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At least 721 records · Page 40Linked to original sources
PubMed1998

Differential induction of rat hepatic microsomal epoxide hydrolase and rGSTA2 by diazines: the role of cytochrome P450 2E1-mediated metabolic activation.

Previous studies have shown that pyridazine (PD) and pyrazine (PZ) are efficacious in inducing microsomal epoxide hydrolase (mEH) in the liver with elevation of the mRNA level. The present study was designed to investigate the expression of mEH and rGSTA2 genes in response to the diazines including PD, PZ and pyrimidine (PM) and the basis for their enzyme induction. Rats treated with either PD or PZ for 3 days resulted in marked increases in mEH and rGSTA2 mRNA levels with concomitant induction of the proteins, whereas PM failed to elevate the mRNA levels. Treatment of rats with a single dose of PD or PZ showed dose-dependent increases in mEH and rGSTA2 mRNA levels at 24 h with ED50 values being approximately 10 mg/kg. Time-course studies showed that the mRNA levels were increased to maximal extents at 24-48 h after treatment. Studies were extended to assess the mechanistic basis for the enzyme induction by PD and PZ. beta-Naphthoflavone (BNF) caused a 6-fold increase of rGSTA2 mRNA in the liver (100 mg/kg per day, p.o., 3 days), as compared to control, whereas the agent failed to increase mEH mRNA level. Administration of PD or PZ (50 mg/kg) to BNF-pretreated rats resulted in no enhanced increase of the mEH mRNA as compared to the individual treatment, while the rGSTA2 mRNA level was additively elevated, suggesting the possibility that increases of the mEH and rGSTA2 mRNAs by PD or PZ might be mediated with antioxidant responsive element(s) in the genes, but not with xenobiotic responsive element. Western blot analysis revealed that cytochrome P450 2E1 was induced 3- to 4-fold by both PD and PZ, whereas PM failed to induce P450 2E1. Concomitant treatment of rats with PD or PZ in combination with acetone, a substrate for P450 2E1, caused no significant increase in the mEH and rGSTA2 mRNA levels relative to that in untreated animals, whereas PD or PZ treatment without a concomitant acetone administration resulted in marked increases of the mRNAs. Diazine-inducible mEH and rGSTA2 mRNA levels were approximately 2-fold enhanced in P450 2E1-induced starved rats, as compared to those in diazine-treated unstarved animals. These data indicate that P450 2E1-mediated bioactivation of the diazines might contribute to transcriptional activation of the mEH and GST genes. These results provide evidence that both PD and PZ efficaciously induce mEH and rGSTA2 in the liver with increases in the mRNA levels, while PM is ineffective, and that induction of mEH and rGSTA2 may be mediated through bioactivation of the diazines by P450 2E1.

Acetone↗
PubMed2000

Effects of RPR 118723, a novel antagonist at the glycine site of the NMDA receptor, in vitro.

RPR 118723 ((8-chloro-5-methyl-2,3-dioxo-1,4-dihydro-5H-indeno[1, 2-b]pyrazin-5-yl) acetic acid) was previously reported to exhibit potent affinity for the glycine site of the N-methyl-D-aspartate (NMDA) receptor-channel complex in the nanomolar range (K(i)=3.1+/-0. 8 nM). We now report on the effects of RPR 118723 in two functional tests reflecting the interaction between the glycine site and the NMDA receptor. First, RPR 118723 potently inhibited [3H]N-[1-(2-thienyl)cyclohexyl]-3,4-piperidine ([3H]TCP) binding in the presence of NMDA (IC(50)=3.5+/-0.4 nM). Second, RPR 118723 antagonized the NMDA-induced increase in [3H]dopamine release in mouse striatal slices (IC(50)=8.0+/-1.1 nM). In both experimental models, an excess of glycine reversed the effect of RPR 118723. These results show that RPR 118723 interferes functionally in the nanomolar range with the glycine site coupled to the NMDA receptor in vitro. The blockade of the glycine site with RPR 118723 may be useful for the therapy of the disorders linked to excessive NMDA stimulation.

Animals↗
PubMed1996

Interaction of S 21007 with 5-HT3 receptors. In vitro and in vivo characterization.

