Selective tracheal relaxation and phosphodiesterase-IV inhibition by xanthine derivatives

The effects of substitutions in the xanthine nucleus on tracheal relaxant activity, atrium chronotropic activity, adenosine A1 affinity, and inhibitory activities on cyclic AMP-phosphodiesterase isoenzymes in guinea pigs were studied. Substitution with a long alkyl chain at the N1-position of xanthine nucleus increased the tracheal relaxant activity without leading to positive chronotropic action, and long alkyl chains at the N3-position increased both activities. N7-substitutions with n-propyl and 2'-oxopropyl groups, such as in denbufylline, increased bronchoselectivity. N7-substitution decreased the adenosine A1 affinity, but substitution at either the N1- or N3-position increased it. The bronchorelaxant activity of xanthine derivatives was closely correlated with their inhibition of phosphodiesterase-IV, but not with their adenosine A1 affinity; the positive chronotropic effects were related to their inhibition of phosphodiesterase-III. This study confirms that the bronchorelaxation of xanthine derivatives is mediated by inhibition of the isoenzyme phosphodiesterase-IV. The results of structure-activity analysis suggest that substitutions at the N1- and N7-positions should be tried in the development of xanthine derivatives that are selective bronchodilators and phosphodiesterase-IV inhibitors.