title: Quantitative structure-activity relationships for dicoumarol antivitamins K in the uncoupling of mitochondrial oxidative phosphorylation.
abstract: The dynamic structure of dicoumarols substituted on the methylene bridge has been studied by nuclear magnetic resonance (nmr) spectroscopy. These molecules may be considered as dimers with restricted rotation around the methylene bridge, held by intramolecular hydrogen bonds; the presence of the substituent R modifies this dynamic process, mainly the facility of exchange of the two hydroxyl protons. These compounds have been compared in respect to their potency in uncoupling oxidative phosphorylation in pig heart mitochondria; the data have been correlated with constants used to characterize the substituent R; to make a potent uncoupler, R should be as small and as hydrophilic as possible. These results are discussed in consonance with the postulated mechanisms of action of the uncouplers, but no simple conclusion can be drawn, especially concerning the role of the dissociable protons.
mesh_terms: D000818:Animals; D003580:Cytochromes / Q000378:metabolism; D001728:Dicumarol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism*; D008968:Molecular Conformation; D009206:Myocardium / Q000648:ultrastructure; D010084:Oxidation-Reduction; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D013329:Structure-Activity Relationship; D013552:Swine; D014475:Uncoupling Agents / Q000494:pharmacology*; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D003580:Cytochromes; D014475:Uncoupling Agents; D014812:Vitamin K; D001728:Dicumarol