Pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine Derivatives as Adenosine Receptor Antagonists. Influence of the N5 Substituent on the Affinity at the Human A3 and A2B Adenosine Receptor Subtypes: A Molecular Modeling Investigation

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Abstract
A new series of pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines bearing various substituents at both the N5-pyrimidinyl and N8-pyrazolyl positions have been synthesized, and their binding affinities at the four human adenosine receptor subtypes (hA1, hA2A, hA2B, and hA3) have been evaluated. All the described compounds contain arylacetyl moieties at the N5 position and arylalkyl substituents at the N8 position. Surprisingly, all the compounds present their most potent affinities at the hA2B adenosine receptor with a range of selectivities against the other subtypes. When bulky groups are present simultaneously at the N5 and N8 positions (e.g., compound 9), the best selectivity for the hA2B receptor was observed (Ki(hA1) = 1100 nM; Ki(hA2A) = 800 nM; Ki(hA2B) = 20 nM; Ki(hA3) = 300 nM, Ki(hA1/A2B) = 55, Ki(hA2A/A2B) = 40, Ki(hA3/hA2B) = 15). To understand the molecular significance of these results, we compared the putative TM (transmembrane) binding motif of compound 9 on both hA2B and hA3 receptors. From our docking studies, compound 9 fits neatly inside the TM region of the hA2B receptor but not in the corresponding hA3 region, illustrating significant differences between the two subtypes. The study herein presented permits an understanding of why the bioisosteric replacement of an −NH, present in previously reported hA3 receptor antagonists, with a −CH2 group at the N5 position induces such large differences in hA2B/hA3 affinity. In the molecular structure of the hA3 receptor, two residues, Ser243 (TM6) and Ser271 (TM7), create a hydrophilic region, which seems to permit a better accommodation of the phenylurea series into this putative hA3 binding site than the phenylacetyl series.