Comparative receptor mapping of serotoninergic 5-HT3 and 5-HT4 binding sites*

The clinical use of currently available drugs acting at the5-HT₄ receptor has been hampered by their lack of selectivityover 5-HT₃ binding sites. For this reason, there is considerableinterest in the medicinal chemistry of these serotonin receptor subtypes, andsignificant effort has been made towards the discovery of potent and selectiveligands. Computer-aided conformational analysis was used to characterizeserotoninergic 5-HT₃ and 5-HT₄ receptorrecognition. On the basis of the generally accepted model of the5-HT₃ antagonist pharmacophore, we have performed a receptormapping of this receptor binding site, following the active analog approach(AAA) defined by Marshall. The receptor excluded volume was calculated as theunion of the van der Waals density maps of nine active ligands(pK_i 8.9), superimposed in pharmacophoric conformations.Six inactive analogs (pK_i < 7.0) were subsequently used todefine the essential volume, which in its turn can be used to define theregions of steric intolerance of the 5-HT₃ receptor. Five activeligands (pK_i 9.3) at 5-HT₄ receptors wereused to construct an antagonist pharmacophore for this receptor, and todetermine its excluded volume by superimposition of pharmacophoricconformations. The volume defined by the superimposition of five inactive5-HT₄ receptor analogs that possess the pharmacophoric elements(pK_i 6.6) did not exceed the excluded volume calculated forthis receptor. In this case, the inactivity may be due to the lack of positiveinteraction of the amino moiety with a hypothetical hydrophobic pocket, whichwould interact with the voluminous substituents of the basic nitrogen ofactive ligands. The difference between the excluded volumes of both receptorshas confirmed that the main difference is indeed in the basic moiety. Thus,the 5-HT₃ receptor can only accommodate small substituents inthe position of the nitrogen atom, whereas the 5-HT₄ receptorrequires more voluminous groups. Also, the basic nitrogen is located at ca.8.0 Å from the aromatic moiety in the 5-HT₄ antagonistpharmacophore, whereas this distance is ca. 7.5 Å in the5-HT₃ antagonist model. The comparative mapping of bothserotoninergic receptors has allowed us to confirm the three-componentpharmacophore accepted for the 5-HT₃ receptor, as well as topropose a steric model for the 5-HT₄ receptor binding site. Thisstudy offers structural insights to aid the design of new selective ligands,and the resulting models have received some support from the synthesis of twonew active and selective ligands: 24 (K_i(5-HT₃)= 3.7 nM; K_i(5-HT₄) > 1000 nM) and 25(K_i(5-HT₄) = 13.7 nM;K_i(5-HT₃) > 10 000 nM).     

A robust multisyringe system for process flow analysis. Part II. A multi-commuted injection system applied to the photometric determination of free acidity and iron(III) in metallurgical solutions

A new software-controlled volume-based system for sample introduction in process flow injection analysis was developed. By using a multi-syringe burette coupled with one or two additional commutation valves, the multi-commuted injection of precise sample volumes was accomplished. Characteristics and performance of the injection system were studied by injecting an indicator in a buffered carrier. Three configurations were implemented in order to achieve two different tasks: the single injection of a sample in a two- or three-channels manifold, and the dual injection into different streams. The two channel flow system using the single injection was applied to the determination of free acidity in diluted samples containing high levels of iron(III), by employing the single point titration methodology. The precipitation of ferric hydroxide was prevented using the ammonium and sodium salts of oxalate and acetate as buffer titrant. Methyl Red was employed as indicator. The procedure allows determination of acid concentration in solutions with a Fe(III)/H+ molar ratio up to 0.2. Samples with higher Fe(III)/H+ molar ratios were spiked with a known strong acid at dilution. The three-channel configuration was applied to the determination of ferric ions, using, as reagent, a merging mixture of sulfuric acid and potassium thiocyanate. The double injection system was implemented in series in a single (three-channel) manifold in such a way that a different injection volume and a changed reagent were used for each analyte. It was applied to the separated or sequential determination of free acidity and ferric ions. In this configuration, iron(III) was determined using 0.5-0.7% (w/v) sodium salicylate solution as reagent. The systems can operate at up to 100, 84 and 78 injections per hour, respectively. Determinations on synthetic and process samples compared well with the reference values and procedures. Recoveries of 95-102% with a maximum RSD value of 5.4% were found for acidity. The respective values obtained for iron determinations were 96-105% and 4.3%.     

