Synthesis and structure-activity relationships of a new set of 2-arylpyrazolo[3,4-c]quinoline derivatives as adenosine receptor antagonists.
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.
Colotta
V
V
Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, Via G. Capponi, 9, 50121 Firenze, Italy.
Catarzi
D
D
Varano
F
F
Cecchi
L
L
Filacchioni
G
G
Martini
C
C
Trincavelli
L
L
Lucacchini
A
A
D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013329:Structure-Activity Relationship
D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D011804:Quinolines; D043705:Receptor, Adenosine A2A; D043684:Receptor, Adenosine A3; D018047:Receptors, Purinergic P1