This technology includes the creation and use of A3 adenosine receptor (A3AR)-selective agonists for treating chemotherapy-induced peripheral neuropathy, chronic neuropathic pain, rheumatoid arthritis, psoriasis, and other conditions. A3 receptors for adenosine are found in most cells and endogenous activation of the A3 receptors can result in apoptosis, thereby relieving the inflammation or targeting a tumor. A3AR agonists have been a promising strategy for the treatment of various diseases. A3AR agonists can reverse neuropathic pain by modulating the production of anti-inflammatory cytokines such as IL-10. A3AR agonists can also induce apoptosis of cancer and inflammatory cells by disrupting the Wnt and NF-KB signaling pathways. The current invention includes A3AR-selective agonists that are methanocarba derivatives. This class of compounds has been shown to be highly selective for A3AR (>3000-fold affinity versus A1AR and A2AAR). This selectively is retained in mice (400-fold affinity versus A1AR), facilitating preclinical development.
A3AR-selective agonists are currently in advanced clinical trials for the treatment of hepatocellular carcinoma, autoimmune inflammatory diseases (such as rheumatoid arthritis), psoriasis, dry eye disease, and other conditions. Other potential applications of such agonists could be osteoarthritis, Crohn's disease, ischemia, and other inflammatory disorders.
This class of compounds produced full agonists of the human A3AR of nanomolar affinity that were consistently highly selective (>3000-fold vs. A1AR and A2AAR). The selectivity at mouse A3 receptors is retained but lower. The compounds are still effective in vivo in reducing or preventing the development of neuropathic pain. Phenotypic screening has identified in vivo activity of specific C2 substituents in a chronic neuropathic pain model. Opioid analgesics in combination with A3 agonists have reduced side effects.