Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “PYRAZINES”

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 253 records · Page 14Linked to original sources
PubMed1998

Chemopreventive effects of 2-(allylthio)pyrazine on hepatic lesion, mutagenesis and tumorigenesis induced by vinyl carbamate or vinyl carbamate epoxide.

2-(Allylthio)pyrazine (2-AP), synthesized for its possible use as a hepatoprotective agent, has been found to selectively inhibit rat hepatic cytochrome P450 2E1 (Kim et al., Biochem. Pharmacol., 53, 261-269, 1997), while it enhances the activities of phase II detoxification enzymes such as glutathione S-transferase and epoxide hydrolase. As part of a program in evaluating the chemopreventive potential of 2-AP, we have determined its effects on hepatotoxicity, mutagenicity and tumorigenicity of vinyl carbamate (VC), a prototypic hepatocarcinogen preferentially activated by P450 2E1 to the ultimate carcinogenic metabolite vinyl carbamate epoxide (VCO), which undergoes detoxification by glutathione conjugation and oxirane hydrolysis. Administration of 2-AP (100 mg/kg body wt) to male Sprague-Dawley rats by gavage, 2 days, 1 day and 4 h prior to VC or VCO, markedly ameliorated the hepatotoxicity of these compounds as determined by decreased serum aspartate aminotransferase and alanine aminotransferase activities. Furthermore, 2-AP pre-treatment significantly suppressed the VC-induced hepatocarcinogenesis in infant male B6C3F1 mice. In a separate experiment, the multiplicities of skin tumors formed in female ICR mice treated with 5.8 micromol of VC or VCO were inhibited 58 and 70%, respectively, by pre-treatment with 2-AP by oral administration. The mutational spectrum of ras-oncogene in papillomas was not altered by 2-AP pre-treatment. 2-AP also inhibited the mutagenicity of VC in the Salmonella-microsome assay. Taken together, these findings suggest that 2-AP is a potential chemopreventive agent.

Animals↗
PubMed1995

Affinities of nutty and green-smelling pyrazines and thiazoles to odorant-binding proteins, in relation with their lipophilicity.

Thirty-two green- and/or nutty-smelling compounds, most of them pyrazine and thiazole derivatives, were tested in ligand binding assays with purified 19 kDa bovine and 22 kDa porcine olfactive binding proteins (OBPs). Unlike the nutty ones, all the green odorants were found to be good ligands for both proteins. Lipophilicity appears as an interesting discriminating physicochemical parameter, predictive of the affinity for OBPs and of the related odour profile.

Animals↗
PubMed1978

A 5-hydroxytryptamine-like mode of anorectic action for 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212).

The mechanism of the reduction in food consumption elicited by 6-chloro-2-[1-piperazinyl]-pyrazine (MK-212) administered systemically was investigated in the rat. (+/-)-Fenfluramine and (+)-amphetamine were included in some studies for comparative purposes. 2 Pretreatment with methergoline, a 5-hydroxytryptamine (5-HT) antagonist, reduced the magnitude of the anorectic effect of 1.5 and 3 mg/kg of MK-212, while the anti-5-HT agents, cyproheptadine and cinanserin, were likewise effective against the 3 mg/kg dose. 3 Xylamidine, an antagonist of 5-HT that penetrates poorly into the central nervous system, completely blocked the decrease in food intake caused by 5-HT administered peripherally, while not antagonizing an equianorectic dose of MK-212. 4 Reduction of brain 5-HT by intraventricular injection of 5,6-dihydroxytryptamine, intraperitoneal administration of p-chloroamphetamine or placement of a lesion in the region of the median raphé nucleus diminished the anorectic response to 3 mg/kg of MK-212. The anorectic effect of amphetamine was reduced by p-chloroamphetamine or lesion in the raphé, but not by 5,6-dihydroxytryptamine. The decrease in food consumption produced by 1.5 mg/kg of MK-212 was antagonized by prior treatment with p-chloroamphetamine, but not by 5,6-dihydroxytryptamine. 5 Haloperidol, which blocks receptors for dopamine, antagonized the anorexigenic effect of amphetamine, but was ineffective in offsetting the action of MK-212, 3 mg/kg. 6 Pretreatment with chlorimipramine to inhibit the 5-hydroxytryptaminergic uptake mechanism did not affect the anorectic response to 3 mg/kg of MK-212, whereas the response to fenfluramine was diminished. 7 The results indicate that the anorectic action of MK-212 involves a 5-HT-like component which is more evident at the higher dose level of the compound. The anorexigenic property of MK-212 may depend, at least partly, upon the integrity of 5-HT-containing neurones in the central nervous system.

