Does the combination of optimal substitutions at the C 2-, N 5- and N 8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A 3 adenosine receptors?

Abstract

In an attempt to study the optimal combination of a phenyl ring at the C 2-position and different substituents at the N 5- and N 8-positions towards the selective modulation of human A 3 adenosine receptors (hA 3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N 8 and chains of variable length at N 5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA 3AR in the low nanomolar range. Compound 16 possessed the best hA 3AR affinity and selectivity profile (K ihA 3 = 1.33 nM; hA 1/hA 3 = 4880; hA 2A/hA 3 = 1100) in the present series of 2-(substituted)phenyl-pyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA 3AR. © 2011 Elsevier Ltd. All rights reserved.