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Biomedical subjects

R Brasseur

Publications and source records attributed to R Brasseur.

At least 181 records · Page 10Linked to original sources
PubMed1984

Mode of organization of lipid aggregates: a conformational analysis.

A computational approach is used to predict the mode of organization of lipid molecules. The calculated aggregate states are fully compatible with the lipid phase preference: bilayers for dipalmitoylphosphatidylcholine, micelles for palmitoyllysophosphatidylcholine, and inverted structures for protonated dioleoylphosphatidic acid. The minimal conformational energy of the isolated molecule is calculated as the sum of the contributions resulting from the Van der Waals interactions, the torsional potentials, the electrostatic interactions, and the transfer energy. Assembly of these structures in monolayers yields the most probable modes of organization of lipids. The described method may represent a useful tool to predict the phase preference of lipids and to give a molecular description of their mode of association.

Chemical Phenomena↗
PubMed1984

Sequence of ionophore conformational changes induced by a simulated membrane/water interface.

We demonstrate how the progressive passage through an interface simulated by a linear increase in dielectric constant may mediate a reversible transconformation of Na+/X537A (lasalocid A) from a cyclic to an extended structure. During the passage through the interface, the complex adopts progressively a more extended conformation favorable to the Na+ complexation or decomplexation at the interface.

Energy Transfer↗
PubMed1984

Conformational analysis of 6-cis- and 6-trans-leukotriene B4-calcium complexes.

We present a computational description of the conformation of a pair of two isomeric molecules (6-cis-and 6-trans-leukotriene B4) forming a complex with one calcium ion. Our theoretical prediction of the membrane-water interface conformation and of the bulk lipid phase conformation of the two different isomeric complexes are in excellent agreement with experimental data on the leukotriene-mediated calcium ionophoresis in liposomes. The two isomers lead to vastly different conformations in the presence of Ca2+, and the most probable conformation of the permeant species shows a globular conformation able to cross a lipid membrane.

Calcium↗
PubMed1984

Evidence of a thromboxane A2-Ca2+ complex: a conformational approach.

Thromboxane A2 has been proposed as an ionophore capable to transport calcium from the platelet dense tubular system to the cytoplasm to activate the contractile proteins. However the half-life (30 sec.) of this compound limits considerably the experimental approach. The conformational analysis is proposed here as a possible way to identify such transient conformations. We bring evidence of the existence of two Ca2+-thromboxane A2 isomeric complexes: one structure responsible for the complexation-decomplexation process at the interface and one lipophilic structure able to cross the lipid membrane.

Calcium↗
PubMed1983

Mode of organization of galactolipids: a conformational analysis.

Despite the fact that photosynthetic membranes show the conventional bilayer structure, their major lipid component monogalactosyldiacylglycerol does not form lamellar structure but takes up an hexagonal-II structure when dispersed alone in water and forms inverted lipids micelle structures when dispersed together with other lipid components of the photosynthetic membrane. We present here evidence that the mode of organization of these lipids can be predicted from a conformational approach allowing to describe the configuration of assembled amphiphilic molecules. The minimal conformational energy is calculated as the sum of the contributions resulting from the Van der Waals interactions, the torsional potentials, the electrostatic interaction and the transfer energy. Because of its calculated "cone shaped" structure monogalactosyldiacylglycerol forms inverted lipid structure with the hydrophilic groups pointing inward; for digalactosyldiacylglycerol, an other essential lipid constituent of photosynthetic membrane, its calculated cylindrical shape induces an organization in bilayer structures.

Galactolipids↗
PubMed1983

Lipid-water interface mediates reversible ionophore conformational change.

A new procedure of conformational analysis was used to demonstrate that the ionophore conformation is mediated by its membrane environment. In the hydrophobic lipid matrix, the ionomycin-Ca++ complex adopts a conformation well suited for translocation across the interior of the membrane whereas at the lipid-water interface, the Ca++ ion is immersed into the aqueous phase in a position favorable to its complexation or decomplexation. The translocation of Ca++ across the lipid bilayer supposes a reversible transformation of the two conformers. The conformational analysis shows how the dielectric constant discontinuity existing at the lipid-water interface mediates the reversible transformation of one structure into the other.