5,6-Dihydroxytryptamine↗
PubMed1979

Synthesis, properties and biological activity of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide -- a new ligand for epithelial sodium channels.

A method is described for the synthesis and purification of tritiated N-benzylamidino-3,5-diamino-6-chloro-pyrazine carboxamide (benzamil). The tritium was inserted at the meta position of the benzyl ring, from which it apparently does not exchange with solvent hydrogen. When stored in ethanol at -4 degrees C the radioligand remains stable for at least 15 months. The pharmacology of benzamil is very similar to that of amiloride in terms of its effects on sodium transporting epithelia except that it has a higher affinity. The affinity of benzamil for sodium channels in amphibian epithelia in the absence of sodium is approximately 10(9) M-1. The new ligand can be used to label sodium channels in epithelia, and may be useful in channel isolation procedures.

Amiloride↗
PubMed2004

Cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine-based inhibitors of human N-myristoyltransferase-1.

N-myristoyltransferase (NMT) is an emerging therapeutic target that catalyzes the attachment of myristate to the N terminus of an acceptor protein. We have developed a medium-throughput assay for screening potential small molecule inhibitors of human NMT-1 consisting of recombinant enzyme, biotinylated peptide substrate, and [3H]myristoyl-CoA. Approximately 16,000 diverse compounds have been evaluated, and significant inhibition of NMT was found with 0.8% of the compounds. From these hits, we have identified the cyclohexyl-octahydropyrrolo[1,2-a]pyrazine (COPP) chemotype as inhibitory toward human NMT-1. Thirty-two compounds containing this substructure inhibited NMT-1, with IC(50) values ranging from 6 microM to millimolar concentrations, and a quantitative structure-activity relationship equation (r(2) = 0.72) was derived for the series. The most potent inhibitor (24, containing 9-ethyl-9H-carbazole) demonstrated competitive inhibition for the peptide-binding site of NMT-1 and noncompetitive inhibition for the myristoyl-CoA site. Computational docking studies using the crystal structure of the highly homologous yeast NMT confirmed that 24 binds with excellent complementarity to the peptide-binding site of the enzyme. To evaluate the ability of 24 to inhibit NMT activity in intact cells, monkey CV-1 cells expressing an N-myristoylated green fluorescent protein (GFP) fusion protein were treated with a known NMT inhibitor or with 24. Each compound caused the redistribution of GFP from the plasma membrane to the cytosol. Furthermore, 24 inhibits cancer cell proliferation at doses similar to those that inhibit protein myristoylation. Overall, these studies establish an efficient assay for screening for inhibitors of human NMT and identify a novel family of inhibitors that compete at the peptide-binding site and have activity in intact cells.

Acyltransferases↗
PubMed1991

Inhibitory effects of tetramethyl and tetraethyl derivatives of pyrazine on dog saphenous vein.

The effects of two structurally similar pyrazine derivatives, tetramethylpyrazine (TMP) and tetraethylpyrazine (TEP) on the contractile responses of dog saphenous vein to KCl (via membrane depolarization), phenylephrine (PHE, alpha 1-adrenergic agonist), and B-HT 920 (alpha 2-adrenergic agonist) were investigated. The relaxant or inhibitory effect of TMP and TEP was most potent on KCl-induced responses and least potent on PHE-induced responses. Their effect on KCl-induced responses was more prominent at 30 mM KCl than at 100 mM KCl. In Ca(2+)-free medium, PHE and B-HT 920 elicited transient responses, which were also markedly and reversibly inhibited by TMP and TEP. Similar results were also obtained when prostaglandin F2 alpha was used as an agonist. In all four types of contractile responses involving different receptors, the inhibitory effect of TEP was consistently more potent than that of TMP. We conclude that both TMP and TEP behave as a nonselective smooth muscle relaxant having similar and multiple actions including their general interference with the processes involving both Ca2+ entry and intracellular Ca2+ release.

Animals↗
PubMed1993

Synthesis and antithyroid activity of pyridine, pyrimidine and pyrazine derivatives of thiazole-2-thiol and 2-thiazoline-2-thiol.

