Structure-activity relationship in N3-alkyl-xanthine derivatives.

Structure-activity studies were carried out to compare the relaxant effects of various xanthine derivatives synthesized by substitution of the alkyl groups of the N3 position in the xanthine molecule. We evaluated the relaxant effects and the inhibitory activities on c-AMP phosphodiesterase (PDE) in tracheal smooth muscle isolated from guinea pigs. A comparative study on their pharmacokinetic characteristics was also carried out in rabbits. Dose-dependent relaxant effects were observed, and the relaxant effect of propylxanthine was nearly equal to the effects of butyl- and isobutylxanthines. Based on the estimation of the Ki values for PDE inhibition, it was found that butylxanthine is a potent inhibitor of PDE. There was good correlation between the alkyl chain length and the Ki value of these derivatives. The results showed that the alkyl chain length plays an important role in the inhibition of PDE. There were no significant differences in the volume of distribution, although the half-life showed significant differences. It is likely that the half-lives of these derivatives are affected by their chain lengths. The present study indicated that butylxanthine may be a new candidate as a bronchodilator. However, clinical studies have to be carried out to compare its efficacy and adverse effects with those of existing bronchodilators such as theophylline.