Pyrazolo[1,5-c]quinazoline derivatives and their simplified analogues as adenosine receptor antagonists: synthesis, structure-affinity relationships and molecular modeling studies.

Abstract A number of 5-oxo-pyrazolo[1,5- c ]quinazolines (series B-1 ), bearing at position-2 the claimed (hetero)aryl moiety (compounds 1 – 8 ) but also a carboxylate group ( 9 – 14 ), were designed as hA 3 AR antagonists. This study produced some interesting compounds endowed with good hA 3 receptor affinity and high selectivity, being totally inactive at all the other AR subtypes. In contrast, the corresponding 5-ammino derivatives (series B-2 ) do not bind or bind with very low affinity at the hA 3 AR, the only exception being the 5- N -benzoyl compound 19 that shows a hA 3 K i value in the high μ-molar range. Evaluation of the synthetic intermediates led to the identification of some 5(3)-(2-aminophenyl)-3(5)-(hetero)arylpyrazoles 20 – 24 with modest affinity but high selectivity toward the hA 3 AR subtype. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA 3 receptor.