A series of compounds was synthesized by linking various derivatives of pyridine, pyrimidine or pyrazine to thiazole-2-thiol or to its partially hydrogenated derivative 2-thiazoline-2-thiol. The reactions of the compounds with molecular iodine and lactoperoxidase were examined in vitro. Their antithyroid activity was also examined in vivo in the rat. T4 and TSH levels were determined, and the thyroid gland was examined histologically. 2-(3-Hydroxy-2-pyridyl)-2-thiothiazoline had the highest antithyroid activity of the compounds tested (Kc = 14931.mol(-1),IC(50)0.65 x 10(-4) M, activity of thyroid gland).

Animals↗
PubMed1998

2-Oxopyrrolidines and 6-oxoperhydropyrrolo[1,2-a]pyrazines as templates in the search for nonpeptide cholecystokinin ligands.

In order to find new classes of non-peptide cholecystokinin (CCK) ligands, the conformational restriction of a series of weak 3-oxoindolizidine-based CCK antagonists has been both decreased and increased. This tactic yielded a series of monocyclic 2-oxopyrrolidine derivatives 4 with selectivity for CCK-A or CCK-B receptors and with slightly improved binding affinity at the CCK-A receptor subtype with respect to the model 3-oxoindolizidines. In contrast, the incorporation of the Trp residue at the secondary amino group of a pyrrolo[1,2-a]pyrazine template 5, involving a drastic restriction in the conformational flexibility of the molecule, resulted in a series of bicyclic derivatives that did not bind to CCK receptors at concentrations up to 10(-5) M.

Animals↗
PubMed2000

Hydrophobicity parameters determined by reversed-phase liquid chromatography. Xiv. Application of a new hydrogen-accepting scale of monosubstituted pyrazines to analysis of the relationship between octanol-water partition coefficients and retention factors measured in different mobile phases.

We recently proposed a new H-accepting scale, SHA, for monosubstituted pyrazines, and demonstrated that this parameter works effectively in expressing the relationship between logP (P: 1-octanol/water partition coefficient) and logk' (k': retention factor derived from reversed phase liquid chromatography) with aqueous methanol solutions as the mobile phase, according to the equation: logk' = alogP+rhosigmaI+sSHA+const., where sigmaI represents the electronic substituent constant. In this work, we have extended the same treatment to analysis of logk' measured in mobile phases containing different organic modifiers such as 1-propanol, acetonitrile, and dioxane, and found that the above equation is still useful. By comparing the correlations obtained, it was confirmed that the parameter SHA could be universally utilized for representing the difference in H-bonding effects involved in different partitioning systems.

Chromatography, Liquid↗
PubMed2002

Synthesis of 2-amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine.

2-Amino-3-benzyl-5-(p-hydroxyphenyl)pyrazine (2), a precursor of Watasenia preluciferin (coelenterazine) (1), is widely distributed in marine bioluminescent animals. It was prepared from p-hydroxyphenylglyoxal aldoxime (5) in two steps; by condensation with or-aminophenylpropiononitrile in the presence of TiCl4 in pyridine, followed by reduction of the resulting N-oxide (6) with Zn-AcOH in CH2Cl2 and produced 2, with an 89% overall yield. This procedure was linked with the facile one-step preluciferin synthesis reported in the previous paper. Thus, Watasenia preluciferin (1), frequently required for various chemiluminescent and bioluminescent studies, was coveniently synthesized in three steps from 5, with a 56% overall yield, overcoming the difficulty of obtaining it from natural sources.

Imidazoles↗
PubMed2004

Synthesis and structure-activity relationships of 4,10-dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine derivatives: highly potent and selective AMPA receptor antagonists with in vivo activity.

The excitatory neurotransmitter glutamate interacts with ionotropic and metabotropic receptors that mediate a variety of normal signalling processes in the brain. However, excessive stimulation of these receptors appears to be involved in neurodegenerative processes, at least in animal models. Ionotropic glutamate receptors can be divided into NMDA and non-NMDA (AMPA and KA) subtypes on the basis of t heir preferential affinities for the synthetic excitatory amino acids N-methyl-D-aspartic acid (NMDA) or 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA), respectively. Although most of the early evidence favoured a role for NMDA receptors in the excitotoxic processes, it has been recognised that AMPA receptors may also be significantly involved in neuronal death. As a consequence, the synthesis of specific AMPA antagonists has raised much interest as source of potential drugs for epilepsy and acute and chronic neurodegenerative diseases. The discovery of RPR117824, a potent and selective AMPA receptors antagonist endowed with anticonvulsant and neuroprotective properties, induced growing interest on dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine series. This review covers the main chemical course leading to the most promising compounds as well as the pharmacological properties of this original class of AMPA receptor antagonists.

