Novel potent and highly selective human A3 adenosine receptor antagonists belonging to the 4-amido-2-arylpyrazolo[3,4-c]quinoline series: Molecular docking analysis and pharmacological studies

Article abstract of DOI:10.1016/j.bmc.2008.10.018

The study of novel 2-arylpyrazolo[3,4-c]quinolin-4-(hetero)arylamides, designed as human (h) A₃ adenosine receptor antagonists, is reported. The new derivatives are endowed with nanomolar hA₃ receptor affinity and high selectivity versus hA₁, hA_2A and hA_2B receptors. Among the (hetero)aroyl residues introduced on the 4-amino group, the 2-furyl and 4-pyridyl rings turned out to be the most beneficial for hA₃ affinity (K_i = 3.4 and 5.0 nM, respectively). An intensive molecular docking study to a rhodopsin-based homology model of the hA₃ receptor was carried out to obtain a 'structure-based pharmacophore model' that proved to be helpful for the interpretation of the observed affinities of the new hA₃ pyrazoloquinoline antagonists.