Pyrimidine Derivatives as Potent and Selective A₃ Adenosine Receptor Antagonists

Abstract

Two regioisomeric series of diaryl 2- or 4-amidopyrimidines have been synthesized and their adenosine receptor affinities were determined in radioligand binding assays at the four human adenosine receptors (hARs). Some of the ligands prepared herein exhibit remarkable affinities (K(i) < 10 nm) and, most noticeably, the absence of activity at the A(1), A(2A), and A(2B) receptors. The structural determinants that support the affinity and selectivity profiles of the series were highlighted through an integrated computational approach, combining a 3D-QSAR model built on the second generation of GRid INdependent Descriptors (GRIND2) with a novel homology model of the hA(3) receptor. The robustness of the computational model was subsequently evaluated by the design of new derivatives exploring the alkyl substituent of the exocyclic amide group. The synthesis and evaluation of the novel compounds validated the predictive power of the model, exhibiting excellent agreement between predicted and experimental activities.

Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

“…The A 3 AR homology model based on an inactive GPCR structure (rhodopsin), still provided useful insights into agonist recognition. A larger than expected gap between His272 and the 3′-OH of agonists (4.21 Å) was speculated to be the site of an interposed water molecule [30]. Retrospectively, it is more likely that the conformational tightening of the receptor residues around the ribose moiety in the agonist-bound structure [35] would explain this gap in the previous model.…”

“…Most hA 3 AR antagonists (17–23, Figure 2) were discovered empirically, by one of three methods: (1) structural modification of a known AR antagonist to bind selectively to the hA 3 AR (e.g., 17 and 22 from [1,2,4]triazolo[1,5- c ]quinazolin-5-amine and 21a and 21b from 8-phenylxanthines); (2) VS of medium to large chemical libraries to identify and optimize binding hits (1,4-dihydropyridines 18 and 19 , pyridine 20 and pyrimidine 23 ); and (3) modification of agonist ligands to reduce relative efficacy in receptor activation without losing binding affinity or A 3 AR selectivity (e.g., antagonist 4) [6,21,28–30]. Typically, radiolabeled 125 I agonist I-AB-MECA is used in binding assays [14], but antagonist [ 3 H] 22 has also been utilized.…”

Diversity-oriented synthetic strategy for developing a chemical modulator of protein–protein interaction

“…The pyrimidine moiety is commonly present in various bioactive small molecules, and it plays a critical role as a nucleoside analogue in various kinase inhibitors or adenosine receptor modulators due to its hydrogen bonding ability (Fig. 1a)202122. Therefore, many synthetic efforts towards pyrimidine-containing species have been focused on aromatic monocyclic or bicyclic skeletons, which limits the structural diversity of the pyrimidine-containing core skeletons.…”

Multiple Cytoproliferative Effects of Elevated Pyrimidines are DNA-Synthesis-Independent and Include p53 Repression: DNA-Synthesis-Independent Proliferative Mechanisms of Elevated Pyrimidines

“…Intriguingly, several pyrimidine derivatives are potent antagonists of adenosine receptors including A3AR, and in some cases are reverse agonists (Baraldi, 1996;Baraldi, 1998;Chebib, 2000;Chang, 2004;Moro, 2006;Wei, 2009;Taliani, 2010;Yaziji, 2011). The derivatives vary in potency, yet the pyrimidine heteroaromatic core appears necessary for antagonistic activity (Chang, 2004).…”