Amyotrophic Lateral Sclerosis↗
PubMed1999

Molecular basis for hepatic detoxifying enzyme induction by 2-(allylthio)pyrazine in rats in comparison with oltipraz: effects on prooxidant production and DNA degradation.

The expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs) by 2-(allylthio)pyrazine (2-AP), an experimental chemopreventive agent, was investigated in rats. Northern blot analysis revealed that 2-AP caused increases in mEH, rGSTA2/3/5, and rGSTM1/2 mRNA levels. mEH and rGSTA2 proteins were also induced. Molecular basis of the enzyme induction by 2-AP was studied in comparison with oltipraz (Olt). Rats exposed to buthionine sulfoximine, a GSH-depleting agent, before treatment with either 2-AP or Olt exhibited greater increases in the mRNA levels than the individual treatment. Conversely, increases of the mRNAs were prevented by cysteine treatment, indicating that metabolic intermediates or reactive oxygens produced from the agents could be reduced by cysteine. Gel shift analysis revealed that nuclear factor-kappaB, which is associated with the altered cellular redox state, was not activated by the agents. Effects of these agents on the breakage of phix-174 DNA were compared in vitro. 2-AP effectively reduced the conversion of supercoiled DNA to the open circular form induced by benzenetriol and prevented benzenetriol- and iron-catalyzed degradation of DNA, whereas Olt failed to prevent strand breakage of DNA. These results provided evidence that: 1) 2-AP was effective in elevating the hepatic mEH and GST gene expression in rats, which might be mediated with the production of reactive oxygen species; 2) nuclear factor-kappaB activation was not involved in the induction of the detoxifying enzymes by either 2-AP or Olt in spite of their production of reactive oxygens in vivo; and 3) the antioxidant effect of 2-AP in vitro differed from that of Olt.

Animals↗
PubMed1998

[The inhibitory effect in vitro of salvia miltiorrhiza and tetramethyl pyrazine on the growth of fibroblasts].

In order to investigate the inhibitory effect of salvia miltiorrhiza (SM) and tetramethyl pyrazine (TP) on scartricial fibroblast, the hypertrophic scar tissue of chest was chosen for culture of fibroblasts, and the influence of SM and TP on fibroblasts was observed, The effect of the drugs on the growth of fibroblasts, on DNA synthesis of fibroblasts and on mitosis index of fibroblasts were all determined quantitatively. The results showed: 1. SM and TP could inhibit significantly the growth of the fibroblasts, the inhibitory effect was irreversible when the concentration of the drugs reached 5 mg/ml and 500 micrograms/ml respectively; 2. SM and TP could inhibit the absorption of 3H-TdR and this effect was correlated positively to the dosage of the drugs and; 3. SM and TP could reduce the mitosis index of fibroblasts. It was concluded that SM and TP had definite depressive effect on growth of fibroblasts which was correlated positively with the concentration of drugs and duration of application. The inhibitory effect of the drugs on fibroblasts was mainly through inhibition of synthesis of DNA.

Burns↗
PubMed1998

[The influence of salvia miltiorrhiza and tetramethyl pyrazine on DNA content of cicatricial fibroblasts and its cellular cycle].

In order to study the mechanism of the inhibitory effect of salvia miltiorrhiza (SM) and tetramethyl pyrazine (TP) on scar fibroblast, the DNA content of fibroblast and the all distribution in cellular cycle was measured by FCM. The hypertrophic scar tissue of chest was chosen for primary culture of fibroblast. Then this cultured cell was reacted with SM and TP. FCM was used to measure the DNA index and duration of cellular cycle. The results showed that: 1. SM and TP had little effect on DNA index, but when the concentration of drugs reached the threshold, they could increase the amount of fibroblasts in C2-M stage and the duration of G2-M stage was prolonged; 2. TP could also prolong the duration of S-stage; 3. SM and TP could prolong the multiplication time of fibroblasts and this effect was correlated postively with the dosage of drug. The conclusions were that the inhibitory effect of SM was the result of inhibiting the mitosis of cells and the cellular cycle be at a standstill in G2-M stage. The inhibitory effect of TP was due to the inhibition of synthesis and duplication of DNA and cellular mitosis, and the cellular cycle was also at a standstill in G2-M stage.

