József Nagy

Evaluation of interfacial interaction in polypropylene/surface treated CaCO3 composites

Abstract Interfacial interactions significantly influence the properties of particulate filled polymers. The adhesion between the particles and the polymer matrix depends on the size (area) of the interface and the strength of the interaction. While the former quantity is related to the specific surface area of the filler, the strength of the interaction can be modified by its surface treatment. In the current experiments polypropylene composites were prepared which contained different amounts of filler treated with eight functional trialkoxy silane coupling agents and the routinely used stearic acid, for comparison. Tensile properties of the composites were determined and the effect of interfacial interaction was evaluated by semi-empirical equations developed previously. Significant difference was detected in the effect of the various silane coupling agents. Amino functional silanes increase the strength of the interaction considerably. The other coupling agents reduce the surface tension of the filler, which leads to a decrease in the reversible work of adhesion between the filler and the polymer. These changes result in a decrease in the tensile strength of the composite. The results also prove the validity of the model equations applied. Parameter B, a measure of the strength of the interaction, was calculated for each silane coupling agent thus quantitatively characterizing their effectiveness.

Possible coupling reactions of functional silanes and polypropylene

Abstract Apparent reactive coupling of CaCO3 to polypropylene (PP) was achieved with the application of aminofunctional silane coupling agents. The strong coupling effect could be attributed to increased CaCO3/silane and PP/silane interaction. A detailed study has shown that aminofunctional silanes bond strongly to the surface of the filler, but in the case of multilayer coverage also to the previous layers. Experiments were carried out to determine the mechanism of interaction between the silane coupling agents and the apolar polypropylene, which does not contain reactive groups. Model reactions followed by (Fourier Transform Infrared Spectroscopy) FTIR analysis demonstrated that during processing at elevated temperatures, oxidation of the polymer takes place in spite of the presence of stabilizers. Reactive carbonyl groups form as a result, which enter into chemical reactions with the amino functionality of the silane, resulting in strong amide bonds.

An organocatalytic ionic liquid

The carbene concentration in 1-ethyl-3-methylimidazolium-acetate ionic liquid is sufficiently high to act as a catalyst in benzoin condensation, hydroacylation and also in oxidation of an alcohol by using CO(2) and air. This observation reveals the potential of ionic liquid organocatalysts, uniting the beneficial properties of these two families of compounds.

Crytal and molecular structures of γ-1-phenylsilatrane: some structural features of silatranes

γ-1-phenylsilatrane crystallizes in the monoclinic space group P 2 1 / n , with a 8.475, b 12.949, c 11.122 » and β 90.86°. The structure was determined by direct methods and was refined to R 0.078 for 1687 observed reflexions and 0.081 for all 1813 reflexions. The →Si bond length is 2.132(4), SiC is 1.894(5) ». The mean SiO bond distance is 1.656 A, angle NSiC is 179.0(2)°. The average NSiO, CSiO and OSiO angles are 83.6, 96.4 and 123.5°. By use of published data for six other silatrane molecules, some structural features were established. Thus, the length of the N→Si bond is affected by the other apical substituents of the silicon atom, the number of oxygen atoms attached to it and steric effects. Increase in the length of the dative N→Si bond is accompanied by further distortion of the trigonal bipyramidal configuration and of the tetrahedron around the nitrogen atom. The relatively long SiC( sp 2 ) bond may be due to decrased d π  p π interaction. The crystalline modifications (α, β, ψ) of the 1-phenyl-derivative possibly result from rapid ring-inversion in solution.

NR2B subunit selective NMDA antagonists inhibit neurotoxic effect of alcohol-withdrawal in primary cultures of rat cortical neurones

