4 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
Enantiospecific Recognition at the A<sub>2B</sub> Adenosine Receptor by Alkyl 2‑Cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahydropyrimidine-5-carboxylates
A novel
family of structurally simple, potent, and selective nonxanthine
A<sub>2B</sub>AR ligands was identified, and its antagonistic behavior
confirmed through functional experiments. The reported alkyl 2-cyanoimino-4-substituted-6-methyl-1,2,3,4-tetrahy-dropyrimidine-5-carboxylates
(<b>16</b>) were designed by bioisosteric replacement of the
carbonyl group at position 2 in a series of 3,4-dihydropyrimidin-2-ones.
The scaffold (<b>16</b>) documented herein contains a chiral
center at the heterocycle. Accordingly, the most attractive ligand
of the series [(±)<b>16b</b>, <i>K</i><sub>i</sub> <b>=</b> 24.3 nM] was resolved into its two enantiomers by
chiral HPLC, and the absolute configuration was established by circular
dichroism. The biological evaluation of both enantiomers demonstrated
enantiospecific recognition at A<sub>2B</sub>AR, with the (<i>S</i>)-<b>16b</b> enantiomer retaining all the affinity
(<i>K</i><sub>i</sub> <b>=</b> 15.1 nM), as predicted
earlier by molecular modeling. This constitutes the first example
of enantiospecific recognition at the A<sub>2B</sub> adenosine receptor
and opens new possibilities in ligand design for this receptor
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
A Positive Allosteric Modulator of the Serotonin 5‑HT<sub>2C</sub> Receptor for Obesity
The 5-HT<sub>2C</sub>R agonist lorcaserin,
clinically approved
for the treatment of obesity, causes important side effects mainly
related to subtype selectivity. In the search for 5-HT<sub>2C</sub>R allosteric modulators as safer antiobesity drugs, a chemical library
from Vivia Biotech was screened using ExviTech platform. Structural
modifications of identified hit VA240 in synthesized analogues <b>6</b>–<b>41</b> afforded compound <b>11</b> (<i>N</i>-[(1-benzyl-1<i>H</i>-indol-3-yl)methyl]pyridin-3-amine,
VA012), which exhibited dose-dependent enhancement of serotonin efficacy,
no significant off-target activities, and low binding competition
with serotonin or other orthosteric ligands. PAM <b>11</b> was
very active in feeding inhibition in rodents, an effect that was not
related to the activation of 5-HT<sub>2A</sub>R. A combination of <b>11</b> with the SSRI sertraline increased the anorectic effect.
Subchronic administration of <b>11</b> reduced food intake and
body weight gain without causing CNS-related malaise. The behavior
of compound <b>11</b> identified in this work supports the interest
of a serotonin 5-HT<sub>2C</sub>R PAM as a promising therapeutic approach
for obesity