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Biomedical subjects

A Makriyannis

Publications and source records attributed to A Makriyannis.

At least 145 records · Page 8Linked to original sources
PubMed1987

The effect of cholesterol on lipid dynamics and packing in diether phosphatidylcholine bilayers. X-ray diffraction and 2H-NMR study.

In order to compare the lipid packing, conformation and dynamics of ether- and ester-linked phosphatidylcholines in the presence of equimolar concentrations of cholesterol, multilamellar dispersions of these lipid-sterol mixtures were investigated by X-ray diffraction and 2H-NMR. A comparison of the X-ray diffraction patterns at 22 degrees C of 1,2-di-O-hexadecyl-sn-glycero-3-phosphocholine (DHPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) dispersion, each containing 50 mol% cholesterol, demonstrate that the structural characteristics of DHPC and DPPC bilayers in the presence of cholesterol are essentially indistinguishable by X-ray diffraction. In contradistinction to the similar structural characteristics of DHPC and DPPC in the presence of cholesterol, the low-angle lamellar reflections of DHPC at 22 degrees C in the absence of cholesterol are indicative of an interdigitated phase, demonstrating that cholesterol facilitates the conversion from an interdigitated to a non-interdigitated phase. Above Tc in each lipid-sterol mixture, the quadrupolar splittings from the alpha-methylene segments of 1,2[1',1'-2H]DHPC and 1,2[2',2'-2H2]DPPC indicate that both chain inequivalence and magnetic inequivalence of any particular alpha-C2H2 deuteron pair are preserved and actually enhanced in the presence of cholesterol. Lowering of the temperature below Tc in 1,2[2',2'-2H2]DPPC/cholesterol dispersion leads to a progressive intensity loss of the sn-2 chain components, a thermotropic effect which is not observed in the corresponding components of the 1,2[1',1'-2H2]DHPC/cholesterol spectra.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1986

Studies on the interaction of anesthetic steroids with phosphatidylcholine using 2H and 13C solid state NMR.

The effects of the anesthetic steroid alphaxalone and its inactive analog delta 16-alphaxalone on model phospholipid membranes were studied using 13C and 2H solid-state nuclear magnetic resonance spectroscopy. Aqueous multilamellar dispersions of dipalmitoylphosphatidylcholine (DPPC) with specific 13C and 2H labels as endogenous probes at the carbonyl and the C-7 methylene groups, respectively, of the sn-2 chain were used to study the conformational and dynamical properties of the bilayer as a function of temperature. There were no significant changes between the 13C and 2H spectra of the DPPC preparation containing the inactive steroid and that of DPPC with no drug. However, the physiologically active steroid produces significant spectral 2H and 13C changes. These changes include a reduction of the main phase transition temperature and a broadening of that transition. Alphaxalone also increases the relative number of gauche conformers in the liquid-crystalline phase of DPPC and increases the rate of axial diffusion in both the gel and liquid-crystalline phase. The thermotropic properties of the above preparations, as monitored by differential scanning calorimetry, were congruent with the spectroscopic data.

Anesthetics↗
PubMed1985

Deuterium NMR investigation of ether- and ester-linked phosphatidylcholine bilayers.

