Permeation of permanently positive charged molecules through artificial membranes--influence of physico-chemical properties. 2007

Holger Fischer, and Manfred Kansy, and Alex Avdeef, and Frank Senner
Pharmaceutical Research, Discovery Chemistry-Molecular Properties, F. Hoffmann-La Roche Ltd., CH-4070 Basel, Switzerland. Holger.Fischer@roche.com

The aim of this study was to investigate the permeation properties of 20 permanently positive charged molecules in the parallel artificial membrane permeability assay (PAMPA). Eight of them were derivatives of the N-alkyl-isoquinolinium salt and 12 were congeners of the dye rhodamine 110. Five out of 12 molecules from the rhodamine 110 series have one additional carboxylic group and two have two carboxylic acids. The experimentally derived effective permeability values (P(e)) cover a range of 3-4 log units. Ten compounds showed low permeabilities (P(e)<0.1x10(-6)cm/s), four medium permeabilities (0.1x10(-6)< or =P(e)<1x10(-6)cm/s) and six were highly permeable (P(e)> or =1x10(-6)cm/s). In addition, computational models were built with a number of calculated molecular descriptors and evaluated for their ability to predict membrane permeability. It turned out that the experimental P(e) values can be explained by electronic properties and parameters describing the shape of molecules. This work provides evidence that permanently charged molecules can have high passive membrane permeabilities provided that the charge can be spread over several aromatic ring systems.

UI MeSH Term Description Entries
D007546 Isoquinolines A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)
D008567 Membranes, Artificial Artificially produced membranes, such as semipermeable membranes used in artificial kidney dialysis (RENAL DIALYSIS), monomolecular and bimolecular membranes used as models to simulate biological CELL MEMBRANES. These membranes are also used in the process of GUIDED TISSUE REGENERATION. Artificial Membranes,Artificial Membrane,Membrane, Artificial
D008968 Molecular Conformation The characteristic three-dimensional shape of a molecule. Molecular Configuration,3D Molecular Structure,Configuration, Molecular,Molecular Structure, Three Dimensional,Three Dimensional Molecular Structure,3D Molecular Structures,Configurations, Molecular,Conformation, Molecular,Conformations, Molecular,Molecular Configurations,Molecular Conformations,Molecular Structure, 3D,Molecular Structures, 3D,Structure, 3D Molecular,Structures, 3D Molecular
D010539 Permeability Property of membranes and other structures to permit passage of light, heat, gases, liquids, metabolites, and mineral ions. Permeabilities
D002627 Chemistry, Physical The study of CHEMICAL PHENOMENA and processes in terms of the underlying PHYSICAL PHENOMENA and processes. Physical Chemistry,Chemistries, Physical,Physical Chemistries
D006575 Heterocyclic Compounds, 3-Ring A class of heterocyclic compounds that include a three-ring fused structure. Both aromatic or non-aromatic ring structures are included in this category. Fused Heterocyclic Compounds, Three-Ring,Heterocyclic Cpds, 3 Ring,Three Ring Heterocyclic Compounds,3-Ring Heterocyclic Compounds,Fused Heterocyclic Compounds, Three Ring,Heterocyclic Compounds, 3 Ring
D006576 Heterocyclic Compounds, 4 or More Rings A class of heterocyclic compounds that include four or more fused rings. Both aromatic or non-aromatic ring structures are included in this category. Heterocyclic Compounds with 4 or More Rings,Five Ring Heterocyclic Compounds,Four Ring Heterocyclic Compounds,Fused Heterocyclic Compounds, Five-Ring,Fused Heterocyclic Compounds, Four-Ring,Heterocyclic Compounds with Four or More Rings,Heterocyclic Compounds, 4-Ring,Heterocyclic Compounds, 5-Ring,Heterocyclic Cpds, 4 Ring,Heterocyclic Cpds, 4 or More Rings,Heterocyclic Cpds, 5 Ring,4-Ring Heterocyclic Compounds,5-Ring Heterocyclic Compounds,Fused Heterocyclic Compounds, Five Ring,Fused Heterocyclic Compounds, Four Ring,Heterocyclic Compounds, 4 Ring,Heterocyclic Compounds, 5 Ring
D006863 Hydrogen-Ion Concentration The normality of a solution with respect to HYDROGEN ions; H+. It is related to acidity measurements in most cases by pH pH,Concentration, Hydrogen-Ion,Concentrations, Hydrogen-Ion,Hydrogen Ion Concentration,Hydrogen-Ion Concentrations
D000644 Quaternary Ammonium Compounds Derivatives of ammonium compounds, NH4+ Y-, in which all four of the hydrogens bonded to nitrogen have been replaced with hydrocarbyl groups. These are distinguished from IMINES which are RN Quaternary Ammonium Compound,Ammonium Compound, Quaternary,Ammonium Compounds, Quaternary,Compound, Quaternary Ammonium
D012235 Rhodamines A family of 3,6-di(substituted-amino)-9-benzoate derivatives of xanthene that are used as dyes and as indicators for various metals; also used as fluorescent tracers in histochemistry. Rhodamine

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