title: Selective tracheal relaxation and phosphodiesterase-IV inhibition by xanthine derivatives.
abstract: The effects of substitutions in the xanthine nucleus on tracheal relaxant activity, atrium chronotropic activity, adenosine A1 affinity, and inhibitory activities on cyclic AMP-phosphodiesterase isoenzymes in guinea pigs were studied. Substitution with a long alkyl chain at the N1-position of xanthine nucleus increased the tracheal relaxant activity without leading to positive chronotropic action, and long alkyl chains at the N3-position increased both activities. N7-substitutions with n-propyl and 2'-oxopropyl groups, such as in denbufylline, increased bronchoselectivity. N7-substitution decreased the adenosine A1 affinity, but substitution at either the N1- or N3-position increased it. The bronchorelaxant activity of xanthine derivatives was closely correlated with their inhibition of phosphodiesterase-IV, but not with their adenosine A1 affinity; the positive chronotropic effects were related to their inhibition of phosphodiesterase-III. This study confirms that the bronchorelaxation of xanthine derivatives is mediated by inhibition of the isoenzyme phosphodiesterase-IV. The results of structure-activity analysis suggest that substitutions at the N1- and N7-positions should be tried in the development of xanthine derivatives that are selective bronchodilators and phosphodiesterase-IV inhibitors.
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: M
authors.initials: M
authors.lastname: Kurita
authors.forename: S
authors.initials: S
authors.lastname: Ohmae
authors.forename: R
authors.initials: R
authors.lastname: Sakai
authors.forename: F
authors.initials: F
authors.lastname: Sanae
authors.forename: K
authors.initials: K
authors.lastname: Takagi
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects*; D014970:Xanthines / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D010726:Phosphodiesterase Inhibitors; D018047:Receptors, Purinergic P1; D014970:Xanthines; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4