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

Maconi, Anna; Pastorin, Giorgia; Ros, Tatiana Da; Spalluto, Giampiero; Gao, Zhan-guo; Jacobson, Kenneth A.; Baraldi, Pier Giovanni; Cacciari, Barbara; Varani, Katia; Moro, Stefano; Borea, Pier Andrea

doi:10.1021/jm020974x.s001

jm020974x_si_001.pdf (515.85 kB)

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

journal contribution

posted on 2002-07-16, 00:00 authored 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 (K_i = 0.01 nM) and selectivity for the hA₃ versus A₁, A_2A, and A_2B 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 K_B value of 0.20 nM.