Deuterium nuclear magnetic resonance (2H NMR) spectra of specifically head-group- and chain-deuterated ester- and ether-linked phosphatidylcholine bilayers were studied as a function of temperature over the range -33 to 50 degrees C. Head-group-deuterated dihexadecylphosphatidylcholine ([alpha-2H2]DHPC) bilayers yield line shapes and spin-lattice relaxation times similar to those observed for its ester-linked counterpart, dipalmitoylphosphatidylcholine ([alpha-2H2]DPPC), in the high-temperature ripple and L alpha bilayer phases. These results indicate the ether linkage has no effect on the dynamics or the orientational order at the alpha-C2H2 segment of the phosphocholine head group. At all temperatures, the 2H NMR spectra of chain-deuterated 1,2[1',1'-2H2]DHPC bilayers exhibit a reduced spectral width compared to 1,2[2',2'-2H2]DPPC bilayers. The most significant feature of the deuterated alkyl chain spectrum of DHPC at 45 degrees C is the observation of four separate quadrupolar splittings from the alpha-methylene segments of the alkyl chains, in comparison to the three quadrupolar splittings reported previously from the alpha-methylene segments of the acyl chains of DPPC. Spin-lattice relaxation experiments performed on DHPC suggest an assignment of the two smaller and the two larger quadrupolar splittings to separate alkyl chains, respectively. Low-temperature (T less than or equal to -20 degrees C) gel-phase spectra of deuterated head-group [alpha-2H2]DHPC remain an order of magnitude narrower than those observed for [alpha-2H2]DPPC.(ABSTRACT TRUNCATED AT 250 WORDS)

Esters↗
PubMed1985

Geometric requirements for membrane perturbation and anesthetic activity. Conformational analysis of alphaxalone and delta 16-alphaxalone and 2H NMR studies on their interactions with model membranes.

2H NMR spectra were obtained for dimyristoylphosphatidylcholine multilamellar dispersions, perdeuterated in the fatty acid chains, in the presence and absence of two steroid analogs. The presence of the active anesthetic steroid alphaxalone results in consistently smaller 2H quadrupolar splittings (delta nu Q) for individual C2H2 segments of the fatty acid chains, indicating increased molecular disorder. In contrast, the inactive analog delta 16-alphaxalone causes no significant change in the 2H spectra of the phospholipid. The conformational analysis of alphaxalone and delta 16-alphaxalone in solution was carried out with the help of 1H and 13C high resolution NMR spectroscopy and the results were used to propose a molecular model for the interaction of the two steroids with membrane phospholipids. The model correlates the observed differences in the manner in which the two steroids interact with model membranes with differences in their respective conformations and provides a molecular basis for anesthetic steroid activity.

Anesthetics↗
PubMed1982

Structure activity correlations in the inhibition of brain synaptosomal 3H-norepinephrine uptake by phenethylamine analogs. The role of alpha-alkyl side chain and methoxyl ring substitutions.

alpha-Ethylphenethylamine proved to be a weaker inhibitor of rat brain synaptosomal [3H]norepinephrine ([3H]NE) uptake than amphetamine, while 2-amino-tetralin and 2-amino-1,2-dihydronaphtalene, compounds in which the alpha-side chain ethyl group is tied to the aromatic ring have a similar inhibiting potency as amphetamine. Hallucinogenic polymethoxy substituted phenethylamine analogs have very low inhibitory potencies indicating that inhibition of NE-reuptake in brain noradrenergic neurons is not associated with the drug-induced hallucinogenic syndrome.

Amphetamine↗
PubMed1982

Conformational requirements for norepinephrine uptake inhibition by phenethylamines in brain synaptosomes. Effects of alpha-alkyl substitution.

Amphetamine is a strong competitive antagonist of brain synaptosomal [3H]norepinephrine ([3H]NE) uptake. Its alpha-ethyl analogue is much less active, while 2-aminotetralin and 1,2-dihydro-2-aminonaphthalene, in which the alpha-ethyl group is tied to the aromatic ring, possess about the same inhibitory potency as amphetamine. The conformational properties of these compounds in solution were studied by 1H and 13C NMR methods. Only small differences between amphetamine and alpha-ethylphenethylamine hydrochlorides were observed in the relative rotamer populations due to rotation around the C alpha -C beta bond of the side chain. In D2O the gauche conformation is slightly favored, while in CDCl3 the trans conformation is the predominant one. Conformational analysis of the alpha-ethyl group in alpha-ethylphenethylamine showed that this group exists in two equally populated conformations in both solvents. It is suggested that these conformations hinder the approach of alpha-ethylphenethylamine to the brain synaptosomal NE uptake sites.

