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Biomedical subjects

G H Loew

Publications and source records attributed to G H Loew.

At least 109 records · Page 6Linked to original sources
PubMed1981

Quantum chemical studies of methyl and fluoro analogs of chrysene: metabolic activation and correlation with carcinogenic activity.

Specific electronic properties related to metabolic transformation and adduct formation by DNA were calculated for a series of methyl, dimethyl and n-fluoro-5-methyl derivatives of chrysene with the aim of identifying molecular properties which could be used as reliable indicators of their relative carcinogenic behavior. Using the semiempirical all valence electron IEHT method, the bay region bonds of 5MC were found to have enhanced nucleophilic reactivity to epoxide formation relative to chrysene. In addition, in one of the nonequivalent bay regions, the 1, 2, 3, 4 region, the distal (1, 2) bond was found to be more reactive than the proximal (3, 4) bond. This reactivity pattern leads to an easily formed diol epoxide carbocation, the postulated ultimate carcinogen. By contrast, in the other (7, 8, 9, 10) bay region, the proximal (9, 10) bond is the more reactive, suggesting formation of the "wrong," i.e., less stable diol epoxide carbocation. Consistent with earlier studies of other PAH, calculations by the INDO method of the ease of carbon cation formation from a bay region diol epoxide yielded a set of values which gave a good correlation with carcinogenicity.

Animals↗
PubMed1980

Quantum chemical studies of anaerobic reductive metabolism of halothane by cytochrome P-450.

Proposed pathways for anaerobic reductive metabolism of the widely used anesthetic halothane by cytochrome P-450s have been investigated using two all-valence semiempirical molecular orbital methods. Molecular conformations and electronic structure of halothane and intermediates in proposed one- and two-electron reductive metabolism were were calculated and results used to explore the feasibility of each step in the pathway to observed metabolites. The results suggest facile bromide ion elimination with formation of a CHClCF3 radical as a consequence of single electron reduction of halothane. Characterization of this radical species and its carbanion which would be formed by a second electron reduction suggests that either species could undergo reasonable nonenzymatic transformations leading to the formation of the two volatile metabolic products observed and the proposed trifluoroethylcarbene intermediate. This carbene, rather than CF3CCl, is predicted to be preferentially formed by either a radical or ionic halide elimination reaction. Moreover, when bound as an axial ligand to the iron atom at the heme site in cytochrome P-450, a carbene complex is formed which gives calculated spectral characteristics consistent with those observed when excess halothane is added to reduced cytochrome P-450 or rat liver microsomes under anaerobic conditions.

Anaerobiosis↗
PubMed1979

Quantum chemical studies of polycyclic aromatic hydrocarbons and their metabolites: correlations to carcinogenicity.

In the context of the bay region hypothesis for polycyclic aromatic hydrocarbon (PAH) carcinogenesis, molecular properties were calculated for seventeen polycyclic aromatic hydrocarbons related to (1) intrinsic substrate reactivities towards activating and detoxifying metabolism and (2) the stabilities of the putative carbocation ultimate carcinogens. All-valence electron methods were used, avoiding the inherent difficulties found in the pi-electron methods. The calculated substrate reactivities were found to predict major metabolites successfully, supporting the validity of their use in attempted correlations with observed carcinogenic potencies. Positive correlations were found between observed carcinogenic potencies and (1) the reactivities of the parent polycyclic aromatic hydrocarbons towards the initial distal bay region epoxidation and (2) the stabilities of the diol epoxide carbocations. The reactivities of the distal bay region diol epoxides, were high for both carcinogenic and non-carcinogenic compounds, implying that the second epoxidation does not determine relative carcinogenic activity. Support for a possible alternative hypothesis, that polycyclic aromatic hydrocarbons are activated by one electron oxidation, was also found.

Carcinogens↗
PubMed1979

Intramolecular hydrogen bonding and conformational studies of bridged thebaine and oripavine opiate narcotic agonists and antagonists.

A conformational study of a series of oripavine derivatives is reported using the PCILO semiempirical quantum mechanical method. Low-energy conformers of carbinol substituents on C7-C19-R1R2OH are found with and without intramolecular hydrogen bonding to the C6-OCH3 group. The relative energies of these conformers depend on the R1 and R2 groups and the diastereoisomerism of the alcohol. The results are consistent with available NMR and IR studies of intramolecular hydrogen bonding and with crystallographic data. The importance of interaction between specific conformations of C19 carbinols and a lipophilic receptor site is suggested. A hypothesis is formulated to explain observed differences in pharmacological activity between diastereoisomers at C19 in the oripavine series and also to explain how these diastereoisomers alter the established pattern of N-substituent effects on relative agonist/antagonist potency found in other rigid opiates. By contrast, conformational studies of the C19 optical isomers of the C7-C8 etheno form of buprenorphine lead to the prediction of greatly reduced intrinsic potency differences between C19 diastereoisomers for this compound and for buprenorphine itself.

