Synthesis, structure-affinity relationships, and molecular modeling studies of novel pyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists

This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c] quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A 1 and A 2A AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA 1 subtype. To rationalize the observed structure-affinity relationships, molecular docking studies at A 2AAR-based homology models of the A 1 and A 3 ARs and at the A 2AAR crystal structure were carried out. © 2011 Elsevier Ltd. All rights reserved.