However, the introduction of other, in particular acidic, functional groups at the 5′-position was never investigated. There are only a few reports on introducing other functional moieties at the 5′-position of adenosine receptor ligands, one of them being the tetrazole compound 3 as a highly potent dual A 1AR and A 3AR ligand. have already established the methyl and ethyl carboxamides as highly efficient substituents at the 5′-position. We were interested in exploring these scaffolds further through various substitutions at 6-position of the purine ring (purine numbering), the introduction of the 1-deazapurine scaffold, and variations of the 5′-position (ribose numbering) at the methanocarba moiety ( Figure 1, general structure I). reported compounds 1a and 1b as highly potent A 3 receptor agonists and most recently, the synthesis of S-thioether (N)-methanocarba adenosine derivatives such as compound 2 ( Figure 1). The introduction of the bicyclohexane scaffold, also known as (N)-methanocarba (N for North), in place of the furanose ring of nucleoside agonists is known to increase the A 3 receptor (A 3AR) potency and selectivity in comparison to other adenosine receptor subtypes. We are particularly interested in targeting the A 3 receptor due to its high overexpression in inflammatory and cancer cells compared to its low expression levels in healthy cells, thus making it a potentially promising therapeutic and diagnostic target. Various P1 receptor agonists have been in clinical trials to name a few, capadenoson (A 1AR agonist) for the treatment of atrial fibrillation (NCT00568945), apadenoson (A 2AAR agonist) for the SPECT-myocardial perfusion imaging (NCT01313572), the A 3 receptor agonists namodenoson in phase III for liver cancer (NCT04697810), and piclidenoson (IB-MECA) for the treatment of psoriasis (NCT03168256), rheumatoid arthritis, and most recently, COVID-19 infections (NCT04333472). In general, adenosine, the endogenous agonist at P1 receptors, exhibits protective functions as a response to organ stress and release of damage-associated-molecular pattern (DAMP) molecules such as e.g., ATP and S100 proteins. The G protein-coupled adenosine (P1) receptors A 1, A 2A, A 2B and A 3 play a central role in the complex mechanisms of purinergic signaling.
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