Discovery of a High Affinity Adenosine A₁/A₃ Receptor Antagonist with a Novel 7-Amino-pyrazolo[3,4-d]pyridazine Scaffold.

ABSTRACT: Here we describe the design and synthesis of pyrazolo[3,4-d]pyridazines as adenosine receptor (AR) ligands. We demonstrate that the introduction of a 3-phenyl group, together with a 7-benzylamino and 1-methyl group at the pyrazolopyridazine scaffold, generated the antagonist compound 10b, which displayed 21 nM affinity and a residence time of ∼60 min, for the human A₁R, 55 nM affinity and a residence time of ∼73 min, for the human A₃R and 1.7 μΜ affinity for the human A_2BR while not being toxic. Strikingly, the 2-methyl analog of 10b, 15b, had no significant affinity. Docking calculations and molecular dynamics simulations of the ligands inside the orthosteric binding area suggested that the 2-methyl group in 15b hinders t

SUBMITTER: Suchankova A 

PROVIDER: S-EPMC9190043 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature