QSAR STUDIES OF 8-SUBSTITUTED XANTHINES AS ADENOSINE RECEPTOR ANTAGONISTS

QSAR investigations on a series of 8-substituted xanthines as adenosin e antagonists have been carried out. The chemical structure was descri bed by LFER-parameters, indicator variables, and quantum chemical indi ces derived from MNDO-MO calculations. It was confirmed that for good affinity towards A1 adenosine receptors, the n-propyl group is the opt imal substituent at the 1- and 3-positions. It was also found that for good A2 affinity, the presence of a hydrophobic substituent, attached to N1, is of greater importance than the same substituent attached to N3. A hydrophobic substituent attached to C8 increases the A1 affinit y, while the optimal R8 substituent for A2 affinity should be hydropho bic and electron-donating. The correlations with MO indices suggest th at N1 and N3 interact electrostatically with the A1 and A2 receptors, respectively, and C8 participates in drug-A2 receptor interactions thr ough a charge transfer, thus acting as a donor. The predictability of the QSAR models was proven by 'leave-one-out' jackknife procedure.