Adenosine A2A receptor antagonists: from caffeine to selective non-xanthines

Abstract

A long evolution of knowledge of the psychostimulant caffeine led in the 1960s to another purine natural product, adenosine and its A_2A receptor. Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four different adenosine receptors in a manner opposite to the pan-antagonist caffeine and serves as an endogenous allostatic regulator. Although detrimental in the developing brain, caffeine appears to be cerebroprotective in aging. Moderate caffeine consumption in adults, except in pregnancy, may also provide benefit in pain, diabetes, and kidney and liver disorders. Inhibition of A_2A receptors is one of caffeine's principal effects and we now understand this interaction at the atomic level. The A_2A receptor has become a prototypical example of utilizing high-resolution structures of GPCRs for the rational design of chemically diverse drug molecules. The previous focus on discovery of selective A_2A receptor antagonists for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued. LINKED ARTICLES: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

FIGURE 1

This Figure shows the structures (compounds 6 – 21) of some synthetic potent and selective heterocyclic A_2A receptor antagonists. When radiolabelled, an asterisk (*) indicates the site of isotopic labelling. The structures of simple alkylxanthines (compounds 1 – 5) are presented in Table 1

FIGURE 2

Crystal structures of the human A_2A receptor in complex with adenosine and antagonists. (a) Receptor structure shown as grey cartoons with the orthosteric binding site highlighted with a transparent blue oval. The antagonist ZM241385 (also shown in Figure 1, as compound 10) is shown as sticks with orange carbon atoms and residue Asn253^6.55 as sticks with white carbon atoms (PDB code: 4EIY, Liu et al., 2012). The bound sodium ion (purple sphere) is coordinated by Asp52^2.50 (shown as sticks). Binding modes are shown for purines: (b) adenosine (PDB code: 2YDO, Lebon et al., 2011), (c) caffeine (Figure 1, compound 1; PDB code: 5MZP, Cheng et al., 2017), (d) XAC (Figure 1, compound 6; PDB code: 3REY, Doré et al., 2011), (e) PSB36 (PDB code: 5N2R, Cheng et al., 2017); and for non-purines: (f) ZM241385 (PDB code: 4EIY), (g) Tozadenant (Figure 1, compound 13; PDB code: 5OLO, Rucktooa et al., 2018), (h) Vipadenant (Figure 1, compound 14; PDB code: 5OLH, Rucktooa et al., 2018), (i) HTL-1071 (PDB code: 6GT3), (j) a triazole-carboximidamide antagonist (PDB code: 5UIG, Sun et al., 2017) and (k) parent drug of LUAA47070, a prodrug in the family of compound 19 in Figure1; PDB code: 5OLV, Rucktooa et al., 2018). The ligands and key residues are shown as sticks. Hydrogen bonds are shown as dashed lines. Water molecules are shown as red spheres