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

Starting from the appropriate azides (4-chlorobenzyl-, 2-thiophenemethyl-, 2-fluorobenzyl-, and 4-fluorobenzylazide in which the variation of the subs tituent is at the basis of the four series of derivatives (a-d), the 7-amin osubstituted 1,2,3-triazolo[4,5-d]pyrimidines 4 were prepared by a well kno wn synthetic route. The biological activity of compounds 4 was expected on the basis of the presence of particular substituents on N(7), and these sub stituents were introduced by the reaction of the 7 lactamic carbonyl functi on, present on precursors 3, with cycloalkyl-, aralkyl- and arylamines. Rad ioligand binding assays at bovine brain adenosine A(1) and A(2A) receptors showed that some compounds possessed a high affinity and selectivity for th e A(1) receptor subtype. Furthermore, biological results indicated that the p-chlorobenzyl substituent lowered receptor binding, compared with the pre viously prepared benzyl and 2-chlorobenzyl derivatives, suggesting certain particular steric requirements of the lipophilic region which interacts wit h the benzyl substituent. The thiophenemethyl substituent conferred more ac tivity than the benzyl one. The presence of a fluorine atom on the benzyl g roup determined a high affinity, especially when it was in the ortho positi on. 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-fluo robenzyl, R' = cyclopentyl, Ki = 26 nM) were the most active for A(1) recep tors. (C) 1999 Editions scientifiques et medicales Elsevier SAS.