1,2,4-Triazolo[1,5-a]quinoxaline as a versatile tool for the design of selective human A3 adenosine receptor antagonists: synthesis, biological evaluation, and molecular modeling studies of 2-(hetero)aryl- and 2-carboxy-substituted derivatives.
A number of 4-oxo-substituted 1,2,4-triazolo[1,5-a]quinoxaline derivatives bearing at position-2 the claimed (hetero)aryl moiety (compounds 1-15) but also a carboxylate group (16-28, 32-36) or a hydrogen atom (29-31) were designed as human A3 (hA3) adenosine receptor (AR) antagonists. This study produced some interesting compounds and among them the 2-(4-methoxyphenyl)-1,2,4-triazolo[1,5-a]quinoxalin-4-one (8), which can be considered one of the most potent and selective hA3 adenosine receptor antagonists reported till now. Moreover, as a new finding, replacement of the classical 2-(hetero)aryl moiety with a 2-carboxylate function (compounds 16-28 and 32-36) maintained good hA3 AR binding activity but, most importantly and interestingly, produced a large increase in hA3 versus hA1 selectivity. A receptor-based SAR analysis provided new interesting insights about the steric and electrostatic requirements that are important for the anchoring of these derivatives at the hA3 receptor recognition site, thus highlighting the versatility of the triazoloquinoxaline scaffold for obtaining potent and selective hA3 AR antagonists.
Catarzi
Daniela
D
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Polo Scientifico, Via U. Schiff, 6-50019 Sesto Fiorentino, Firenze, Italy. daniela.catarzi@unifi.it
Colotta
Vittoria
V
Varano
Flavia
F
Lenzi
Ombretta
O
Filacchioni
Guido
G
Trincavelli
Letizia
L
Martini
Claudia
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Montopoli
Christian
C
Moro
Stefano
S
D058918:Adenosine A3 Receptor Antagonists; D020816:Amino Acid Motifs; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D002540:Cerebral Cortex / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D043684:Receptor, Adenosine A3 / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C507629:2-(4-methoxyphenyl)-1,2,4-triazolo(1,5-a)quinoxalin-4-one; D058918:Adenosine A3 Receptor Antagonists; D011810:Quinoxalines; D043684:Receptor, Adenosine A3; D014230:Triazoles