5,7-Disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as pharmacological tools to explore the antagonist selectivity profiles toward adenosine receptors

Eur J Med Chem. 2016 Jan 27:108:529-541. doi: 10.1016/j.ejmech.2015.12.019. Epub 2015 Dec 15.


The structure-activity relationship of new 5,7-disubstituted-[1,2,4]triazolo[1,5-a][1,3,5]triazines as adenosine receptors (ARs) antagonists has been explored. The introduction of a benzylamino group at C5 with a free amino group at C7 increases the affinity toward all the ARs subtypes (10: KihA1 = 94.6 nM; KihA2A = 1.11 nM; IC50hA2B = 2214 nM; KihA3 = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA2A AR antagonist (14: hA2A AR Ki = 1.44 nM; hA1/hA2A = 216.0; hA3/hA2A = 20.6). This trend diverges from the analysis on the pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine series previously reported. With the help of an in silico receptor-driven approach, we have rationalized these observations and elucidated from a molecular point of view the role of the benzylamino group at C5 in determining affinity toward the hA2A AR.

Keywords: Adenosine receptors; Antagonists; G protein-coupled receptor; Molecular modeling; Structure activity relationship; Triazolo-triazine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Purinergic P1 Receptor Antagonists / chemical synthesis
  • Purinergic P1 Receptor Antagonists / chemistry
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Receptors, Purinergic P1 / metabolism*
  • Structure-Activity Relationship
  • Triazines / chemical synthesis
  • Triazines / chemistry
  • Triazines / pharmacology*
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*


  • (1,2,4)triazolo(1,5-a)(1,3,5)triazine
  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1
  • Triazines
  • Triazoles