2 research outputs found
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoretical–experimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies
Effect of Nitrogen Atom Substitution in A<sub>3</sub> Adenosine Receptor Binding: <i>N</i>‑(4,6-Diarylpyridin-2-yl)acetamides as Potent and Selective Antagonists
We
report the first family of 2-acetamidopyridines as potent and
selective A<sub>3</sub> adenosine receptor (AR) antagonists. The computer-assisted
design was focused on the bioisosteric replacement of the N1 atom
by a CH group in a previous series of diarylpyrimidines. Some of the
generated 2-acetamidopyridines elicit an antagonistic effect with
excellent affinity (<i>K</i><sub>i</sub> < 10 nM) and
outstanding selectivity profiles, providing an alternative and simpler
chemical scaffold to the parent series of diarylpyrimidines. In addition,
using molecular dynamics and free energy perturbation simulations,
we elucidate the effect of the second nitrogen of the parent diarylpyrimidines,
which is revealed as a stabilizer of a water network in the binding
site. The discovery of 2,6-diaryl-2-acetamidopyridines represents
a step forward in the search of chemically simple, potent, and selective
antagonists for the hA<sub>3</sub>AR, and exemplifies the benefits
of a joint theoretical–experimental approach to identify novel
hA<sub>3</sub>AR antagonists through succinct and efficient synthetic
methodologies