STRUCTURE-ACTIVITY-RELATIONSHIPS OF ALKYLXANTHINE INHIBITORS OF PHOSPHODIESTERASE-IV ISOENZYME

The structural and electronic properties of seventeen alkylxanthine de rivatives were calculated using the MO program PM3 to elucidate the ke v features related to their inhibitory activity on phosphodiesterase ( PDE) IV isoenzyme. Except for 7-alkylxanthine derivatives, a good corr elation could be established between the distance between the tops of the two alkyl groups at the N-1 and N-3 positions of the xanthine skel eton (molecular length) and the PDE IV inhibitory activity (r=0.973, n =13), The same inhibitory activity could also be significantly correla ted with the following electronic parameters of alkylxanthines: HOMO e nergy (r=0.850), absolute hardness (r=-0.806), and absolute electroneg ativity (r=-0.825), These results suggest that the electronic properti es are partly responsible for PDE IV inhibition as far as the effects of structural properties associated with molecular length are concerne d. Alkylxanthines may also act as electron donors in the charge-transf er interaction with the active sites on PDE IV isoenzyme.