Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 21, Issue 1, Pages 283-294Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.10.031
Keywords
G protein-coupled receptors; Adenosine receptor antagonists; Pyrazoloquinazolines; Tricyclic heteroaromatic systems; Ligand-receptor modeling studies
Funding
- Italian Ministry for University and research (MIUR) [FIRB RBNE03YA3L]
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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 mu-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. (C) 2012 Elsevier Ltd. All rights reserved.
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