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At least 217 records · Page 12Linked to original sources
PubMed2000

8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines: highly potent in vivo AMPA antagonists.

A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]++ +pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinities (IC50=4 and 19 nM, respectively) and antagonist properties (IC50 = 2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration.

Animals↗
PubMed2000

4,10-Dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid derivatives: highly potent and selective AMPA receptors antagonists with in vivo activity.

A novel series of 2-substituted-4,5-dihydro-4-oxo-4H-imidazo[1,2-a]indeno[1,2-e]pyrazine derivatives was synthesised. One of them, 4e-a highly water soluble compound exhibited a nanomolar affinity and demonstrated competitive antagonist properties at the ionotropic AMPA receptors. This compound also displayed potent anticonvulsant properties against electrically or sound-induced convulsions in mice after systemic administration, thus suggesting adequate brain penetration.

Animals↗
PubMed1999

Spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives are mixed AMPA and NMDA glycine-site antagonists active in vivo.

Original spiro-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one derivatives were synthesised and led to the identification of 3e which showed good affinities for both the AMPA and the NMDA glycine-site receptors, and displayed good anticonvulsant effects after i.p. and i.v. administrations in the electroshock-induced convulsion assay in mice. The corresponding dextrorotatory isomer (+)-3e was notably more potent than the levorotatory isomer (-)-3e in in vitro and in vivo assays.

Animals↗
PubMed2002

9-Carboxymethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one-2-carbocylic acid (RPR117824): selective anticonvulsive and neuroprotective AMPA antagonist.

Excessive release of glutamate, a potent excitatory neurotransmitter, is thought to play an important role in a variety of acute and chronic neurological disorders, suggesting that excitatory amino acid antagonists may have broad therapeutic potential in neurology. Here, we describe the synthesis, pharmacological properties and neuroprotective activity of 9-carboxymethyl-imidazo-[1-2a]indeno[1-2e]pyrazin-4-one-2-carboxylic acid (RPR117824), an original selective AMPA antagonist. RPR117824 can be obtained through a six-step synthesis starting from (1-oxo-indan-4-yl) acetic acid, which has been validated on a gram-scale with an overall yield of 25%. Monosodium or disodium salts of the compound exhibit excellent solubility in saline (> or = 10 g/L), enabling intravenous administration. RPR117824 displays nanomolar affinity (IC(50)=18 nM) for AMPA receptors and competitive inhibition of electrophysiological responses mediated by AMPA receptors heterologously expressed in Xenopus oocytes (K(B)=5 nM) and native receptors in rat brain slices (IC(50)=0.36 microM). In in vivo testing, RPR117824 behaves as a powerful blocker of convulsions induced in mice or rats by supramaximal electroshock or chemoconvulsive agents such as pentylenetetrazole, bicuculline, isoniazide, strychnine, 4-aminopyridine and harmaline with half maximal effective doses ranging from 1.5 to 10 mg/kg following subcutaneous or intraperitoneal administration. In disease models in rats and gerbils, RPR117824 possesses significant neuroprotective activity in global and focal cerebral ischemia, and brain and spinal cord trauma.

Animals↗
PubMed2001

Calculated gas-phase infrared spectra of 2,2,5,5,8,8-hexamethylhexahydroimidazo [1,2-a]-pyrazine-3,6-dione: relative performance of Hartree-Fock and hybrid density functional theory methods.

Geometric parameters and IR spectra of 2,2,5,5,8,8-hexamethylhexahydroimidazo[1,2-a]pyrazine-3,6-dione were computed by the HF, B3LYP, B3P86 and B3PW91 methods with the 6-31G(d) basis set. All the computation methods produce a boat conformation of the six-membered ring with the orientation opposite to the one experimentally observed, that is obviously due to incapability of such calculations to take into account mutual influence of the molecules in a crystal package. Quality of predicting the interatomic distances observed experimentally decreases in the series HF, B3LYP, B3PW91 and B3P86; for bond angles, in the series B3LYP, P3PW91, B3P86 and HF. At the same time, the IR spectra computed are in a good agreement with the observed FTIR spectrum. The correlation between the calculated and experimental vibration frequencies is characterized by the coefficients higher than 0.9999 for all three DFT methods; for HF it is slightly lower than 0.9995. The calculated absolute band intensities satisfactory match the observed relative intensities as well. Optimal uniform scaling factors calculated are 0.8973, 0.9593, 0.9540 and 0.9552 for HF, B3LYP, B3P86 and B3PW91, respectively.