Calcium↗
PubMed1983

Mode of insertion of miconazole, ketoconazole and deacylated ketoconazole in lipid layers. A conformational analysis.

The conformation of three imidazole derivatives, miconazole, ketoconazole and deacylated ketoconazole (R 39 519) inserted in a lipid layer was calculated using a procedure of conformational analysis. For each imidazole derivative all probable conformers were inserted into a dipalmitoyl phosphatidylcholine (DPPC) monolayer. Miconazole maintains its two dichlorophenyl groups in the hydrophobic phase whereas the imidazole moiety is orientated in the hydrophilic phase. Ketoconazole orientates its dichlorophenyl group in the hydrophobic phase whereas its acylated piperazine moiety is orientated towards the hydrophobic region. Deacylation inverses completely the orientation of the compound. The most probable conformer of R 39 519 is inserted in the lipid layer with its piperazine moiety orientated towards the aqueous phase. The inversion increases the area occupied per drug molecule from 30 A2 for ketoconazole to 90 A2 for R 39 519 equal to the mean area occupied per miconazole molecule and higher than that occupied per DPPC molecule (60 A2). Such a conformation should result in a destabilizing effect of miconazole and R 39 519; this was proved using differential scanning calorimetry.

Antifungal Agents↗
PubMed1983

Conformational analysis of the calcium-antagonist gallopamil.

Conformational analysis of gallopamil was performed in order to gain insight into the molecular determinant of its calcium-antagonistic property. Whereas the neutral form of gallopamil was characterized by a single, largely predominant configuration, the protonated form of the drugs yielded several conformers, some of which were characterized by a readily accessible ionized site. The capacity of gallopamil to inhibit ionophore-mediated calcium translocation in a two-phase bulk system was inversely related to the pH of the aqueous phase. These findings indicate that the capacity of gallopamil to interfere with the transport of cations is critically dependent on the availability of a protonated configuration of the drug.

Calcimycin↗
PubMed1983

Calcium transport by a beta-diketone in model membranes.

The beta-diketone 1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,6-dione (FOD) translocates calcium from an aqueous medium into an organic phase. FOD is less efficient than but acts synergistically with A23187 in causing calcium translocation. The FOD-mediated process of calcium translocation is inhibited by NaCl, although the translocation of sodium by FOD is two to three orders of magnitude lower than that of calcium, when expressed relative to the concentration of these cations in the aqueous medium. At pH 7.4, FOD mediates calcium exchange-diffusion in fluid liposomes as efficiently as A23187. The extent of exchange-diffusion depends on the rigidity and cholesterol content of the liposomes. Conformational analysis of the complex formed by two molecules of FOD and one calcium atom at a simulated membrane interface reveals the existence of several interconvertible, asymmetrical and more-or-less planar configurations. The efficiency of FOD-mediated calcium ionophoresis thus appears to be regulated in a multifactorial manner by such factors as the concentration of calcium and monovalent cations, chemical composition and fluidity of the membrane, availability of other ionophoretic molecules and spatial configuration of the calcium complex.

Calcium↗
PubMed1983

Conformational analysis of phorbol esters at a simulated membrane/water interface.

The conformation at a simulated membrane/water interface of four distinct phorbol esters, selected for their vastly different tumor-promoting potency, was predicted by a modification of the usual computing approach for the conformational analysis of macromolecules. In the modified procedure, the transfer energy of each part of the molecule in either a hydrophobic or hydrophilic domain was taken into account in order to define the orientation of the molecule at the simulated interface. The results of this study are compatible with known tensioactive properties of these phorbol esters, and may help to explain differences in their biological potency by the relative facility of their insertion in lipid bilayers.

Carcinogens↗
PubMed1983

Theoretical study on conformation-related activity of hypoglycemic sulfonylureas.

Theoretical conformational analysis has been carried out for different hypoglycemic sulfonylurea -Ca complexes. The formed complex has an hydrophobic external surface and a low amphiphilic character. Our results suggest that Calcium may effectively be transported across membranes of Langerhans B cells and that the different biological potencies of the drugs may be due in part to the shape of the different complexes.

