Effects of alkyl substitutions of xanthine skeleton on bronchodilation.
Article Details
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Sakai R, Konno K, Yamamoto Y, Sanae F, Takagi K, Hasegawa T, Iwasaki N, Kakiuchi M, Kato H, Miyamoto K
Effects of alkyl substitutions of xanthine skeleton on bronchodilation.
J Med Chem. 1992 Oct 30;35(22):4039-44.
- PubMed ID
- 1331453 [ View in PubMed]
- 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.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Enprofylline Adenosine receptor A1 Ki (nM) 60700 N/A N/A Details Enprofylline Adenosine receptor A2a EC 50 (nM) 7200 N/A N/A Details Theophylline Adenosine receptor A1 Ki (nM) 9800 N/A N/A Details Theophylline Adenosine receptor A2a EC 50 (nM) 28200 N/A N/A Details