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  • lipophilicity  (4)
  • enantiomers
  • 1995-1999  (5)
  • 1
    Electronic Resource
    Electronic Resource
    The pH-Partition Profile of the Anti-Ischemic Drug Trimetazidine May Explain Its Reduction of Intracellular Acidosis (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 616-624 
    Details
    ISSN: 1573-904X
    Keywords: trimetazidine ; lipophilicity ; proton transfer ; ionic partition diagram ; ITIES
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The anti-ischemic drug trimetazidine (TMZ) acts by a combination of molecular mechanisms which begin to be understood. Thus, it acts in the micromolar range to significantly reduce intracellular acidification during ischemia. To search for a possible physicochemical explanation of this phenomenon, we investigated the transfer mechanisms of the various electrical forms of this dibasic drug. Methods. The transfer characteristics of TMZ were studied by electrochemistry at the water/1,2-dichloroethane interface. Cyclic voltammetry was used to measure the formal transfer potentials of singly and doubly protonated forms of TMZ (noted TH+ and TH2 2+, respectively ) as a function of aqueous pH, and the partition coefficient of neutral TMZ (log P T) was measured by two-phase titration. Results. log P T was measured to be 1.04 ± 0.06, and the acid-base dissociation constants in water were deduced to be pK w a1 = 4.54 ± .02 and pK w a2 = 9.14 ± 0.02. The partition coefficients of TH+ and TH2 2+ were found to be respectively log P 0′ TH+ = −3.78 ± 0.16 and log P 0′ TH 2 2+= −9.84 ± 0.30, which agrees well with the charge being delocalized on two nitrogen atoms in TH+. The pH-partition profile of TMZ was then established in the form of its ionic partition diagram, which showed that the affinity of the ions for the organic phase is pH-dependent and strongly increased by the interfacial potential. Conclusions. This behavior suggests a physiochemical mechanism whereby efflux of protonated TMZ out of an acidified cell is facilitated, in effect exporting protons to extracellular space.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018899802836
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  • 2
    Electronic Resource
    Electronic Resource
    Insight into the Lipophilicity of the Aromatic N-Oxide Moiety (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 1186-1190 
    Details
    ISSN: 1573-904X
    Keywords: lipophilicity ; polarity ; partition coefficients ; N-oxygenation ; aromatic N-oxides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A systematic study to assess the influence of N-oxygenation on the lipophilicity of aromatic weak bases was performed. Methods. The methods used were experimental (CPC and shake-flask techniques) and computational (AM1 semi-empirical method). Results. The intrinsic increment in the log Poct system for an oxygen atom added to form an aromatic N-oxide, designated as diff(log PN(O)−N), was −1.91, but the presence of para-substituents markedly affected this value. The good linear relationship (r2 = 0.92) between diff(log PN(O)−N), and the electronic density on the oxygen atom suggests that H-bond acceptor basicity is the main structural factor responsible for the variations in lipophilicity of aromatic N-oxides. Partition coefficients of aromatic N-oxides in dodecane/buffer and chloroform/buffer systems also support this hypothesis. Conclusions. The solvent-dependent polarity of the N-oxide moiety is mainly due to its marked H-bond acceptor basicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016056018517
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  • 3
    Electronic Resource
    Electronic Resource
    Lipophilicity in Molecular Modeling (1996)
    Springer
    Pharmaceutical research 13 (1996), S. 335-343 
    Details
    ISSN: 1573-904X
    Keywords: lipophilicity ; partition coefficients ; intermolecular forces ; intramolecular interactions ; conformation ; molecular lipophilicity potential ; MLP ; 3D-QSAR ; comparative molecular field analysis (CoMFA) ; receptor docking
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The molecular lipophilicity potential (MLP) offers a three-dimensional representation of lipophilicity, a molecular property encoding intermolecular recognition forces and intramolecular interactions. Methods. The interest and applications of the MLP in molecular modeling are varied, as ilustrated here. Results. The MLP is a major tool to assess the dependence of lipophilicity on conformation. As a matter of fact, the MLP combined with an exploration of the conformational space of a solute reveals its "chameleonic” behavior, i.e. its capacity to adapt to its molecular environment by hydrophobic collapse or hydrophilic folding. Another successful application of the MLP is its concatenation into 3D-QSAR (Comparative Molecular Field Analysis, CoMFA). Conclusions. Work is in progress to expand the MLP into a docking tool in the modeling of ligand-receptor interactions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016024005429
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  • 4
    Electronic Resource
    Electronic Resource
    Mechanisms of Liposomes/Water Partitioning of (p-Methylbenzyl)alkylamines (1998)
    Springer
    Pharmaceutical research 15 (1998), S. 1407-1413 
    Details
    ISSN: 1573-904X
    Keywords: lipophilicity ; liposomes ; intermolecular forces ; ionic bonds ; hydrogen bonds ; hydrophobic interactions ; pH-metric method ; NMR relaxation rates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The objective of this study was to compare and interpret the variations in lipophilicity of homologous (p-methylbenzyl)alkylamines (MBAAs) in isotropic (octanol/water) and anisotropic (zwitterionic liposomes/water) system. Methods. Two experimental approaches were used, namely the pH-metric method to measure lipophilicity parameters in octanol/water and liposomes/water systems, and changes in NMR relaxation rates to validate the former method and to gain additional insights into the mechanisms of liposomes/water partitioning. Results. For long-chain homologues (N-butyl to N-heptyl), the octanol/ water and liposomes/water systems mostly expressed hydrophobicity. In contrast, the lipophilicity of the shorter homologues (N-methyl to N-propyl) in the two systems expressed various electrostatic and polar interactions. Conclusions. The study sheds light on the molecular interactions between zwitterionic liposomes and amphiphilic solutes in neutral and cationic form.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011953622052
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  • 5
    Electronic Resource
    Electronic Resource
    Racemization, enantiomerization, diastereomerization, and epimerization: Their meaning and pharmacological significance (1995)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 7 (1995), S. 396-400 
    Details
    ISSN: 0899-0042
    Keywords: configurational lability ; enantiomers ; diastereomers ; epimers ; macroscopic processes ; microscopic processes ; pharmacological time scale ; pharmaceutical time scale ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The configurational lability of enantiomers can be characterized by different terms, each defining a specific process. Racemization relates to the macroscopic and statistical process of the irreversible transformation of one of the enantiomers into the racemic mixture. Enantiomerization refers to the microscopic and molecule process of the reversible conversion of one enantiomer into the other. Methods allowing the experimental determination of rate constants of racemization (krac) and enantiomerization (kenant) are discussed, and it is shown that kenant = 1/2 krac. Neglect of this fact is a source of some confusion in the literature. When two or more elements of chirality are present in a molecule and one of them is configurationally labile, epimerization occurs, a particular case of diastereomerization. These processes of interconversion between diastereomers are kinetically more complicated than racemization and enantiomerization since the rate constants of the forward and reverse reactions are always different (kdiast/A-to-B ≠ kdiast/B-to-A), however small the difference. An important aspect of the configurational lability of stereoisomeric drugs is the time scale of the phenomenon. When interconversion occurs to a significant extent during the residence time of a drug in the body, a pharmacological time scale is implied. In contrast, the pharmaceutical time scale refers to slower rates of interconversion that affect the configurational purity of a drug during its shelf-life. © 1995 Wiley-Liss, Inc.
    Additional Material: 5 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530070603
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