals in the age range 20-81 years using [3H]GBR 12935 as a radioligand. No significant changes in binding parameters were obtained, while in the same region a significant decrease in number of dopamine uptake sites occurred. Thus, in aging, P450IID6 and dopaminergic degeneration seem not to be functionally related in this region. Whether such a relation exists in PD is still to be examined.

Adult↗
PubMed1991

High-performance liquid chromatographic assay with ultraviolet detection for the determination of etoperidone and two active metabolites, 5-(1-hydroxyethyl) etoperidone and 1-(3-chlorophenyl)piperazine, in plasma.

A selective and sensitive high-performance liquid chromatographic assay with ultraviolet detection for the determination of the antidepressant drug etoperidone and two active metabolites in plasma is described. The drug, metabolites and internal standard are isolated from plasma using a two-step liquid-liquid extraction procedure. The resulting sample is chromatographed on a C18 column (10 cm x 2.1 mm I.D.) with ultraviolet detection at 254 nm. Standard curves are linear for each compound over the concentration range 2-1000 ng/ml. The accuracy and precision of the assay, expressed as the percentage deviation of measured values from the true value and the relative standard deviation (inter-run), are less than or equal to 10% at all concentrations except the minimum quantification limit. Using an automated injector and computerized data acquisition, eighty samples can be routinely processed in one day. The assay has been successfully used for the analysis of plasma samples from pharmacokinetic studies in mice, rats, dogs and humans.

Animals↗
PubMed2006

Synthesis of some substituted pyrazinopyridoindoles and 3D QSAR studies along with related compounds: piperazines, piperidines, pyrazinoisoquinolines, and diphenhydramine, and its semi-rigid analogs as antihistamines (H1).

3D QSAR studies on the title compounds led to the development of a model with three biophoric sites and six secondary sites viz. H-acceptor (ACC), H-donor (DON), heteroatom (presence), hydrophobic (hydrophobicity), steric (refractivity), and a ring (presence) along with total hydrophobicity and total refractivity as global properties. The model predicted the test set of compounds reasonably well. Three of the five newly synthesized 2-substituted octahydropyrazinopyridoindoles have shown potent antihistaminic H(1) activity with less toxicity and sedation potential.

Animals↗
PubMed2006

Privileged structure based ligands for melanocortin-4 receptors--aliphatic piperazine derivatives.

Aliphatic carbocyclic replacement of the benzyl group of compound 1 yielded compounds with high affinity for the melanocortin-4 receptor (MC4R). Compounds with a cyclohexyl group showed a consistent high affinity, while different polar groups with less basicity were good replacements for the original diethyl amines. Substitution of the polar group found in these privileged structures with an aliphatic moiety produced compounds with high affinity for MC4R.

Ligands↗
PubMed2006

Synthesis, antibacterial and antitubercular activities of some 7-[4-(5-amino-[1,3,4]thiadiazole-2-sulfonyl)-piperazin-1-yl] fluoroquinolonic derivatives.

In the present study, a series of 7-[4-(5-amino-1,3,4 thiadiazole-2-sulfonyl)]-1-piperazinyl fluoroquinolonic derivatives VIIa-d were synthesized in good yields and characterized by IR, (1)H-NMR, (13)C-NMR, FAB Mass spectral and elemental analyses. The compounds were evaluated for their preliminary in vitro antibacterial activity against some Gram-positive and Gram-negative bacteria and selected compounds VIIa, b were screened for antitubercular activity against Mycobacterium tuberculosis H(37)Rv strain by broth dilution assay method. The antibacterial data of the tested N-sulfonylfluoroquinolones VIIa-d indicated that all the synthesized compounds showed better activity against Gram-positive bacteria S. aureus, E. faecelis, Bacillus sp. (MIC=1-5 microg ml(-1), respectively) compared to reference drugs. The MIC values of tested derivatives connotes that the sparfloxacin and gatifloxacin derivatives VIIc, d were most active against the tested Gram-positive bacterial strains (MIC=1-5 microg ml(-1)). All the tested compounds VIIa-d showed poor activity against the Gram-negative bacteria. The in vitro antitubercular activity reports of selected compounds VIIa, b against M. tuberculosis strain H(37)Rv showed moderate activity at MIC of 10 microg ml(-1).

Anti-Bacterial Agents↗
PubMed2006

Structure-antibacterial activity of arylcarbonyl- and arylsulfonyl-piperazine 5-triazolylmethyl oxazolidinones.