N-Methyl-D-aspartate (NMDA) receptor-mediated glutamatergic neurotransmission is thought to play a central role in the development of alcohol dependence and this alteration is supposed to be due to a differential up-regulation of the NR2B type of subunits. In this work, we examined the effect of some known (CP-101,606; CI-1041 and Co-101,244) and novel indole-2-carboxamide derivative NR2B subunit selective NMDA receptor antagonists (SSNAs) (RG-13579 and RG-1103) on the neurotoxic effect of withdrawal in ethanol pre-treated cultures of rat cortical neurones. The extent of neurotoxicity was estimated by measuring the activity of lactate dehydrogenase (LDH) that was released into the culture medium during the 24h withdrawal period. Here, we demonstrate that NR2B SSNAs given in the course of the withdrawal potently reduced the LDH release in ethanol pre-treated cultures. One of our novel compound, RG-1103, proved to be more potent than the reference NR2B SSNAs tested in this work having similar potency as the most potent but non-subunit selective NMDA receptor antagonist dizocilpine (MK-801). Acamprosate, a currently used therapeutic drug for the treatment of alcoholism was also effective although only in high micromolar concentrations. According to these observations, NR2B SSNAs are potent inhibitors of ethanol-withdrawal-induced neurotoxicity and considering that these agents have acceptable side effect profiles, they could be promising therapeutic candidates in the pharmacotherapy for physical signs of acute alcohol-withdrawal and associated neuronal damage.

An abnormal N-heterocyclic carbene-carbon dioxide adduct from imidazolium acetate ionic liquids: the importance of basicity.

In the reaction of 1-ethyl-3-methylimidazolium acetate [C2C1Im][OAc] ionic liquid with carbon dioxide at 125 °C and 10 MPa, not only the known N-heterocyclic carbene (NHC)-CO2 adduct I, but also isomeric aNHC-CO2 adducts II and III were obtained. The abnormal NHC-CO2 adducts are stabilized by the presence of the polarizing basic acetate anion, according to static DFT calculations and ab initio molecular dynamics studies. A further possible reaction pathway is facilitated by the high basicity of the system, deprotonating the initially formed NHC-CO2 adduct I, which can then be converted in the presence of the excess of CO2 to the more stable 2-deprotonated anionic abnormal NHC-CO2 adduct via the anionic imidazolium-2,4-dicarboxylate according to DFT calculations on model compounds. This suggests a generalizable pathway to abnormal NHC complex formation.

GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine.

Accumulating evidence has indicated the involvement of glutamatergic neurotransmission in the pathophysiology of excitotoxicity and in the mechanism of action of antidepressants. We have previously shown that tricyclic desipramine and the selective serotonin reuptake inhibitor fluoxetine inhibit NMDA receptors (NMDARs) in the clinically relevant, low micromolar concentration range. As the different subtypes of NMDARs are markedly different in their physiological and pathological functions, our aim was to investigate whether the effect of antidepressants is subtype-specific. Using whole-cell patch-clamp recordings in rat cortical cell cultures, we studied the age-dependence of inhibition of NMDA-induced currents after treatment with desipramine and fluoxetine, as the expression profile of the NMDAR subtypes changes as a function of days in vitro. We also investigated the inhibitory effect of these antidepressants on NMDA-induced currents in HEK 293 cell lines that stably expressed rat recombinant NMDARs with GluN1a/GluN2A or GluN1a/GluN2B subunit compositions. The inhibitory effect of desipramine was not age-dependent, whereas fluoxetine displayed a continuously decreasing inhibitory profile, which was similar to the GluN1/GluN2B subtype-selective antagonist ifenprodil. In HEK 293 cells, desipramine equally inhibited NMDA currents in both cell lines, whereas fluoxetine showed an inhibitory effect only in cells that expressed the GluN1/GluN2B subtype. Our data show that fluoxetine is a selective inhibitor of GluN2B-containing NMDARs, whereas desipramine inhibits both GluN1/GluN2A and GluN1/GluN2B subtypes. As the clinical efficacy of these drugs is very similar, the putative NMDAR-associated therapeutic effect of antidepressants may be mediated only via inhibition of the GluN2B-containing subtype. The manifestation of the GluN1/GluN2B-selectivity of fluoxetine suggests the neuroprotective potential for this drug in both acute and chronic neurodegenerative disorders.

