title: Effects of alkyl substituents of xanthine on phosphodiesterase isoenzymes.
abstract: The structure-activity relationships of a series of alkylxanthine derivatives were investigated. The partition coefficient of alkylxanthines enlarged with an elongation of the alkyl chain at the 1-, 3-, or 7-position of xanthine. There was a mild correlation between the apparent partition coefficient and the tracheal relaxant activity or the inhibitory activity on phosphodiesterase (PDE) IV isoenzyme, while the tracheal relaxant activity closely correlated with the PDE IV inhibitory activity. Regarding substituents at different positions, the alkylation at the 3-position increased the inhibitory activity on every PDE isoenzyme. The alkylation at the 1-position potentiated the inhibitory activity on PDE IV with the alkyl chain length, but decreased the activities on other PDE isoenzymes. The alkylation at the 7-position was characteristic in its decrease in inhibitory activity on PDE III. These results suggested that the potency of the inhibitory activity of xanthine derivatives on PDE isoenzymes is not dependent simply upon their hydrophobicity but upon change in the affinity for the active sites on PDE isoenzymes by the introduction of the alkyl group at particular positions of the xanthine skeleton.
authors.affiliation: Research Laboratory for Development of Medicine, Faculty of Pharmaceutical Sciences, Hokuriku University, Kanazawa, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
authors.forename: R
authors.initials: R
authors.lastname: Sakai
authors.forename: M
authors.initials: M
authors.lastname: Kurita
authors.forename: S
authors.initials: S
authors.lastname: Ohmae
authors.forename: F
authors.initials: F
authors.lastname: Sanae
authors.forename: H
authors.initials: H
authors.lastname: Sawanishi
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: K
authors.initials: K
authors.lastname: Takagi
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000478:Alkylation; D000818:Animals; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D007700:Kinetics; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects / Q000502:physiology; D014970:Xanthines / Q000494:pharmacology*
chemical_list: D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D014970:Xanthines; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4