Determination of six metals in galician red wines (in northwestern Spain) by capillary electrophoresis

A simple technique is described for the routine simultaneous capillary electrophoretic determination of 6 cations in wine. Separation was achieved on a fused silica capillary column with a UV-Cat-1, alpha-hydroxysobutyric acid and 18-crown-6-ether buffer at pH 4.5 and indirect UV detection at 214 nm. The content of magnesium, sodium, potassium, calcium, manganese, and lithium was determined. The method is quantitative, with recoveries in the 92-102% range, and linear over more than one order of magnitude. The precision is better than 2.5-3.4%. The method is sensible, with detection limits between 0.01 and 0.06 mg/L. Twenty-five red wines with a Certified Brand of Origin from Galicia (north-western Spain) were analyzed by the proposed method. Various wines showed very similar electrophoretic profiles, but significant quantitative differences were observed.     

Mössbauer Investigation of Characteristic Distribution of Iron Oxides in Sediments from the Antarctica

Sediments from the Admiralty Bay, King George Island, Antarctica, were investigated by ⁵⁷Fe Mössbauer spectroscopy, X-ray diffractometry, and radiometry. Quartz, feldspar, chlorite, calcite, dolomite, mica, kaolinite, hematite and magnetite were identified as constituent minerals in the sediment samples. The phase composition and the iron distribution among the crystallographic sites of iron-bearing minerals (silicates, magnetite and hematite) of samples from different location have been derived from the complex Mössbauer spectra. At different locations sediments had significant characteristic differences in the mineral composition, in the iron distribution among the crystallographic site of silicates, and in the specific radioactivity of Cs radionuclides. These results indicate differences in the rock formation and alteration by the sediments in this maritime part of Antarctica. There is a much higher amount of iron oxides in the sediments from south part of the geological fault across the Admiralty Bay than in the north part. This can be associated with much more alteration in the rocks in the south part compared to the northern one. This finding can contribute to the question of the history of the formation and alteration of volcanic rocks in the border of Antarctica.     

Photoinduzierte umlagerung von isoxazolinen: Syntheseweg zu 2,4,5,8-Tetrahedron-1,3-dicx-5-azocinen

A high yield 2,4,5,8-tetrahydro-1,3-diox-5-azocine synthesis, which employs a sequence of cycloaddition and photoinduced rearrangement has been developed.     

Lattice locations determination of trace amount carbon in gallium arsenide by theoretical calculation of CPAA with channeling

Combining the Charged Particle Activation Analysis (CPAA) and the Channeling Technique, the partial concentrations of the impurity carbon atoms in different crystal lattice locations of GaAs were claculated. The calculated results show that at lower total concentrations (0.3 ppm), carbon atoms occupy principally the octahedral and displaced octahedral interstitial positions, but at higher total concentrations (2 ppm), the substitutional carbon plays a principal role.     

Axial dispersion in a liquid fluidized bed of particles akin to immobilized enzymes

The axial dispersion of a liquid fluidized bed of controlled pore silica (CPS) particles has been determined by the pulse tracer method. The CPS used was the same as for enzyme immobilization, having an average diameter of 0.436 mm and mean pore size of 37.5 nm. The fluidization liquid is α-amylase liquefied manioc starch, 30% w/v, 45°C pH=4.5. Nominal bed porosities tested were 0.7 and 0.8. The results show that the axial dispersion coefficient increases with greater superficial liquid velocities. Various available correlations tested disagree with each other to a large extent and are unable to represent collected experimental data.     

Elucidating the N−N and C−N Bond-breaking Mechanism in the Photoinduced Formation of Nitrile Imine

In this study, we revealed the significance of chemical bonding for the photochemically induced mechanism of 2-phenyl tetrazole derivatives generating nitrile imines. The correlated electron localization function shows that the formation of imine nitrile involves two key bond events: (i) the heterolytic C−N breakage taking place in the T₁ state and (ii) the homolytic N−N rupture occurring in the T₂ excited state. In particular, a cation-radical specie results from the C−N cleavage, whereas the N−N rupture creates a biradical resonant form of imine nitrile. Additionally, we noticed that the substantial pair delocalization of the C−C-N bonded structure could play a significant role in the conversion of the biradical imine nitrile into both the propargylic and allenic forms via the T₁→S₀ deactivation.