Imidazoles↗
PubMed1995

Differential effects of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate analogs modified at position C2 on tubulin polymerization, binding, and conformational changes.

NSC 613863 (R)-(+) and NSC 613862 (S)-(-) (CI980) are two chiral isomers of ethyl 5-amino 2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate which have potent antitubulin activity. The S-isomer is a more potent antimitotic compound than the R-isomer, and the two isomers differ markedly in binding to tubulin [Leynadier, D., Peyrot, V., Sarrazin, M., Briand, C., Andreu, J. M., Rener, G. A., & Temple, C., Jr. (1993) Biochemistry 32, 10675-10682]. To understand the origin of such differences, we studied the interactions of three R- and S-isomer structural analogs which differ in C2 (the chiral carbon), i.e., C179, NSC 337238, and NSC 330770. C179 is a methylated dehydrogenated achiral compound. It bound to tubulin with an apparent affinity Ka of (2.29 +/- 0.17) x 10(4) M-1, inhibited tubulin polymerization in vitro at a half-inhibitory concentration (IC50) of 100 microM, and presented no GTPase activity. The substitution of -CH3 by -H leads to the NSC 337238 compound. It bound to tubulin with a higher affinity [Ka = (2.62 +/- 0.35) x 10(5) M-1] and inhibited tubulin polymerization at a lower concentration (IC50 = 14 microM). It presented no GTPase activity and induced the formation of abnormal polymers at a protein critical concentration (Cr) of 2 mg mL-1. NSC 330770, a demethylated hydrogenated molecule, interacted strongly with tubulin [Ka = (3.30 +/- 0.56) x 10(6) M-1].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1998

The active GTP- and ground GDP-liganded states of tubulin are distinguished by the binding of chiral isomers of ethyl 5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3,4-b]pyrazin-7-yl carbamate.

NSC 613862 (S)-(-) and NSC 613863 (R)-(+) are the two chiral isomers of ethyl-5-amino-2-methyl-1,2-dihydro-3-phenylpyrido[3, 4-b]pyrazin-7-yl carbamate. Both compounds bind to tubulin in a region that overlaps the colchicine site. They induce formation of abnormal polymers from purified GTP-Mg-tubulin, the active assembly form of tubulin, in glycerol-free buffer with magnesium [De Ines, C., Leynadier, D., Barasoain, I., Peyrot, V., Garcia, P., Briand, C., Rener, G. A., and Temple, C., Jr. (1994) Cancer Res. 54, 75-84]. In this study, we observed that the S-isomer can promote polymerization of GDP-tubulin, the inactive assembly-incompetent form of tubulin, into nonmicrotubular structures at a critical protein concentration of 1 mg/mL (12 mM MgCl2). Neither the R-isomer nor colchicine have this ability. By electron microscopy, these tubulin polymers showed the same poorly defined filamentous structure when GDP-tubulin or GTP-Mg-tubulin were used. By HPLC measurements, we demonstrated that a dissociated GTP hydrolysis and exchange of nucleotide occurred during the isomer-induced abnormal assembly. Both isomers inhibited the Mg2+-induced tubulin self-association leading to 42 S double ring formation from GTP-Mg-tubulin or GDP-tubulin. Measurement of their binding under nonassociation conditions revealed a 3-fold decrease in the apparent equilibrium binding constant of the R-isomer to GDP-tubulin relative to GTP-Mg-tubulin. For the S-isomer, the decrease in the binding constant was less pronounced. Binding data, analyzed in terms of a system of linked conformational and association equilibria, provide evidence that the active ("straight") rather than the inactive ("curved") conformation of tubulin differentially recognizes these ligands. Whereas binding of colchicine to tubulin is well-known to induce GTP hydrolysis, this is the first case in which the interaction of a ligand with the colchicine site is shown to be sensitive to the presence of GDP or GTP at the distant nucleotide binding site.