A series of novel arylcarbonyl- and arylsulfonyl-piperazinyl 5-triazolylmethyl oxazolidinones were synthesized and tested against a panel of Gram-positive and Gram-negative bacterial clinical isolates. The arylcarbonyl oxazolidinone derivatives showed strong in vitro antibacterial activity against susceptible and resistant Gram-positive pathogenic bacteria and were more active than the arylsufonyl derivatives. Substitution of varied electron-withdrawing and electron-donating groups on the phenyl ring in the arylcarbonyl series did not alter antibacterial activity significantly. However, in the arylsufonyl series, methyl substitution on the phenyl ring resulted in the loss of antibacterial activity. Antibacterial activity could not be directly correlated with the calculated partition coefficient (ClogP) values in this series of compounds.

Anti-Bacterial Agents↗
PubMed2005

Identification, design, synthesis, and pharmacological activity of (4-ethyl-piperazin-1-yl)-phenylmethanone derivatives with neuroprotective properties against beta-amyloid-induced toxicity.

In search of novel therapeutic approaches for Alzheimer's disease (AD), we report herein the identification, design, synthesis, and pharmacological activity of (4-ethyl-piperaz-1-yl)-phenylmethanone derivatives with neuroprotective properties against beta-amyloid-induced toxicity. (4-ethyl-piperaz-1-yl)-phenylmethanone is a common substructure shared by molecules isolated from plants of the Asteraceae genus, traditionally used as restorative of lost or declining mental functions. (4-Ethyl-piperaz-1-yl)-phenylmethanone displayed strong neuroprotective properties against Abeta1-42 and reversed Abeta1-42-induced ATP depletion on neuronal cells, suggesting a mitochondrial site of action. Abeta1-42 has been described to induce a hyperactivity of the glutamate network in neuronal cells. (4-Ethyl-piperaz-1-yl)-phenylmethanone also inhibited the neurotoxic effect that glutamate displayed on PC12 cells, suggesting that the reduction of glutamate-induced neurotoxicity may be one of the mechanisms by which this compound exerts its neuroprotective properties against the deleterious effects of the Abeta1-42. These data suggest that the identified (4-ethyl-piperaz-1-yl)-phenylmethanone chemical entity exerts neuroprotective properties and may serve as a lead compound for the development of novel therapies for AD.

Adenosine Triphosphate↗
PubMed1996

Expression of Ca2+/calmodulin-dependent protein kinase types II and IV, and reduced DNA synthesis due to the Ca2+/calmodulin-dependent protein kinase inhibitor KN-62 (1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenyl piperazine) in small cell lung carcinoma.

Because changes in intracellular Ca2+ affect progression through the mitotic cell cycle, we investigated the role of Ca2+-binding proteins in regulating cell cycle progression. Evidence was found demonstrating that the activation of Ca2+/calmodulin-dependent protein kinase (CaM kinase) inhibits cell cycle progression in small cell lung carcinoma (SCLC) cells. We also demonstrated that SCLC cells express both CaM kinase type II (CaMKII) and CaM kinase type IV (CaMKIV). Five independent SCLC cell lines expressed proteins reactive with antibody to the CaMKII beta subunit, but none expressed detectable proteins reactive with antibody to the CaMKII alpha subunit. All SCLC cell lines tested expressed both the alpha and beta isoforms of CaMKIV. Immunoprecipitation of CaMKII from SCLC cells yielded multiple proteins that autophosphorylated in the presence of Ca2+ / calmodulin. Autophosphorylation was inhibited by the CaMKII(281-302) peptide, which corresponds to the CaMKII autoinhibitory domain, and by 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4- phenylpiperazine (KN-62), a specific CaM kinase antagonist. Influx of Ca2+ through voltage-gated Ca2+ channels stimulated phosphorylation of CaMKII in SCLC cells, and this was inhibited by KN-62. Incubation of SCLC cells of KN-62 potently inhibited DNA synthesis, and slowed progression through S phase. Similar anti-proliferative effects of KN-62 occurred in SK-N-SH human neuroblastoma cells, which express both CaMKII and CaMKIV, and in K562 human chronic myelogenous leukemia cells, which express CaMKII but not CaMKIV. The expression of both CaMKII and CaMKIV by SCLC cells, and the sensitivity of these cells to the anti-proliferative effects of KN-62, suggest a role for CaM kinase in regulating SCLC proliferation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