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Biomedical subjects

G H Loew

Publications and source records attributed to G H Loew.

119 records · Page 7Linked to original sources
PubMed1975

Quantum chemical studies of morphine-like opiate narcotics. Effect of N-substituent variations.

Quantum chemical calculations including extensive conformational variations are performed on three morphine-like analgesics with varying N-substituents using the PCILO and INDO methods. The three compounds, morphine, nalorphine, and N-phenethylmorphine, have been shown experimentally to exemplify opiate narcotic agonism, antagonism, and increased agonism, respectively. In this study, these properties are correlated with the electronic and conformational results. The electronic properties of the fused ring skeleton including specifically the cationic region around the nitrogen are relatively unaffected by varying N-substituents. The properties studied include net charges, bond polarities, and the nature and energy of the highest filled and lowest empty molecular orbitals. The conformational behavior appears to be the main cause of differing receptor binding and interaction with the active site and is discussed in these terms.

Binding Sites↗
PubMed1975

Quantum chemical studies of meperidine and prodine.

Extensive quantum chemical calculations have been made of the electronic distribution and conformational behavior of meperidine and desmethyl-, (+)-alpha, and (+)-beta-prodine using PCILO, a semiempirical molecular orbital method. For this series of opiates, a phenyl equatorial conformation was preferred over a phenyl axial one, with the equatorial conformer most favored in the most potent compounds. Using the low-energy equatorial conformer obtained for each compound, together with calculated net atomic charges, their observed potency variation could successfully be explained. From the results, these compounds appear to act at the morphine receptor with an identical piperidine rather than phenyl ring site.

Alphaprodine↗
PubMedDate not supplied

Quantum chemical study of the thermodynamics, kinetics of formation and bonding of H2CN: relevance to prebiotic chemistry.

Using the Iterative Extended Huckel Theory (IEHT), energy-conformation studies have been carried out for H2CN (I), trans-HCNH (IIA), and cis-HCNH (IIB), three possible isomers formed by addition of a hydrogen atom to hydrogen cyanide. Calculations show that the order of decreasing thermodynamic stability is I greater than IIA greater than IIB. Additionally, from calculated energies along simulated reaction pathways, the formation of I from HCN+H appears to be kinetically favored over IIA. Calculated properties of the minimum energy conformers of I and IIA are described and the potential role of H2CN (I) as a reactive intermediate in prebiotic organic synthesis and its possible relevance to interstellar organic chemistry are discussed.

Atmosphere↗
PubMedDate not supplied

Food palatability and hunger modulated effects of CGS 9896 and CGS 8216 on food intake.

The effect of food palatability and duration of food deprivation on the modulation of food intake by two benzodiazepine receptor (BDZR) ligands, CGS 9896 and CGS 8216, were investigated. Three diets differing in palatability (high, medium, or standard) and three different periods of food deprivation (0, 16, or 24 h) were used in all combinations to compare the effect of these variations on the observed modulation of food consumption by both BDZR ligands. Increasing diet palatability and/or food deprivation increased the baseline food consumption and reduced the sensitivity of the test to the detection of the hyperphagic effect of CGS 9896 but increased the sensitivity to detect the anorexic effect of CGS 8216. Only for the intermediate conditions of food deprivation (16 h) and for a standard or medium palatable diet were both significant hyperphagic effect of CGS 9896 and anorexic effect of CGS 8216 detected. Neither increased palatability nor hunger enhanced the modulation of feeding, indicating that neither "taste preference" nor "hunger" is the key factor in the mechanism of BDZR ligand-induced feeding response.

Animals↗
PubMedDate not supplied

Nitrosamine carcinogen activation pathway determined by quantum chemical methods.

Multiple reactions are thought to be involved in transforming dialkynitrosamines to active carcinogens. The first proposed step is enzymatic alpha-hydroxylation by the active oxygen species of cytochrome P-450, followed by nonenzymatic N-dealkylation and formation of diazohydroxides (RNNOH). The latter transformation can reasonably occur by a two-step mechanism via tautomerization of a monoalkylnitrosamine intermediate or directly from the alpha-hydroxylated species in one step. Both of these pathways in the transformation of hydroxymethylnitrosamine to diazohydroxide and formaldehyde were examined by the semiempirical molecular orbital method MNDO (modified neglect of diatomic differential overlap) and the ab initio method using STO-3G and 3-21G basis sets. Complete geometry optimizations of all reactants, intermediates, transition states, and products were performed. MNDO was also used to compare the similar transformation of the dimethyl analog. Both methods show that in the gas phase a concerted pathway involving a six-membered ring transition-state pathway is kinetically favored over a two-step pathway involving N-demethylation followed by tautomerization via two four-membered ring transition states. This reaction appears to be a viable one to formation of an ultimate carcinogen by parent dialkylnitrosamines in the hydrophobic substrate binding site of cytochrome P-450.

Biotransformation↗
PubMedDate not supplied

Correlation of calculated electronic parameters of fifteen aniline derivatives with their mutagenic potencies.

Electronic parameters for a series of amino-, chloro-, and nitro-substituted anilines relative to their potential for activation to hydroxylamines, aryl-nitrenium ions, and ring epoxides, and to their potential deactivation to phenols were calculated using semi-empirical molecular orbital methods. The relative mutagenic activities of aminoanilines could be explained by parameters reflecting potential for N-hydroxylation and stability of the arylnitrenium ions. Both chloro and nitro groups deactivate the amine group to N-hydroxylation and the ring to epoxidation, and no active products from cytochrome P-450 would be predicted. This result is consistent with lack of mutagenic activity observed for chloro derivatives, but does not account for activity of the nitro derivatives, which is presumed to be due to transformation of the nitro group itself to an active mutagenic species by other enzyme systems.

Aniline Compounds↗