Abstract
A library of potent and highly A3AR selective pyrimidine-based compounds was designed to explore non-orthosteric interactions within this receptor. Starting from a prototypical orthosteric A3AR antagonist (ISVY130), the structure-based design explored functionalized residues at the exocyclic amide L1 region and aimed to provide additional interactions outside the A3AR orthosteric site. The novel ligands were assembled through an efficient and succinct synthetic approach, resulting in compounds that retain the A3AR potent and selective profile while improving the solubility of the original scaffold. The experimentally demonstrated tolerability of the L1 region to structural functionalization was further assessed by molecular dynamics simulations, giving hints of the non-orthosteric interactions explored by these series. The results pave the way to explore newly functionalized A3AR ligands, including covalent drugs and molecular probes for diagnostic and delivery purposes.
Highlights
A library of potent and highly A3AR selective pyrimidinebased compounds was designed to explore non-orthosteric interactions within this receptor
From a pathological point of view, extracellular levels of Ado result in two well-defined and opposed effects.[4−6] While in some cases it is shown to impede the progression of the disease, in others the overproduction of Ado has a protective and stimulant effect that facilitates the progression of the pathology
A3AR is heavily implicated in a variety of cardiovascular and neurological disorders[10] but is overexpressed in several cancer cells,[5] making them a possible biomarker for cancer diagnosis, prognosis, and therapeutic monitoring
Summary
The computational studies were conducted with the resources available from the Swedish National Infrastructure for Computing (SNIC). The project was carried out within the framework of the collaborative EU COST action ERNEST (CA18133). A1AR, A1 adenosine receptor; A2AAR, A2A adenosine receptor; A2BAR, A2B adenosine receptor; A3AR, A3 adenosine receptor; Ado, adenosine; AR, adenosine receptor; Cmpd, compound; Cy, cyclohexyl; MD, molecular dynamics; PAINS, pan-assay interference compounds; U-4CR, Ugi four component reaction
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