Burns↗
PubMed1999

Prophylactic effects of tetramethyl pyrazine on mice with endotoxemia and its relationship with platelet-activating factor.

AIM: To study the prophylactic effects of tetramethyl pyrazine (TMP) on mice with endotoxemia and its relationship with platelet-activating factor (PAF). METHODS: LD80 of lipopolysaccharides (LPS, 15 mg.kg-1) was injected into mice (i.v.) pretreated with TMP (i.p.). The survival rate and the level of serum PAF were observed. The PAF induced by LPS in vivo and in vitro, and the activities of PLA2 and acetyl-CoA: lyso-PAF acetyltransferase were determined. RESULTS: TMP (10, 30, 90 mg.kg-1) obviously lowered the mortality of mice and also dose-dependently decreased the level of serum PAF [(25.5 +/- 1.7), (13.4 +/- 3.2), (9.6 +/- 2.1) micrograms.L-1, vs control (29.3 +/- 2.1) micrograms.L-1, P < 0.01]. TMP (0.05, 0.5, 5, 50 mumol.L-1) dose-dependently decreased the release of PAF [(12.7 +/- 1.6), (8.9 +/- 1.2), (6.9 +/- 0.8), (5.5 +/- 1.0) micrograms.L-1 vs control (11.9 +/- 1.8) micrograms.L-1, P < 0.01] from PMO cultured with LPS (5 mg.L-1), reduced the PLA2 activity [(149.9 +/- 2.8), (117.5 +/- 2.0), (89.6 +/- 2.0), (75.0 +/- 2.8) U vs control (170.8 +/- 3.9) U, P < 0.01] and acetyl-CoA: lyso-PAF acetyltransferase activity [PAF (9.5 +/- 0.7), (5.2 +/- 0.7), (2.9 +/- 0.3), (2.5 +/- 0.3) micrograms.g-1 (protein).min-1 vs control (11.0 +/- 0.7) micrograms.g-1 (protein).min-1, P < 0.01] of PMO lysate. CONCLUSION: TMP protected the mice with endotoxemia from the death by decreasing the biosynthesis of PAF through the inhibition of the activities of PLA2 and acetyl-CoA: lyso-PAF acetyl-transferase.

Acetyltransferases↗
PubMed2001

Effect of tetramethyl pyrazine on L-type calcium channel in rat ventricular myocytes.

To elucidate possible ionic mechanisms of antimyocardial ischemia and antiarrythmia of tetramethyl pyrazine (TP), we studied L-type Ca2+ currents (I(Ca.L)) in adult rat ventricular myocytes using the whole-cell patch-clamp technique. The results showed: (i) under physiological conditions, 0.25 mmol/L TP decreased amplitude of I(Ca.L) to 60.6% and this inhibition was increased with increasing concentration of TP. ID50 was 0.20 mmol/L. (ii) The Ca2+-antagonistic effect of TP was voltage-dependent. A marked negative shift of the steady-state inactivation curve was observed with long (10 s) conditioning prepulses, but not with short (350 ms) ones. (iii) The time course of inhibition during TP treatment was increased with an increase in drug concentration, and recovery from TP-induced inactivation of I(Ca.L) was slower than in control cases. (iv) Tonic block and use-dependent block with TP treatment, which was induced by increasing the frequency of stimulation, occurred. We suggest that TP inhibits the I(Ca.L) mainly by binding to inactivated Ca2+ channels. The high affinity of TP for the inactivated state of I(Ca.L) may play an important role in developing therapies for pathological conditions.

Animals↗
PubMedDate not supplied

[Comparison of DNA complexation with antitumor therapeutic cis-DDP and binuclear bivalent platinum compound containing pyrazine].

Conformational properties of DNA molecule upon its complexation with binuclear compounds of bivalent platinum in the cis configuration containing pyrazine ligand were studied by circular dichroism, viscometry, and dynamic birefringence. Comparison with active antitumor therapeutic cis-diamminedichloroplatinum (cis-DDP) was made. Experimental data indicates that interaction of these compounds with DNA results in the formation of coordination bond of platinum with nitrogen bases. The structure of the complex depends on the ratio of platinum and DNA concentrations in initial solution. The study of DNA protonation in complex with the binuclear coordination compound showed that the binding of platinum with DNA bases occurs at the N7 atom of guanine. It was observed a competition between the studied compound and cis-DDP for binding site on DNA. The macromolecule binds stronger to the binuclear platinum compound as compared with cis-DDP.

Antineoplastic Agents↗