EFFECTS OF ALKYL SUBSTITUENTS OF XANTHINE ON PHOSPHODIESTERASE ISOENZYMES

The structure-activity relationships of a series of alkylxanthine deri vatives were investigated. The partition coefficient of alkylxanthines enlarged with an elongation of the alkyl chain at the 1-, 3-, or 7-po sition of xanthine. There was a mild correlation between the apparent partition coefficient and the tracheal relaxant activity or the inhibi tory activity on phosphodiesterase (PDE) IV isoenzyme, while the trach eal relaxant activity closely correlated with the PDE IV inhibitory ac tivity. Regarding substituents at different positions, the alkylation at the 3-position increased the inhibitory activity on every PDE isoen zyme. The alkylation at the 1-position potentiated the inhibitory acti vity on PDE IV with the alkyl chain length, but decreased the activiti es on other PDE isoenzymes. The alkylation at the 7-position was chara cteristic in its decrease in inhibitory activity on PDE III. These res ults suggested that the potency of the inhibitory activity of xanthine derivatives on PDE isoenzymes is not dependent simply upon their hydr ophobicity but upon change in the affinity for the active sites on PDE isoenzymes by the introduction of the alkyl group at particular posit ions of the xanthine skeleton.