Ia. Doichinova et al., QSAR STUDIES OF 8-SUBSTITUTED XANTHINES AS ADENOSINE RECEPTOR ANTAGONISTS, European journal of medicinal chemistry, 29(2), 1994, pp. 133-138
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.