Hydrogen Bonding↗
PubMed1979

Quantum chemical studies of the metabolism of polycyclic aromatic amines and the stabilities and electrophilicities of their arylnitrenium ions in relation to their mutagenic/carcinogenic potencies.

Electronic parameters related to the cytochrome P450-catalyzed reactions of eight polycyclic aromatic amines have been calculated using all valence electron semiempirical molecular orbital methods. The reactions considered lead to the presumably carcinogenic arylnitrenium ions and to the competing hydroxylation and epoxidation products. The stabilities of the arylnitrenium ions relative to the N-hydroxylamines and their sulfate esters were also calculated, together with electrophilic reactivity parameters of the ions. The resulting parameters were used to predict major metabolites of the parent compounds and also to correlate with observed mutagenic activities of the four pairs of polycyclic aromatic amines studied. The major factor in determining mutagenic potencies of parent compounds appears to be the extent of N-hydroxylation and competing ring oxidations, as well as the electrophilic properties of the arylnitrenium ions.

Amines↗
PubMed1978

Semiempirical calculations of model deoxyheme. Variation of calculated electromagnetic properties with electronic configuration and distance of iron from the plane.

The electronic structure of deoxyheme units and the electric field gradient at the iron nucleus are calculated as a function of the displacement of the iron from the heme plane. The high spin state has a calculated minimum energy with the iron out of plane at a distance similar to that observed for metMb. This could correspond to a relaxed form of deoxyHb, while the greater displacement observed in the intact protein could be strained. The calculated electric field gradient is relatively insensitive to iron displacement from the heme plane. This insensitivity could account for the very similar values of quadrupole splittings observed in low-affinity deoxyhemoglobin A and its separate high-affinity alpha and beta subunits, and still allow small differences in iron displacement consistent with the stereochemical trigger mechanism of cooperativity.

Heme↗
PubMed1978

Quantum chemical studies of N-substituent variation in the oxymorphone series of opiate narcotics.

Quantum chemical calculations were performed on six N-derivatives of oxymorphone including N-methyl- (oxymorphone), N-allyl- (naloxone), N-dimethylallyl- (nalmexone), N-methylcyclopropyl- (naltrexone), N-methylcyclobutyl-(nalbuphone), and N-phenethylnoroxymorphone using the PCILO method. The object of the study was to identify conformational features of the N-substituents which might be responsible for the intrinsic observed pharmacological properties of opiate agonism and antagonism. Both axial and equatorial N-substituent conformers were considered, as well as possible interactions of the C14-OH group with such substituents. Variations of agonist/antagonist potency ratios within this series could not be explained by differing relative energies of equatorial and axial conformations or by varying rates of interconversion between the two. Direct effects of the C14-OH group on conformations of N-substituents also could not account for their relative agonist/antagonist potencies. Consistent with a previous hypothesis, the observed potencies and binding data could be explained most consistently by the availability of several low-energy equatorial conformations of N-substituents and their interactions with the C14-OH group through a common anionic receptor site.

Analgesics, Opioid↗
PubMed1978

Analgesics. 1. Synthesis and analgesic properties of N-sec-alkyl- and N-tert-alkylnormorphines.

A series of N-sec- and N-tert-alkylnormorphines was synthesized and evaluated for analgesic potency, antagonist activity, and opiate receptor binding. Computer-assisted conformational analysis profiles were utilized to assist in the selection of compounds for synthesis and correlation of receptor events with in vivo observations. N-tert-Alkylnormorphines 5a-c were devoid of agonist activity; however, some sec-alkyl analogues showed interesting mixed agonist-antagnoist actions. N-sec-Butyl- and N-(alpha-methylally)normorphine were separated into R and S isomers, which exhibited quantitative pharmacological differences. The N-sec-butyl S isomer 10a showed analgesia approximating morphine with nalorphine-like antagonist activity. Preliminary testing indicates only slight evidence for physical dependence with this compound.

Analgesics↗
PubMed1978

Energy conformation study of Met-enkephalin and its D-Ala2 analogue and their resemblance to rigid opiates.