Alkylation↗
PubMed1981

Studies on phenethylamine hallucinogens. 2. Conformations of arylmethoxyl groups using 13C NMR.

Carbon-13 chemical shift (delta) and spin-lattice relaxation time (T1) measurements were used to determine the conformation around the Ar-OCH3 bond of the arylmethoxyl groups in a series of substituted phenethylamines. Methoxyl groups flanked by two ortho substituents have delta 13C values higher (60.5-62.5 ppm) than those with one or no ortho substituents ((55.5-57.5 ppm) and T1 values considerably longer than those of the other methoxyl groups in the same molecule. These measurements indicate that methoxyl groups with two ortho substituents acquire the out-of-plane conformation, while those with one or no ortho substitutents exist in the planar conformation. Phenethylamine analogues with methoxyl groups in the out-of-plane conformation have low or no psychotomimetic activity. A possible explanation is that the out-of-plane methoxyl group interferes with the binding of the electron-rich methoxy-substituted aromatic ring to a corresponding electron-deficient component on the active site of the receptor.

Hallucinogens↗
PubMed1981

Synthesis and adrenoceptor affinity of some highly polar beta-substituted catecholamines.

In order to assess the potential for sympathomimetic or sympatholytic activity within the series of catecholamine beta-sulfonates 3a-c, alpha- and beta-adrenoceptor binding affinities were determined using rat brain homogenate preparations. Furthermore, their potential for indirect activity was assessed by measurement of blockade of norepinephrine uptake into rat synaptosomal preparations. Activity was uniformly low or nonexistent throughout the series. The possibility of unfavorable solution conformational distribution within the series was investigated by examination of the side chain vicinal 1H NMR coupling constants, but no differences that could account for the lack of affinity were found. The observed behavior may be due to receptor intolerance of the bulky beta-sulfonate substituent or an electronic mismatch in which normal H bonding is significantly altered.

Animals↗
PubMed1980

Effects of anesthetics on sulfate transport in the red cell.

We measured the effect of anesthetics on sulfate transport in the human erythrocyte and have found that a wide variety of chemical classes of anesthetics, including the anesthetic steroid alphaxalone, inhibit sulfate transport in human erythrocytes at concentrations paralleling the concentrations that block nerve conduction. These experiments suggest that anesthetics act through a general mechanism and that the sulfate transport system in the red blood cell is a good model for studying the mechanism of action of anesthetics.

Anesthetics↗
PubMed1980

Conformational energy differences between side chain alkylated analogues of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane.

Theoretical conformational energy calculations were carried out for the (+) and (-) isomers of the hallucinogen 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM, STP). Energies were also calculated for two analogues of DOM, 1-amino-1-(2,5-dimethoxy-4-methylbenzyl)cyclopropane and 1-(2,5-dimethoxy-4-methylphenyl)-2-methyl-2-aminopropane. This method utilized classical, empirical potential-energy functions. A previously proposed active conformational region was studied. Compounds could be ranked in order of potency based on relative conformational energies in this region. Measurement of 13C spin--lattice relaxation times (T1) for the two alpha, alpha-disubstituted DOM analogues confirmed theoretical predictions of very restricted conformational freedom for the dimethyl compound but more flexibility for the cyclopropane analogue.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗
PubMed1979

Nortropacocaine hydrochloride conformation in aqueous and hydrophobic media.

The nortropacocaine hydrochloride PMR spectra in deuterium oxide and in deuterochloroform differed markedly. A detailed conformational analysis using vicinal 1H-1H coupling constants revealed the molecular conformation to be identical in both solvents. The preferred conformation was one in which the piperidine component existed as a deformed chair. The spectral differences were due to a decreased deshielding of the protonated nitrogen on the neighboring bicyclic ring protons, resulting in chemical shift changes.

Chloroform↗