Guanosine Diphosphate↗
PubMed2000

Threshold-based structure-activity relationships of pyrazines with bell-pepper flavor.

Quantitative structure activity relationships (QSAR) and comparative molecular field analysis (CoMFA) are applied in order to explain the aroma of 46 bell-pepper aroma compounds. Biological activities log(1/c) values are used, where c stands for the detection threshold value of the aroma compound in water. Results of conventional QSAR and CoMFA are both satisfactory in statistical significance and predictive ability. We construct a qualitative model using the graphic features of CoMFA together with the results of "classical" QSAR analysis, which is performed by multiple linear regression. Finally, the human olfactory detection threshold values of excluded pyrazines are successfully predicted. This makes CoMFA and QSAR two important tools for designing new aroma compounds and in elucidating the mechanism of odor-receptor interaction.

Humans↗
PubMed2002

Aroma quality differentiation of pyrazine derivatives using self-organizing molecular field analysis and artificial neural network.

The encoding of various aroma impressions and the distinction between different aroma qualities are unsolved problems, as differences between aroma impressions can be described only in a qualitative but not in a quantitative manner. As a consequence, classifications of various aroma qualities cannot easily be performed by standard QSAR methods. To find a proper way to encode aroma impressions for SAR studies, a total of 50 pyrazine-based aroma compounds showing the aroma quality of earthy, green-earthy, or green are analyzed. Special attention is thereby turned on the mixed aroma impression green-earthy. Classifications on the whole data set as well as on smaller subsets are calculated using self-organizing molecular field analysis (SOMFA) and artificial neural networks (ANNs). SOMFA classifies between two or three aroma impressions, leading to models satisfying in predictive power. ANN analysis using multilayer perceptron network architecture with one hidden layer and nominal output as well as genetic regression neural network) with two hidden layers and numerical output both lead to a rather good performance rate of 94%.

Neural Networks, Computer↗
PubMed1999

Effects of roasting on pyrazine contents and oxidative stability of red pepper seed oil prior to its extraction.

Red pepper seeds were roasted with constant stirring for 6, 9, 10, and 12 min at 210 degrees C, and oils were extracted from the roasted red pepper seeds using an expeller. The iodine values and fatty acid compositions of red pepper seed oils did not change with roasting time. The fatty acid composition of the oil obtained from the red pepper seeds roasted for 6 min was 0.24% myristic acid, 13. 42% palmitic acid, 0.33% palmitoleic acid, 2.07% stearic acid, 10. 18% oleic acid, 73.89% linoleic acid, and 0.37% linolenic acid, showing a fatty acid composition similar to that of high-linoleate safflower oil. Thirteen alkylpyrazines were identified in the roasted red pepper seed oils: 2-methylpyrazine, 2,5-dimethylpyrazine, 2,6-dimethylpyrazine, 2-ethylpyrazine, 2-ethyl-6-methylpyrazine, 2-ethyl-5-methylpyrazine, trimethylpyrazine, 2,6-diethylpyrazine, 2-ethyl-3,5-dimethylpyrazine, tetramethylpyrazine, 2, 3-diethyl-5-methylpyrazine, 2-isobutyl-3-methylpyrazine, and 3, 5-diethyl 2-methylpyrazine. The pyrazine content increased markedly as the roasting time increased, showing 2.63, 5.01, 8.48, and 13.10 mg of total pyrazine/100 g of oils from the red pepper seeds roasted for 6, 8, 10, and 12 min, respectively, at 210 degrees C. 2, 5-Dimethylpyrazine in the roasted red pepper seed oil seemed to be the component most responsible for the pleasant nutty aroma of the oils. The oxidative stabilities of oils increased greatly as the roasting time increased.

