Synthesis, biological properties, and molecular modeling investigation of the first potent, selective, and water-soluble human A(3) adenosine receptor antagonist

A new, highly potent, selective, and water-sol. antagonist of the hA3 adenosine receptor was synthesized and tested in binding and functional assays. Pyridyl substituted pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine hydrochloride I displayed high water soly. (15 mM) and the highest affinity (Ki = 0.01 nM) and selectivity for the hA3 vs. A1, A2A, and A2B receptors (>10000-fold) ever reported. A Schild anal. of the antagonism by I of agonist-induced inhibition of cAMP prodn. in CHO cells expressing the hA3 receptor indicated a KB value of 0.20 nM