Hypoglycemic Agents↗
PubMed1983

Synergistic effect of hypoglycemic sulfonylureas and negative phospholipids on calcium transport: ionic and conformational aspects.

In a two-phase bulk system for the study of ionophoresis, the capacity of hypoglycemic sulfonylureas to translocate Ca2+ was enhanced in a synergistic manner by negatively charged phospholipids. High concentrations of Na+ or K+ had relatively little effect on sulfonylurea-mediated Ca2+ translocation. The acidity constant of hypoglycemic sulfonylureas ranged from 10(-5) to 10(-6). The conformation analysis of Ca2+ -gliquidone complexes with a 1:1 or 1:2 stoichiometry and of a hybrid complex between Ca2+ and both gliquidone and phosphatidylserine revealed configurations suitable for Ca2+ transport across a hydrophobic domain. These findings raise the possibility that the cationic response of the pancreatic B-cell to hypoglycemic sulfonylureas may be due primarily to an alteration of both Ca2+ and H+ transport.

Biological Transport↗
PubMed1983

Stoichiometry of calcium binding by hypoglycemic sulfonylureas.

In a two-phase bulk system for the study of Ca ionophoresis, certain hypoglycemic sulfonylureas, when added to the organic phase, were translocated into the aqueous medium. Nevertheless, the stoichiometry of Ca binding by these agents could be assessed by repeated mixing of the aqueous medium with organic phases. At saturation, the binding of Ca ranged from 0.5 to 1.0 mole/mole of sulfonylurea. A 1:1 molar ratio was observed with glibenclamide, and this was found to be compatible with the conformational analysis of the Ca-glibenclamide complex. There was a tight correlation between the stoichiometry of the Ca-sulfonylurea complex and the biological potency of each drug. This suggests that such a stoichiometry may be responsible, in part at least, for differences in the insulinotropic capacity of distinct hypoglycemic sulfonylureas.

Calcium↗
PubMed1983

Conformational analysis of mixed monolayers of phorbol ester and phospholipid.

A computational approach was used to study the conformation of mixed monolayers of amphiphilic molecules in order to characterize the assemblage of phospholipids around tumor-promoting and biologically inactive phorbol esters. The theoretical model was in fair agreement with both experimental data obtained in mixed monolayers of phorbol esters and dipalmitoylphosphatidylcholine spread at an air-water interface and the binding of phorbol esters to phospholipid bilayers. Thus, the present method may represent a useful tool to predict the orientation and molecular interaction of amphiphilic drugs at the membrane level.

Liposomes↗
PubMed1982

Evaluation of the anesthetic-lipid association constant. A monolayer approach.

A new approach is presented which allows to describe the binding of different local anesthetics to lipids. Lipids (DL- alpha-dipalmitoylphosphatidylcholine, phosphatidylserine, cardiolipin) are spread at the air-water interface and the anesthetic (procaine, butacaine, tetracaine) injected into the aqueous subphase. The equilibrium constants associated to the interfacial reaction: D+ (subphase) +L- (monolayer) in equilibrium DL (monolayer) (where D+ denotes the anesthetics, L- the lipid anionic site and DL the complex) are calculated from an experimental evaluation of the surface potential of the lipid monolayer. This mode of determination is based essentially on the good correlation between the experimental values of the surface potential and the theoretical predictions from the Gouy-Chapman theory. Fluorescence measurements on liposomes are carried out in order to locate the position of the drug in the lipid layer. This method can be extended to any positively charged drug-anionic lipid interaction.

4-Aminobenzoic Acid↗
PubMed1982

Homologous and hybrid calcium complexes of A23187 and hypoglycemic sulfonylureas: nuclear magnetic resonance and conformational analysis.

Hypoglycemic sulfonylureas (e.g., gliclazide) are able to transport calcium across hydrophobic domains. Gliclazide and the ionophore A23187 act synergistically upon calcium transport. One calcium atom is complexed by either two molecules of sulfonylureas (or A23187) or one molecule each of sulfonylurea and A23187; the existence of such hybrid complexes has been documented by nuclear magnetic resonance. Conformation analysis of the calcium-gliclazide complex suggests close apposition of the toluyl groups in the gliclazide molecules.

Anti-Bacterial Agents↗