New 2-arylpyrazolo[3,4-c]quinoline derivatives as potent and selective human A3 adenosine receptor antagonists.: Synthesis, pharmacological evaluation, and ligand-receptor modeling studies

This paper reports the study of some 2-arylpyrazolo[3,4-c]quinolin-4-ones, 4-amines, and 4-amino-substituted derivatives designed as human A(3) adenosine receptor (AR) antagonists. Most of the herein reported compounds showed a nanomolar affinity toward the hA(3) receptor subtype and different degrees of selectivity that resulted to be strictly dependent on the presence and nature of the substituent on the 4-amino group. Bulky and lipophilic acyl groups, as well as the benzylcarbamoyl residue, afforded highly potent and selective hA(3) receptor antagonists. The selected 4-diphenylacetylamino-2-phenylpyrazoloquinoline (25) and 4-dibenzoylamino-2-(4-methoxyphenyl)pyrazoloquinoline (36), tested in an in vitro rat model of cerebral ischemia, prevented the irreversible failure of synaptic activity induced by oxygen and glucose deprivation in the hippocampus. The observed structure-affinity relationships of this class of antagonists were also exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach.