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Synthesis, Biological Properties, and Molecular Modeling Investigation of the First Potent, Selective, and Water-Soluble Human A3 Adenosine Receptor Antagonist

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journal contribution
posted on 16.07.2002 by Anna Maconi, Giorgia Pastorin, Tatiana Da Ros, Giampiero Spalluto, Zhan-guo Gao, Kenneth A. Jacobson, Pier Giovanni Baraldi, Barbara Cacciari, Katia Varani, Stefano Moro, Pier Andrea Borea
A new, highly potent, selective, and water-soluble antagonist of the hA3 adenosine receptor was synthesized and tested in binding and functional assays. Compound 4 (5-[[(4-pyridyl)amino]carbonyl]amino-8-methyl-2-(2-furyl)-pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine hydrochloride) displayed high water solubility (15 mM) and the highest affinity (Ki = 0.01 nM) and selectivity for the hA3 versus A1, A2A, and A2B receptors (>10000-fold) ever reported. A Schild analysis of the antagonism by 4 of agonist-induced inhibition of cAMP production in CHO cells expressing the hA3 receptor indicated a KB value of 0.20 nM.