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

作者：Federico Stephanie; Ciancetta Antonella; Porta Nicola; Redenti Sara; Pastorin Giorgia; Cacciari Barbara; Klotz Karl Norbert; Moro Stefano^*; Spalluto Giampiero^*

来源：European Journal of Medicinal Chemistry, 2016, 108: 529-541.

DOI：10.1016/j.ejmech.2015.12.019

• G protein-coupled receptor
• Antagonists
• Molecular modeling
• Structure activity relationship
• Triazolo-triazine
• Adenosine receptors

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: K(i)hA(i) = 94.6 nM; K(i)hA(2A) = 1.11 nM; IC(50)hA(2B) = 2214 nM; K(i)hA(3) = 30.8 nM). Replacing the free amino group at C7 with a phenylureido moiety yields a potent and quite selective hA(2A) AR antagonist (14: hA(2A) AR K-i = 1.44 nM; hA(1)/hA(2A) = 216.0; hA(3)/hA(2A) = 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 hA(2A) AR.

• 出版日期2016-1-27