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, 53 (9), 3748-55

Structure-based Discovery of A2A Adenosine Receptor Ligands


Structure-based Discovery of A2A Adenosine Receptor Ligands

Jens Carlsson et al. J Med Chem.


The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 microM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target.


Chart 1
Chart 1. Structures of Known Agonists (13) and Antagonists (46) of the A2A Adenosine Receptor
Figure 1
Figure 1
Binding mode of the cocrystallized ligand 6 (A) and the predicted binding modes of the seven ligands discovered in the docking screen (B−H). The A2A AR binding site is shown in white ribbons with the side chains of Glu169 and Asn253 in sticks. In (A) the cocrystallized ligand 6 is shown using orange carbon atoms. In (B−H), the crystallographic ligand is shown using blue lines and the docking poses for the ligands are depicted with orange carbon atoms. Black dotted lines indicate hydrogen bonds. The compounds are (B) 7, (C) 8, (D) 9, (E) 10, (F) 11, (G) 12, and (H) 13.
Figure 2
Figure 2
Representative dose−response curves for displacement of binding of the radiolabeled A2A AR agonist 3 by compounds 9, 10, and 11.
Figure 3
Figure 3
Functional assay based on measuring the production of cAMP for 3 (control), a potent A2A AR agonist, with or without 10 μM 9 or 11. The dose−response curve is shifted for both compounds, as expected in the case of competitive antagonistic inhibition. The % activation refers to production of cAMP normalized to the effect of 3 at 100 μM.

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