New 8-substituted xanthiene derivatives as potent bronchodilators

The synthesis and structure determination of 8-aryl /alkyl aryl 1, 3-dimethyl-3, 7-dihydropurin-2, 6-dione derivatives (1-13), was carried out in this study. Bronchodilator activity is investigated using isolated guinea-pig tracheal strips, pre-contracted by acetylcholine and histamine. Spasmolytic activity of the compounds was compared to theophylline. Synthesized compounds (1-13) did not inhibit the acetylcholine-induced pre-contractions except compound (8) at 10⁻⁵ M concentration. In contrast, some of the compounds, especially (7), (11), (12) at 10⁻⁵ M and (3), (4), (9) and (11) in 10⁻⁴ M displayed inhibitory activity on the tracheal strips pre-contracted by histamine. The potency of the compounds at human adenosine receptors was evaluated using radioligand binding assay and a cyclic AMP functional assay in CHO cells expressing these receptors. Compound (11) displayed the greatest activity against radioligand binding of specific agonists to A_2 A and A_2B receptors. The compounds were relatively selective for both A_2 A and A_2B compared with A₁ and A₃ receptors. All compounds were also tested for the inhibition of NECA-induced cAMP accumulation mediated by the A_2B adenosine receptor and compound (11) was found to be the most effective. Our results showed that these compounds are acting as selective adenosine antagonists, especially for adenosine A_2B receptors, and are promising as potent anti-inflammatory agents rather than bronchodilator for the treatment of asthma.