A2AR agonists/A3R antagonists: design, synthesis, and biological evaluation of new ligands with dual activity

Adenosine receptors and in particular the A2A and A3 (A2AR and A3R) receptor subtypes control a range of key physiological processes during inflammation in different conditions. Potent and selective A3AR agonists/antagonists could provide tools for the characterization of the role of these receptors and for the development of new drugs having anti-inflammatory, anticancer, and cardioprotective effects [1,2]. The A2AR crystallographic structures furnished important information about the interaction of the receptor with the co-crystallized ligands [3]. In particular, some polar interactions between the 6-amino group of adenosine and the residue Asn253 and Glu169 and hydrophobic (π-stacking bonding) interaction of the aromatic scaffold of adenosine and Phe168 are formed [4]. The A2A and A3 AR sequence comparison analysis shows that, among these residues, only Phe168 and Asn253 are conserved while Glu169 of A2AAR is replaced by Val169 in the A3AR [5]. Furthermore, it has been found that replacement of the hydoxymethyl group of the ribose moiety of 2-alkoxyadenosine with a C-tetrazolyc function led to compounds endowed with high A2AR potency [6]. On these bases, known A2A ligands modified through the introduction of an N6-amino or N6-alkylamino group were designed and synthesized. Additionally, 5’-C-tetrazolic-adenosine derivatives, bearing analogue chains in 2 position of the first series, were prepared. The new compounds were tested in binding and functional studies at human A1, A2A, A2B, andA3 receptors transfected in CHO cells. Preliminary results show that the synthesized derivatives present pronounced affinity and potency at theA3AR subtype and reduced interaction with the A2AR. In addition, the newly synthesized Ado derivatives are endowed with a dual pharmacological activity, resulting potent agonists at A2AR and antagonists at A3R.