Synthesis and adenosine receptor affinity of a series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine

Article abstract of DOI:10.1021/jm00113a031

Pyrazolo[3,4-d]pyrimidines are pyrazolo analogues of purines. They have been shown to be a general class of compounds which exhibit A1 adenosine receptor affinity. Two series of pyrazolo[3,4-d]pyrimidine analogues of 1-methylisoguanosine have been synthesized. The first involved substitution of the N1-position while the second involved substitution of the N5-position. Both alkyl and aryl substituents were examined. All compounds were tested for A₁ adenosine receptor affinity by using a (R)-[³H]-N⁶-(phenylisopropyl)adenosine binding assay. The 3-chlorophenyl group showed the greatest activity in the N1-position and the butyl group produced the greatest activity in the N5-position. Combination of the best substituent in each of these positions enhanced the overall activity. The most potent compound was 4-amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-6(5H)-one with an IC₅₀ of 6.4 X 10^-6 M. Selectivity at the receptor subclasses was examined by performing an A₂ adenosine receptor affinity assay with [³H]CGS 21680. This series of compounds were slightly less potent at A₂ receptors. 4-Amino-5-N-butyl-1-(3-chlorophenyl)-1H-pyrazolo[3,4-d] pyrimidin-6(5H)-one was the most potent compound with an IC₅₀ of 19.2 X 10^-6 M.