1,2,4-triazolo[4,3-a]quinoxalin-1-one moiety as an attractive scaffold to develop new potent and selective human A3 adenosine receptor antagonists: synthesis, pharmacological, and ligand-receptor modeling studies.

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Colotta V, Catarzi D, Varano F, Calabri FR, Lenzi O, Filacchioni G, Martini C, Trincavelli L, Deflorian F, Moro S

J Med Chem. 2004 Jul 1;47(14):3580-90.

PubMed ID

15214785 [ View in PubMed

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Abstract

In the past few years much effort in our laboratory has been directed toward the study of adenosine receptor antagonists, and recently we focused our attention on 2-aryl-1,2,4-triazolo[4,3-a]quinoxaline-1,4-diones and 2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-4-amino-1-ones, some of which were potent and/or selective A(3) receptor antagonists. In the present paper, a new series of triazoloquinoxaline derivatives is described. Most of the new compounds, biologically evaluated in radioligand binding assays at bovine (b) A(1) and A(2A) and at human (h) A(1) and A(3) adenosine receptors, showed high hA(3) adenosine receptor affinity and selectivity. In particular, 2-(4-nitrophenyl)-1,2,4,5-tetrahydro-1,2,4-triazolo[4,3-a]quinoxaline-1,4-dione (1), also tested at the hA(2A) ARs, shows the best binding profile with a high hA(3) affinity (K(i) = 0.60 nM) and strong selectivity vs hA(1) and vs hA(2A) receptors (both selectivity ratios greater than 16 600). To interpret our experimental results, we decided to theoretically depict the putative transmembrane binding motif of our triazoloquinoxaline analogues on hA(3) receptor. Structure-activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Theophylline	Adenosine receptor A1	Ki (nM)	6200	N/A	N/A	Details
Theophylline	Adenosine receptor A2a	Ki (nM)	21000	N/A	N/A	Details