181702-33-0Relevant academic research and scientific papers
Synthesis and structure-activity relationship of pyrazolo[3,4- d]pyrimidines: Potent and selective adenosine A1 receptor antagonists
Poulsen, Sally-Ann,Quinn, Ronald J.
, p. 4156 - 4161 (1996)
A series of 12 substituted 1-phenylpyrazolo[3,4-d]pyrimidines were synthesized and evaluated for rat brain adenosine A1 and A(2a) receptor binding affinity. Substituents at C-4 and C-6 were varied in order to define these regions in terms of molecular recognition by the receptor subtypes. At C-4, the effects of a mercapto, methylthio, and amino substituent were evaluated, while at C-6, amides with varying alky] groups extending from the α-carbon were examined. This study identified both potent and selective adenosine A1 receptor antagonists. The most potent of the 12 compounds was α-[(4-amin-1-phenylpyrazolo[3,4-d]pyrimidin-6-yl)thio]hexanamide (14); with an A1 K(i) of 0.939 nM and an A(2a) K(i) of 88.3 nM, this compound is 94- fold A1 selective. The most selective of the 12 compounds was α-[[4- (methylthio)-1-phenylpyrazolo[3,4-d]pyrimidin6-yl]thio]hexanamide (10); with an A1 K(i) of 6.81 nM and an A(2a) K(i) > 40 000 nM, this compound is >5900- fold A, selective. The structure-activity relationships for the complete series has identified discrete structural differences between the A1 and A(2a) receptors with respect to the binding of pyrazolo[3,4-d]pyrimidines. This study resulted in prediction that increased A1 affinity could be achieved by incorporation of NH-alkyl substituents at C-4. This was confirmed by synthesis of α-[[4-(methylamino)-1-phenylpyrazolo[3,4-d]pyrimidin-6- yl]thio1]hexanamide (15) which was found to have an A1 K(i) of 0.745 nM.