The interaction of S 21007 [5-(4-benzyl piperazin-1-yl)4H pyrrolo [1,2-a]thieno[3,2-e]pyrazine] with serotonin 5-HT3 receptors was investigated using biochemical, electrophysiological and functional assays. Binding studies using membranes from N1E-115 neuroblastoma cells showed that S 21007 is a selective high affinity (IC50 = 2.8 nM) 5-HT3 receptor ligand. As expected of an agonist, S 21007 stimulated the uptake of [14C]guanidinium (EC50 approximately 10 nM) in NG 108-15 cells exposed to substance P, and this effect could be prevented by the potent 5-HT3 receptor antagonist ondansetron. In addition, like 5-HT and other 5-HT3 receptor agonists (phenylbiguanide and 3-chloro-phenylbiguanide), S 21007 (EC50 = 27 microM) produced a rapid inward current in N1E-115 cells. The 5-HT3 receptor agonist action of S 21007 was also demonstrated in urethane-anaesthetized rats as this drug (120 micrograms/kg i.v.) triggered the Bezold-Jarisch reflex (rapid fall in heart rate), and this action could be prevented by pretreatment with the potent 5-HT3 receptor antagonist zacopride. Finally, in line with its 5-HT3 receptor agonist properties, S 21007 also triggered emesis in the ferret. Evidence for 5-HT3 receptor antagonist-like properties of S 21007 was also obtained in some of these experiments since previous exposure to this compound prevented both the 5-HT-induced current in N1E-115 cells and the Bezold-Jarisch reflex elicited by an i.v. bolus of 5-HT (30 micrograms/kg) in urethane-anaesthetized rats. These data suggest that S 21007 is a selective 5-HT3 receptor agonist which can exhibit antagonist-like properties either by triggering a long lasting receptor desensitization or by a partial agonist activity at 5-HT3 receptors in some tissues.

Animals↗
PubMed1997

Chelerythrine, a protein kinase C inhibitor, interacts with cyclic nucleotide phosphodiesterases.

Chelerythrine, a potent inhibitor of protein kinase C, was evaluated for its effect on cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta. Chelerythrine activated basal PDE2 and inhibited activated PDE2, PDE4 and PDE5. The effect of chelerythrine (10 microM) was also investigated on vasorelaxation induced by a beta-adrenoceptor agonist or a PDE3 inhibitor. Chelerythrine attenuated the isoprenaline-mediated relaxation whereas it potentiated the relaxation induced by SK & F 94120 (5-(4)acetamidophenyl)pyrazin-2(1 H)-one, a PDE3 inhibitor). The present study demonstrates that chelerythrine, at a concentration generally reported in the literature to inhibit protein kinase C, interacts with cyclic nucleotide phosphodiesterases and consequently modulates vasorelaxation. These results cast some doubt on the use of chelerythrine as a specific inhibitor of protein kinase C.

Adrenergic beta-Agonists↗
PubMed1997

Effects of SCA40 on bovine trachealis muscle and on cyclic nucleotide phosphodiesterases.

While UK-93,928 (1-[[3-(6,9-dihydro-6-oxo-9-propyl-1H-purin-2-yl)-4-ethoxyphenyl] sulfonyl]-4-methylpiperazine; 5 nM-5 microM) was devoid of relaxant activity, benzafentrine, isoprenaline, levcromakalim and SCA40 (6-bromo-8-methylaminoimidazo[1,2-a]pyrazine-2-carbonitrile) each relaxed histamine (460 microM)-precontracted bovine isolated trachealis. Each of these relaxants was antagonised by a K+-rich (80 mM) medium. Except in the case of levcromakalim, nifedipine (1 microM) offset this antagonism. Charybdotoxin (100 nM) antagonised isoprenaline in a nifedipine-sensitive manner but did not antagonise SCA40 or benzafentrine. Iberiotoxin (100 nM) did not antagonise SCA40. Acting on tissue precontracted with carbachol, SCA40 potentiated isoprenaline but did not potentiate sodium nitroprusside. While levcromakalim (1 and 10 microM) induced hyperpolarisation, SCA40 (1 and 10 microM) induced little change in the membrane potential of bovine trachealis. In trachealis preloaded with 86Rb+, levcromakalim (1 and 10 microM) promoted efflux of the radiotracer while SCA40 (1 and 10 microM) had no effect. Tested as an inhibitor of isoenzymes of cyclic nucleotide phosphodiesterase, SCA40 was most potent against the type III, less potent against the type IV and least potent against the type I isoenzyme. It is concluded that neither inhibition of phosphodiesterase type V nor the promotion of BKCa channel opening explains the tracheal smooth muscle relaxant activity of SCA40. This compound relaxes bovine tracheal smooth muscle mainly by inhibiting phosphodiesterase isoenzyme types III and IV.

Animals↗
PubMed1997

1,2-Diacylglycerol hydroperoxides induce the generation and release of superoxide anion from human polymorphonuclear leukocytes.

