Studies on enantioselectivity of chiral 4-acetylamino-6-alkyloxy-2-alkylthiopyrimidines acting as antagonists of the human A₃ adenosine receptor.

ABSTRACT: Three A₃ adenosine receptor (AR) antagonists (1-3) selected from 4-acylamino-6-alkyloxy-2-alkylthiopyrimidines previously investigated by us were modified by inserting a methyl group on their ether or thioether side chains. These compounds gave us the chance to evaluate whether their higher lipophilicity, reduced conformational freedom and chirality might improve the potency towards the A₃ AR. Racemic mixtures of 1-3 were resolved using chiral HPLC methods and the absolute configurations of the enantiomers were assigned by chiroptical spectroscopy and density functional theory calculations. We measured the affinity for human A₁, A_2A, A_2B and A₃ ARs of the racemic mixtures and the pure enantiomers of 1-3 by radioligand competition binding experiments. Cell-based assays of the most potent enantiomers confirmed their A₃ AR antagonist profiles. Our research led to the identification of (S)-1 with high potency (0.5 nM) and selectivity as an A₃ AR antagonist. Moreover we built a docking-model useful to design new pyrimidine derivatives.

SUBMITTER: Cosimelli B 

PROVIDER: S-EPMC6072526 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature