1,2,4-Triazolo[5,1-i]purine Derivatives as Highly Potent and Selective Human Adenosine A3 Receptor Ligands

Publisher Website
Google Scholar
Abstract
A series of triazolopurines showed structural similarity to human adenosine A3 receptor antagonist, 9-chloro-2-(2-furanyl)-5-[(phenylacetyl)amino][1,2,4]triazolo[1,5-c]quinazoline (MRS 1220, 1). In this study, we found novel 1,2,4-triazolo[5,1-i]purine derivatives (2) showing human adenosine A3 receptor affinities. The compounds were obtained in two steps from 5-amino-4-cyanoimidazole (33). The affinity was determined in radioligand binding assays for the cloned human adenosine A1, A2A, A2B, and A3 receptors. After the structure−activity relationship was analyzed, we determined that there was a mild parabolic relationship between the length of alkyl groups at the 5-position and the affinities at the A3 receptor and positive correlation between the length of the substituents on phenyl groups at the 8-position and the affinities at the A2A receptor. These investigations led to potent and selective human adenosine A3 receptor ligands. The most potent A3 receptor ligand (5-n-butyl-8-(4-methoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (27, Ki = 0.18 nM) and the most selective A3 receptor ligand against A1, A2A, and A2B receptors, (5-n-butyl-8-(4-n-propoxyphenyl)-3H-[1,2,4]triazolo[5,1-i]purine (29, >19 600), were discovered.