New amino derivatives of 1,2,3-triazolo[4,5-d]pyrimidines and their affinity towards A 1 and A 2A adenosine receptors

Abstract

Starting from the appropriate azides (4-chlorobenzyl-, 2-thiophenemethyl-, 2-fluorobenzyl-, and 4-fluorobenzylazides) in which the variation of the substituent is at the basis of the four series of derivatives ( a–d), the 7-aminosubstituted 1,2,3-triazolo[4,5-d]pyrimidines 4 were prepared by a well known synthetic route. The biological activity of compounds 4 was expected on the basis of the presence of particular substituents on N(7), and these substituents were introduced by the reaction of the 7 lactamic carbonyl function, present on precursors 3, with cycloalkyl-, aralkyl- and arylamines. Radioligand binding assays at bovine brain adenosine A 1 and A 2A receptors showed that some compounds possessed a high affinity and selectivity for the A 1 receptor subtype. Furthermore, biological results indicated that the p-chlorobenzyl substituent lowered receptor binding, compared with the previously prepared benzyl and 2-chlorobenzyl derivatives, suggesting certain particular steric requirements of the lipophilic region which interacts with the benzyl substituent. The thiophenemethyl substituent conferred more activity than the benzyl one. The presence of a fluorine atom on the benzyl group determined a high affinity, especially when it was in the ortho position. Compounds 4c.1 (R = 2-fluorobenzyl, R′ = cyclopentyl, Ki = 10.5 nM), 4c.2 (R = 2-fluorobenzyl, R′ = cyclohexyl, Ki = 19.5 nM) and 4d.1 (R = 4-fluorobenzyl, R′ = cyclopentyl, Ki = 26 nM) were the most active for A 1 receptors.