1-Phenylpyrazolo[3,4-d]pyrimidines as adenosine antagonists: The effects of substituents at C4 and C6

Article abstract of DOI:10.1016/S0968-0896(96)00240-4

Forty-two 1-phenyl-pyrazolo[3,4-d]pyrimidines substituted at C6 with thioethers containing distal amide substituents and substituted at C4 with thiol, thiomethyl or amino were synthesized and tested for adenosine A₁ and A(2a) receptor binding. Compared with a thiol at C4, both S-methylation and conversion to an amino resulted in increased affinity at both receptors with the C4 amino compounds having the highest affinity. The C-4 region of the receptor consists of an alkyl pocket containing a hydrogen-bonding site. The study established that for high affinity at both the A₁ and A(2a) adenosine receptors the distal amide should be separated from the C6 thiol by only one carbon. In this study, 2'-(4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6-ylthio)- N-ethyl-ethanamide (4b) had the highest affinity at the A₁ receptor with a K(i) of 12.1 nM while 2'-(4-amino-1-phenylpyrazolo[3,4-d]pyrimidin-6- ylthio)ethanamide (4a) had the highest affinity at the A(2a) receptor with a K(i) of 44.9 nM.