The A3 adenosine receptor (A3AR) is a promising therapeutic target for a variety of chronic diseases including psoriasis, glaucoma, rheumatoid arthritis, and cancer. (N)-Methanocarba adenosine 5'-methyluronamides containing known A3AR-enhancing modifications, i.e., 2-(arylethynyl)adenine and N6-methyl or N6-(3-substituted-benzyl) groups, were nanomolar full agonists of human and mouse A3AR and highly selective (>3000-fold vs. other ARs). Combined 2-arylethynyl-N6-3-chlorobenzyl substitutions preserved A3AR affinity/selectivity in the (N)-methanocarba series better than that for ribosides. Receptor docking identified a large, mainly hydrophobic binding region and the vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A2AAR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. 2-(3,4-Difluorophenyl)ethynyl N6-(3-chlorobenzyl) derivative MRS5698 was identified as a lead compound in a SAR study of receptor binding and in vivo. Chronic neuropathic pain is poorly managed and represents a huge unmet medical need. In models of chronic constriction injury (CCI) and chemotherapy-induced neuropathic pain (CIPN), we demonstrate the analgesic effects of the selective and orally available A3AR agonist MRS5698. In mice and rats with CCI, systemic MRS5698 reversed mechano-allodynia in a dose-dependent manner. These effects were blocked by a selective A3AR antagonist, lost in A3AR-/- mice and had both peripheral and spinal sites of action. Our findings provide the pharmacological rationale towards the clinical development of A3AR agonists for chronic pain.                            Figure 1

Discovery of next generation A<sub>3</sub> adenosine receptor selective agonists for treatment of chronic neuropathic pain

247th National Meeting (2014)

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Discovery of next generation A3 adenosine receptor selective agonists for treatment of chronic neuropathic pain

Discovery of next generation A₃ adenosine receptor selective agonists for treatment of chronic neuropathic pain