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, resp., when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compds. with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A2A AR (range 18.3-96.5 nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA3 AR (range 311-633 nM) with respect to the unsubstituted derivs. The binding profiles of the synthesized analogs seemed to correlate with the substitutions at the C5 and N7 positions. At the hA2B AR, deriv. 5 (I), which contained a free amino group at the 7 position, was the most potent (EC50 3.42 μM) and could represent a starting point for searching new non-xanthine hA2B AR antagonists. Mol. models of the rA2A and hA3 ARs were constructed by homol. to the recently reported crystallog. structure of the hA2A AR. A preliminary receptor-driven structure-activity relationship (SAR) based on the anal. of antagonist docking has been provided.
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
CACCIARI, Barbara;
2010
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, resp., when utilized on the pyrazolo-triazolopyrimidine nucleus as we reported in the past. In general, compds. with a free amino group at the 7 position (5, 6), showed good affinity at the rat (r) A2A AR (range 18.3-96.5 nM), while the introduction of a phenylcarbamoyl moiety at the N7 position (12, 19, 24) slightly increased the affinity at the hA3 AR (range 311-633 nM) with respect to the unsubstituted derivs. The binding profiles of the synthesized analogs seemed to correlate with the substitutions at the C5 and N7 positions. At the hA2B AR, deriv. 5 (I), which contained a free amino group at the 7 position, was the most potent (EC50 3.42 μM) and could represent a starting point for searching new non-xanthine hA2B AR antagonists. Mol. models of the rA2A and hA3 ARs were constructed by homol. to the recently reported crystallog. structure of the hA2A AR. A preliminary receptor-driven structure-activity relationship (SAR) based on the anal. of antagonist docking has been provided.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
