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

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, hA2A and hA2B 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 (Ki = 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.

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 studiesFigure optionsDownload as PowerPoint slide