Capsicum↗
PubMed1992

Antimitotic agents: ring analogues and derivatives of ethyl [(S)-5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7- yl]carbamate.

The synthesis of ring analogues and derivatives of the S isomer of ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl[carbamate, (S)-1, a potent antimitotic agent with anticancer activity, was directed toward the determination of the contribution of several structural features of this compound to biological activity. Replacement of the 5-amino with a 5(6H)-oxo group and either transposing the 6-ring nitrogen to or incorporation of a ring nitrogen at the 8-position caused a significant decrease in in vitro activity and destroyed in vivo activity. Although in vivo cytotoxicity was reduced, in vitro activity at higher doses relative to (S)-1 was retained by replacement of the 5-amino group with hydrogen and by expansion of the 1,2-dihydropyrazine to give a dihydro-1,4-diazepine ring.

Animals↗
PubMed1991

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 3.1 Synthesis and biological properties of aminodeoxystatine and difluorostatone derivatives.

Two series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity have been synthesized which incorporate the transition-state mimetics (3S,4S)- and (3R,4S)-5-cyclohexyl-3,4-diaminopentanoic acid ((S)- and (R)-CDAPA), and (4S)-4-amino-5-cyclohexyl-2,2-difluoro-3-oxopentanoic acid (ACDFOPA). Several compounds in these series, for example 13a, 19c, and 19f, were highly potent inhibitors of partially purified human renin (IC50 values of 3.9, 1.6, and 1.4 nM, respectively). The ACDFOPA-based compounds 19c and 19f contain no natural amino acid fragments and have molecular weights which compare well with those of previously reported inhibitors of nanomolar in vitro potency. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 3 mg/kg, compounds 13a and 19c caused a marked reduction in mean arterial pressure, but in the same animal model at 30 mg/kg, oral activity was not seen.

Amino Acids, Diamino↗
PubMed1990

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives.

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

Amino Acids↗
PubMed1983

1,2-Dihydropyrido[3,4-b]pyrazines: structure-activity relationships.

Certain derivatives containing the 1,2-dihydropyrido[3,4-b]pyrazine (1-deaza-7,8-dihydropteridine) ring system are active against experimental neoplasms in mice. The mechanism of action of these agents has been attributed to the accumulation of cells at mitosis. Identification of the structural features that are necessary for activity was accomplished by evaluation of modified 1-deazapteridines and ring and ring-opened analogues. Relative to ethyl 4-amino-1-deaza-7,8-dihydro-6-[(N-methylanilino)methyl]pteridine-2-carbamate (11) and the corresponding 6-phenyl compound (12), no antitumor activity was observed with 7,8-dihydropteridines, 3-deaza-7,8-dihydropteridines, and the corresponding heteroaromatic compounds. Also, activity was diminished or destroyed when 1-deaza-7,8-dihydropteridines were oxidized to 1-deazapteridines or reduced to 1-deaza-5,6,7,8-tetrahydropteridines. In addition, replacement of the 4-amino group with other substituents destroyed activity. The presence of a 6-substituent containing an aryl group appeared to be necessary for activity, which was increased when a methyl group was substituted at the 7-position.

Animals↗
PubMed1984

Biological activity and a modified synthesis of 8-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-a]pyrazine, an isomer of formycin.

A two-step synthesis of 8-amino-3-beta-D-ribofuranosyl-1,2,4-triazolo[4,3-a]pyrazine (3), which is an isomer of formycin that resembles 3-deazaadenosine, is reported. Compound 3 is also described as as being a very poor substrate for adenosine deaminase and to be both a competitive and an irreversible inhibitor of S-adenosylhomocysteinase in the synthesis direction. L1210 cell growth in culture was inhibited by 3. Compound 3 was not converted to the nucleotide level in erythrocytes but was found to inhibit both the cellular uptake of nucleic acid precursors and their incorporation into the nucleic acids of L1210 cells. Finally, 3 was found to be a weak antiviral agent and coronary vasodilator.

Adenosine Deaminase↗