title: Effects of alkyl substitutions of xanthine skeleton on bronchodilation.
abstract: Structure-activity relationships in a series of 1,3,7-trialkyl-xanthine were studied with guinea pigs. Relaxant actions in the tracheal muscle were increased with alkyl chain length at the 1- and 3-positions of the xanthine skeleton, but decreased by alkylation at the 7-position. Positive chronotropic actions in the right atrium were potentiated with 3-alkyl chain length but tended to decrease with 1-alkylation and diminish by 7-substitution. Consequently, while the 1- and 3-substitutions were equally important for the tracheal smooth muscle relaxation, the substitution at the 1-position was more important than the 3-substitution for bronchoselectivity. The 7-alkylation may be significant to cancel heart stimulation. There were good correlations between the smooth muscle relaxant action and the cyclic AMP-PDE inhibitory activity in 3-substituents and the affinity for adenosine (A1) receptors in 1-, 3-, and 7-substituents. This suggests that not only the cyclic AMP-PDE inhibitory activity but also the adenosine antagonistic activity is important in the bronchodilatory effects of alkylxanthines. Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.
authors.affiliation: Research Laboratory for Development of Medicine, Hokuriku University, School of Pharmacy, Kanazawa, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Sakai
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: Y
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: F
authors.initials: F
authors.lastname: Sanae
authors.forename: K
authors.initials: K
authors.lastname: Takagi
authors.forename: T
authors.initials: T
authors.lastname: Hasegawa
authors.forename: N
authors.initials: N
authors.lastname: Iwasaki
authors.forename: M
authors.initials: M
authors.lastname: Kakiuchi
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: K
authors.initials: K
authors.lastname: Miyamoto
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D009928:Organ Specificity; D011983:Receptors, Purinergic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014132:Trachea / Q000187:drug effects; D014970:Xanthines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001993:Bronchodilator Agents; D011983:Receptors, Purinergic; D014970:Xanthines; D015105:3',5'-Cyclic-AMP Phosphodiesterases