Methylene substitution at the α-β bridging position within the phosphate chain of dUDP profoundly perturbs ligand accommodation into the dUTPase active site

dUTP pyrophosphatase, a preventive DNA repair enzyme, contributes to maintain the appropriate cellular dUTP/dTTP ratio by catalyzing dUTP hydrolysis. dUTPase is essential for viability in bacteria and eukaryotes alike. Identification of species‐specific antagonists of bacterial dUTPases is expected to contribute to the development of novel antimicrobial agents. As a first general step, design of dUTPase inhibitors should be based on modifications of the substrate dUTP phosphate chain, as modifications in either base or sugar moieties strongly impair ligand binding. Based on structural differences between bacterial and human dUTPases, derivatization of dUTP‐analogous compounds will be required as a second step to invoke species‐specific character. Studies performed with dUTP analogues also offer insights into substrate binding characteristics of this important and structurally peculiar enzyme. In this study, α,β‐methylene‐dUDP was synthesized and its complex with dUTPase was characterized. Enzymatic phosphorylation of this substrate analogue by pyruvate kinase was not possible in contrast to the successful enzymatic phosphorylation of α,β‐imino‐dUDP. One explanation for this finding is that the different bond angles and the presence of the methylene group may preclude formation of a catalytically competent complex with the kinase. Crystal structure of E. coli dUTPase:α,β‐methylene‐dUDP and E. coli dUTPase:dUDP:Mn complexes were determined and analyzed in comparison with previous data. Results show that the “trans” α‐phosphate conformation of α,β‐methylene‐dUDP differs from the catalytically competent “gauche” α‐phosphate conformation of the imino analogue and the oxo substrate, manifested in the shifted position of the α‐phosphorus by more than 3 Å. The three‐dimensional structures determined in this work show that the binding of the methylene analogue with the α‐phosphorus in the “gauche” conformation would result in steric clash of the methylene group with the protein atoms. In addition, the metal ion cofactor was not bound in the crystal of the complex with the methylene analogue while it was clearly visible as coordinated to dUDP, arguing that the altered phosphate chain conformation also perturbs metal ion complexation. Isothermal calorimetry titrations indicate that the binding affinity of α,β‐methylene‐dUDP toward dUTPase is drastically decreased when compared with that of dUDP. In conclusion, the present data suggest that while α,β‐methylene‐dUDP seems to be practically nonhydrolyzable, it is not a strong binding inhibitor of dUTPase probably due to the altered binding mode of the phosphate chain. Results indicate that in some cases methylene analogues may not faithfully reflect the competent substrate ligand properties, especially if the methylene hydrogens are in steric conflict with the protein. Proteins 2008.

Indole-2-carboxamides as Novel NR2B Selective NMDA Receptor Antagonists

A novel series of indole-2-carboxamide derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the number and position of OH groups on the indole skeleton as well as the substitution of the piperidine ring on the biological activity of the compounds was studied.

Inducible expression and pharmacology of recombinant NMDA receptors, composed of rat NR1a/NR2B subunits.

An ecdysone-inducible mammalian expression system was used to study expression of recombinant N-methyl-D-aspartate (NMDA) receptors. Human embryonic kidney (HEK) 293 cells expressing the regulatory vector pVgRXR (EcR 293 cells) were transfected with rat NR1a and NR2B cDNAs using the inducible vector pIND (Invitrogen). Inducible expression of the NR2B subunit in cell clone designated EcR/rNR1a2B was investigated using quantitative RT-PCR and flow cytometry based immunocytochemical methods. The mRNA level of the NR2B subunits in EcR/rNRa2B cells was dependent on the concentration of the ecdysone analogue inducing agent, muristerone A (MuA). Similarly, NR2B subunit protein expression was higher in cells pre-treated with the inducing agent. Functionally active NMDA receptors were also detected in EcR/rNR1a2B cells after MuA induction. In presence of the inducing factor, NMDA-evoked ion currents as well as increase in cytoplasmic calcium-concentrations were measured using whole-cell patch clamp and fluorometric calcium measuring techniques. The pharmacological profile of the expressed NMDA receptors was characterised by comparing the inhibitory activity of several NR2B subunit selective NMDA antagonists in EcR/rNR1a2B cells with that observed in primary cultures of rat cortical neurones. Whereas the efficacies of the NR2B subunit selective NMDA antagonists were similar in EcR/rNR1a2B cells and in neurones, their maximal inhibitory effects were significantly higher in cells expressing NR1a/NR2B recombinant receptors. This study demonstrates that recombinant NMDA receptors can be expressed in an inducible way in non-neuronal cell lines using the ecdysone-inducible mammalian expression system. Such cell lines can be suitable tools in high throughput functional screening for potential subtype selective modulators of the NMDA receptor.