Novel 3-Aralkyl-7-(amino-substituted)-1,2,3-triazolo[4,5-d]pyrimidines with High Affinity toward A1 Adenosine Receptors

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Abstract
Three series of several 1,2,3-triazolo[4,5-d]pyrimidine derivatives bearing various amino substituents at the 7 position and one of three lipophilic substituents at the 3 position (benzyl, phenethyl, or 2-chlorobenzyl) were prepared starting from the corresponding 7-chloro compounds, by nucleophilic substitution by the appropriate amine. Radioligand binding assays at bovine brain adenosine A1 and A2A receptors showed that some compounds possessed a high affinity and selectivity for the A1 receptor subtype. In particular the biological results suggested the compounds bearing cycloalkylamino (cyclopentyl- and cyclohexylamino) or aralkylamino (alpha-methylbenzyl- and 1-methyl-2-phenylethylamino or amphetamino) substituents at the 7 position were the most active derivatives. The best lipophilic substituent at the 3 position was the 2-chlorobenzyl (A1 affinity Ki < 50 nM) followed by the benzyl and then the phenethyl groups. This pattern of structure-activity relationship (SAR) was similar to that previously reported for analogous 1,2,3-triazolopyridazino derivatives (Biagi et al., 1994, 1995, 1996) except for the compounds bearing substituted aromatic amines which presented a generalized and strong decrease of the A1 receptor affinity. These facts allowed us to attribute to these molecules a binding mode within the A1 adenosine receptor analogous to that of the corresponding triazolopyridazines