We examined the effect of 1-palmitoyl-2-linoleoylglycerol (PLG), PLG hydroxide (PLG-OH), and PLG hydroperoxide (PLG-OOH) on the release of superoxide anion from human PMNs monitored by the chemiluminescence generated by the superoxide anion-sensitive reagent, 2-methyl-6-(p-methoxyphenyl)-3,7-dihydroimidazo[1,2-a]pyrazin++ +-3-one (MCLA). PLG-OOH at low micromolar concentrations stimulated human PMNs whereas PLG and PLG-OH did not. 1,3-Dilinoleoylglycerol hydroperoxide, 1-palmitoyl-2-linoleoylphosphatidylcholine hydroperoxide, and linoleic acid hydroperoxide were much less efficient in stimulating human PMNs than PLG-OOH. The PKC inhibitors, chelerythrine chloride and staurosporine, inhibited the stimulation of PMNs. Possible pathophysiological role of 1,2-diacylglycerol hydroperoxides is discussed.

Diglycerides↗
PubMed2000

Headspace solid-phase microextraction method for determining 3-alkyl-2-methoxypyrazines in musts by means of polydimethylsiloxane-divinylbenzene fibres.

A method for determining 2-methoxypyrazine, 3-methyl-, 3-ethyl-, 3-isopropyl-, 3-sec.-butyl- and 3-isobutyl-2-methoxypyrazine in musts is described. It involves headspace solid-phase microextraction (SPME) and determination by capillary gas chromatography using nitrogen-phosphorous detection. Pyrazines were satisfactorily separated under isothermal conditions, and quantification was carried out using 3-isopropyl-2-ethoxypyrazine as the internal standard. Ionic strength, time and temperature were studied in order to make SPME as efficient as possible. The developed method enabled detection limits at the 0.1 ng(-1) levels for some of the analytes. The method was successfully applied to identify and quantify different 3-alkyl-2-methoxypyrazines in experimental musts of Cabernet Sauvignon and Merlot. Their evolution during the ripening was also monitored.

Osmolar Concentration↗
PubMed2004

Different roles of 5-HT2A and 5-HT2C receptors in regulation of female rat paced mating behaviour.

Serotonin (5-HT) receptor 2A (5-HT2A) and 2C (5-HT2C) agonists have been reported to facilitate female rat lordosis behaviour. This study investigated the acute effects of the 5-HT2A receptor agonist DOI ((+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane) and the 5-HT2C receptor agonist MK-212 (2-chloro-6-(1-piperazinyl) pyrazine) on paced mating behaviour in a population of sexually receptive female rats in order to explore the role of 5-HT2A and 5-HT2C receptors in the mediation of female rat sexual motivation. DOI (0.5 and 1.0 mg/kg) increased female rat sexual motivation during the first of two consecutive copulatory series seen as a tendency towards a decrease in return latencies following ejaculation and decreased inter-intromission intervals. MK-212 generally increased approach latencies. 0.5 mg/kg MK-212 increased post-ejaculatory exit latency, while 1.0 and 2.0 mg/kg MK-212 increased both post-ejaculatory exit latencies and post-ejaculatory return latencies. The possibility that an increased level of anxiety confounded the effects of MK-212 on sexual motivation behaviour is discussed. The results may support the hypothesis that both 5-HT2A and 5-HT2C receptors are important in regulation of female sexual behaviour.

Amphetamines↗
PubMed2001

Imidazo[1,2-a]quinoxalines: synthesis and cyclic nucleotide phosphodiesterase inhibitory activity.

A group of imidazo[1,2-a]quinoxalines have been synthesised from quinoxaline by condensation of an appropriate haloester or intramolecular cyclisation of a keto moiety on an intracyclic nitrogen atom. The reactivity of the heterocycle was explored through diverse reactions such as electrophilic substitution, lithiation and halogen-metal exchange to give access to a new series of derivatives. Confirmation of their structure was mainly performed by NMR, after careful assignment of the signals in comparison to previous attributions made on the parent imidazo[1,2-a]quinoxaline and discussion of available data in the literature. The cyclic nucleotide phosphodiesterase inhibitor activity of some of these derivatives has been assessed on isoenzymes type III and type lV. Compound 15, 4-(methylamino)imidazo[1,2-a]quinoxaline-2-carbonitrile, exhibited potent relaxant activity on smooth muscle, with a potency similar to the one measured with SCA 40, its structural analogue in the imidazo[1,2-a]pyrazine series.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2001

Inhibitory effect of nicergoline on superoxide generation by activated rat microglias measured using a simple chemiluminescence method.

