SELECTIVE TRACHEAL RELAXATION AND PHOSPHODIESTERASE-IV INHIBITION BY XANTHINE DERIVATIVES

The effects of substitutions in the xanthine nucleus on tracheal relax ant activity, atrium chronotropic activity, adenosine A(1) affinity, a nd 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 activ ity without leading to positive chronotropic action, and long alkyl ch ains at the N3-position increased both activities. N7-substitutions wi th, n-propyl and 2'-oxopropyl groups, such as in denbufylline, increas ed bronchoselectivity. N7-substitution decreased the adenosine A(1) af finity, but substitution at either the N1- or N3-position increased it . The bronchorelaxant activity of xanthine derivatives was closely cor related with their inhibition of phosphodiesterase-IV, but not with th eir adenosine A(1) affinity; the positive chronotropic effects were re lated to their inhibition of phosphodiesterase-III. This study confirm s that the bronchorelaxation of xanthine derivatives is mediated by in hibition of the isoenzyme phosphodiesterase-IV. The results of structu re-activity analysis suggest that substitutions at the N1- and N7-posi tions should be tried in the development of xanthine derivatives that are selective bronchodilators and phosphodiesterase-IV inhibitors.