In a recent paper (Colotta et al. J. Med. Chem. 2000, 43, 1158-1164) we reported the synthesis and adenosine receptor binding activity of two sets of 2-aryl-1,2,4-triazolo[4,3-a] quinoxalines (A and B) some of which were potent and selective A(1) or A(3) antagonists. In this paper the synthesis of a set of 2-arylpyrazolo[3,4-c]quinolin-4-ones 1-10, 4-amines 11-18, and 4-amino-substituted derivatives 19-35 are reported. The binding activity at bovine A(1) and A(2A) and human cloned A(3) adenosine receptors showed that (i) the substituent on the appended 2-phenyl ring could be used to modulate A(1) and A(3) affinity, (ii) the 4-amino group was necessary for A(1) and A(2A) binding activity, and (iii) a nuclear or extranuclear C=O proton acceptor at position 4 yielded potent and selective A(3) antagonists. These results are in agreement with those of the previously reported series A and B suggesting a similar adenosine receptor binding mode. In particular, the A(3) nanomolar affinity of 1-8, 31-33, and 35 confirms the hypothesis of the presence in the N-6 region of the adenosine A(3) subtype of a proton donor able to bind to a C=O proton acceptor at position 4.
|Autori:||COLOTTA V.; CATARZI D.; VARANO F.; CECCHI L.; FILACCHIONI G.; MARTINI C.; TRINCAVELLI M.L.; LUCACCHINI A.|
|Titolo:||Synthesis and structure-activity relationships of a new set of 2-arylpyrazolo[3,4-c] quinoline derivatives as adenosine receptor antagonists|
|Anno del prodotto:||2000|
|Digital Object Identifier (DOI):||10.1021/jm000936i|
|Appare nelle tipologie:||1.1 Articolo in rivista|