Substituted pyrazolo[3,4-b]pyridines as human A(1) adenosine antagonists: Developments in understanding the receptor stereoselectivity

作者：Tuccinardi Tiziano; Zizzari Alessandra Tania; Brullo Chiara; Daniele Simona; Musumeci Francesca; Schenone Silvia^*; Trincavelli Maria Letizia; Martini Claudia; Martinelli Adriano; Giorgi Gianluca; Botta Maurizio

来源：Organic and Biomolecular Chemistry, 2011, 9(12): 4448-4455.

DOI：10.1039/c0ob01064b

A(1) adenosine receptor antagonists have been proposed to possess an interesting range of potential therapeutic applications. We have already reported the synthesis and the biological characterization of a family of pyrazolo[3,4-b]pyridine derivatives as A(1) adenosine ligands endowed with an antagonistic profile. In the present work, we report the LC separation of enantiomers of our most active A(1) antagonists together with the determination of their absolute configuration by means of X-ray crystal structure analysis. Biological assays confirmed a different activity for the two enantiomers, with the R one showing the higher human A(1)AR affinity. We also developed a homology model of this receptor subtype in order to suggest a binding disposition of the ligands into the hA(1)AR. All of the obtained data suggest that the compound's chirality plays a key role in A(1) affinity.

• 出版日期2011