Effects of alkyl substitutions of xanthine skeleton on bronchodilation

J Med Chem. 1992 Oct 30;35(22):4039-44. doi: 10.1021/jm00100a008.


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.

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • Airway Resistance / drug effects
  • Animals
  • Bronchodilator Agents / chemical synthesis
  • Bronchodilator Agents / chemistry*
  • Bronchodilator Agents / pharmacology
  • Guinea Pigs
  • Heart Rate / drug effects
  • In Vitro Techniques
  • Male
  • Organ Specificity
  • Receptors, Purinergic / metabolism
  • Structure-Activity Relationship
  • Trachea / drug effects
  • Xanthines / chemical synthesis
  • Xanthines / chemistry*
  • Xanthines / metabolism
  • Xanthines / pharmacology


  • Bronchodilator Agents
  • Receptors, Purinergic
  • Xanthines
  • 3',5'-Cyclic-AMP Phosphodiesterases