Conformational similarities of Met-enkephalin and its D-Ala2 analogue to rigid opiates were studied by both empirical and quantum mechanical methods. By both methods, conformers with maximum resemblance to rigid opiates have the highest energies. Conformers with the lowest energy had no resemblance to rigid opiates. However, several low and intermediate energy conformers were identified in which at least the NH2-terminal tyrosine residue overlaps with the phenethylamine moiety of rigid opiates and which could equally well accommodate either Gly2 or D-Ala2. The conformer among these with greatest additional resemblance to other binding sites of rigid opiates is proposed as the most likely candidate for an induced fit at the receptor site.

Endorphins↗
PubMed1978

Structure-activity studies of narcotic agonists and antagonists from quantum chemical calculations.

Three classes of flexible opiates have been studied: 4-phenyl piperdines, methadone and enkephalins. Our results show that low energy conformers of the 4-phenyl piperidines have equatorial phenyl rings and cannot completely overlap with rigid opiates at the receptor. A combination of calculated conformational and electronic properties could account for observed potency differences in meperidine, desmethyl, alpha+, alpha-, beta+ and beta- prodines. Our results also indicate that both meperidine and its reverse ester bind to the receptor in a similar mode with the phi ring in approximmately the same position as the phenyl substituent in 5-phenyl benzomorphans. Conformers of methadone which maximally resemble morphine have very high relative energies. The lowest energy conformer has a partial H-bond between the NH and O=C groups. In this conformation methadone resembles meperidine more than morphine. The electronic structure of all three types of opiates indicate a similar cationic charge distribution around the amine nitrogen and imply that their binding to an anionic receptor site could be similar. The determination of peptide opiate conformations present a challenge of a different order of magnitude than the most flexibe exogenous opiates. Because of the extremely large number of possible conformations, search strategies based on energy optimized conformations alone are not adequate to select plausible receptor site candidates. Other criteria such as consistency with known structure activity data and similarities to rigid opiates must be used. With this rationale, we have predicted and characterized a low energy conformer of Met-enkephalin and D-ala2 Met-enkephalin as a likely candidate at the receptor site. With a modest energy input (deltaE approximately 3 kcal/mole) significant overlap of this conformer with the potent opiate PET was obtained. The tyrosine and phenyalanine side chains and the terminal amine and carboxyl groups play a crucial role in this overlap. It is hoped that this calculation with help establish a template for peptide opiate receptor interactions.

Animals↗
PubMed1977

Conformational studies of a family of related antimalarial phenanthrene amino alcohols.

A conformational study utilizing quantum chemical methods was performed on a family of antimalarial alpha-(piperidyl)-3,6-bis(trifluoromethyl)-9-phenanthrenemethanols whose structures differ by the placement of the substituent on either the 2,3, or 4 position of the piperidyl ring. The antimalarial activity of these 3-substituted compounds has been shown experimentally to be highly stereospecific while the 2-substituted compounds are not and the 4-substituted compounds are inactive. In this study, such observed differences in behavior are correlated with conformational results and a pharmacophore is postulated. The identity of the active racemate of the 3-piperidyl compound is predicted.

Amino Alcohols↗
PubMed1976

Quantum chemical studies of methadone.

Quantum chemical calculations were performed on the flexible methadone molecule to test the hypothesis that it structurally mimics the fused ring structure of morphine. In these calculations using the semiempirical, PCILO method, protonated and nonprotonated conformations were considered representative of different types of intramolecular interaction at the morphine receptor. Calculated energies for these conformations were compared to those calculated for protonated and nonprotonated extended chain and crystal structure conformers. Lowest energy conformations showed intramolecular bonding but the resultant molecular geometries were not very morphine-like. A comparison of the structure of methadone to that of meperidine seemed equally as valid.

Chemical Phenomena↗
PubMed1975

Quantum chemical study of relative reactivities of a series of amines and nitriles: relevance to prebiotic chemistry.

Using the Iterative Extended Hucken Theory (IEHT) calculations of the elctron distribution and orbital energies of a series of thirteen amines, nitriles and amino-nitriles relevant to prebiotic and cosmo-chemistry have been carried out. Ground state properties such as the energy and nature of the highest occupied (HOMO) and lowest empty (LEMO) molecular orbitals, net atomic charges and number of non-bonding electrons have been identified as criteria for correlating the relative nucleophilicity of amine and nitrile nitrogens and the electrophilicity of nitrile and other unsaturated carbon atoms. The results of such correlations can be partially verified by known chemical behavior of these compounds and are used to predict and understand their role in prebiotic organic synthesis.

Amines↗