Molecular modeling study on potent and selective adenosine A3 receptor agonists.

Adenosine A3 receptor (A3AR) is involved in a variety of key physio-pathological processes and its agonists are potential therapeutic agents for the treatment of rheumatoid arthritis, dry eye disorders, asthma, as anti-inflammatory agents, and in cancer therapy. Recently reported MECA (5-N-methylcarboxamidoadenosine) derivatives bearing a methyl group in N6-position and an arylethynyl substituent in 2-position demonstrated to possess sub-nanomolar affinity and remarkable selectivity for the human A3AR, behaving as full agonists of this receptor. In this study, we made an attempt to get a rationalization of the high affinities and selectivities of these molecules for the human A3AR, by using adenosine receptor (AR) structural models based on the A2AAR crystal structure and molecular docking analysis. Post-docking analysis allowed to evaluate the ability of modeling tools in predicting AA3R affinity and in providing interpretation of compound substituents effect on the A3AR affinity and selectivity.