Synthesis and pharmacological characterization of a new series of 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazine derivatives as adenosine receptor antagonists: A preliminary inspection of ligand–receptor recognition process

Abstract

A new series of triazolotriazines variously substituted at the C5 and N7 (5–25) positions was synthesized and fully characterized at the four adenosine receptor (AR) subtypes. In particular, arylacetyl or arylcarbamoyl moieties were introduced at the N7 position, which enhanced affinity at the hA2B and hA3 ARs, respectively, when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compounds with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A2A AR (range 18.3–96.5nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA3 AR (range 311–633nM) with respect to the unsubstituted derivatives. The binding profiles of the synthesized analogues seemed to correlate with the substitutions at the C5 and N7 positions. At the hA2B AR, derivative 5, which contained a free amino group at the 7 position, was the most potent (EC50 3.42μM) and could represent a starting point for searching new non-xanthine hA2B AR antagonists. Molecular models of the rA2A and hA3 ARs were constructed by homology to the recently reported crystallographic structure of the hA2A AR. A preliminary receptor-driven structure–activity relationship (SAR) based on the analysis of antagonist docking has been provided.