We evaluated the effect of nicergoline on superoxide production by rat microglias using a 2-methyl-6-(p-methoxyphenyl)-3, 7-dihydroimidazo[1,2-a]pyrazin-3-one-dependent chemiluminescence assay. Nicergoline dose-dependently inhibited superoxide production by microglias stimulated with phorbol myristate acetate or opsonized zymosan, while it had no effect on superoxide production by a hypoxanthine-xanthine oxidase system. These results indicate that nicergoline does not have a scavenging effect, but has an inhibitory effect on superoxide generation by microglias. Although this drug is commonly used for treating chronic cerebral infarction, it may also have a protective effect on progression of Parkinson's disease or Alzheimer's disease.

Animals↗
PubMed2000

Synthesis and potent anticonvulsant activities of 4-oxo-imidazo[1,2-a]inden.

The over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a] indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid derivatives. One of these compounds, 4f, exhibited nanomolar binding affinity, potent competitive antagonism at the ionotropic AMPA receptor and a long duration of anticonvulsant activity after administration by parenteral route in vivo.

Animals↗
PubMed2001

Synthesis of anticonvulsive AMPA antagonists: 4-oxo-10-substituted-imidaz.

The overstimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been implicated in the physiopathogenesis of epilepsy as well as in acute and chronic neurodegenerative disorders. An original series of readily water soluble 4-oxo-10-substituted-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives was synthesized. The most potent derivative 6a exhibited nanomolar binding affinity (IC50 = 35nM) and antagonist activity (IC50 = 6nM) at ionotropic AMPA receptor. This compound also demonstrated potent anticonvulsant properties in MES in mice and rats with long durations of action with ED50 values in the 1-3 mg/kg dose range following ip and iv administration.

Animals↗
PubMed2003

Protective effect of imidazolopyrazinone antioxidants on ischemia/reperfusion injury.

A series of 2-substituted 3,7-dihydroimidazolo[1,2-a]pyrazine-3-ones has been synthesized and evaluated for their antioxidant activity. Compounds 1-8 are inhibitors of AAPH-induced lipid peroxidation (in vitro) and excellent protectors against microvascular damages in ischemia/reperfusion (in vivo). Hence, the bicyclic structure typical of coelenterazine (luciferin) could be considered as a useful lead in medicinal chemistry.

Amidines↗
PubMed2001

Catechol derivatives of aminopyrazine and cell protection against UVB-induced mortality.

A series of 5-aryl- and 3,5-bis-aryl-2-amino-1,4-pyrazine derivatives 4 and 6, and related imidazolopyrazinones 7, has been synthesized, the aryl groups of which are catechol and/or phenol substituents. These compounds, tested against human keratinocyte cells stressed by UVB irradiation, showed high antioxidative properties. One compound (6f) was more active than EGCG/ECG (green tea extract) in reducing cell mortality.

Antioxidants↗
PubMed1997

TRH mimetics: differentiation of antiamnesic potency from antidepressant effect.

For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a- octahydro-5H,10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln2]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH.

Amino Acid Sequence↗
PubMed1985

Proton NMR of aequorin. Structural changes concomitant with calcium-independent light emission.

Aequorin, a Ca(II)-sensitive bioluminescent protein from jellyfish, emits light at 469 nm from an excited state of a substituted pyrazine (oxyluciferin) which results from the oxidation of a chromophore molecule that is noncovalently bound to the protein. The chromophore is oxidized when Ca(II) or other activating metal ions are bound by aequorin. In the absence of Ca(II), spontaneous emission of light, referred to as Ca(II)-independent light emission, occurs at a rate less than 10(-6) of that for Ca(II)-induced emission. Proton nuclear magnetic resonance (NMR), circular dichroism (CD), and fluorescence were used to study structural changes of aequorin accompanying Ca(II)-independent light emission. Time course studies by 1H NMR and CD demonstrate that as a result of Ca(II)-independent light emission, aequorin progressively changes from a rigid, fully active form showing little segmental mobility to a practically unfolded, discharged (i.e., inactive) form in which a number of amino acid residues are significantly mobile. This slow discharged protein (SDP) is distinct in nature and conformation from aequorin which has been discharged by Ca(II), i.e., the blue fluorescent protein. The rate of Ca(II)-independent discharge of aequorin is substantially reduced in the presence of excess Mg(II); the time constant for inactivation at 5 degrees C is 30 days with no Mg(II) present and 70 days with Mg(II) present. The NMR spectra are nearly identical at a given stage of inactivation whether or not Mg(II) is present. Oxyluciferin remains bound to SDP. If it is removed, however, by column chromatography, the resulting apo-SDP partially refolds, and the segmental mobility acquired in the formation of SDP is significantly attenuated particularly for some of the aromatic amino acid residues.

Aequorin↗