Extracellular
nucleosides and
nucleotides have widespread functions in responding to physiological stress. The "purinome" encompasses 4
G-protein-coupled receptors (GPCRs) for
adenosine, 8 GPCRs activated by
nucleotides, 7
adenosine 5'-triphosphate-gated P2X
ion channels, as well as the associated
enzymes and transporters that regulate native agonist levels. Purinergic signaling modulators, such as receptor agonists and antagonists, have potential for treating
chronic pain.
Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3
adenosine receptors (ARs), but safely harnessing this pathway to clinically treat
pain has not been achieved. Both A2AAR agonists and antagonists are efficacious in
pain models. Highly selective A3AR agonists offer a novel approach to treat
chronic pain. We have explored the structure activity relationship of
nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for
pain control containing a bicyclic ring system (
bicyclo [3.1.0] hexane) in place of
ribose were designed and screened using an in vivo phenotypic model, which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (>10,000-fold selective for A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists are well tolerated in vivo and highly efficacious in models of chronic
neuropathic pain. Furthermore, signaling molecules acting at P2X3, P2X4, P2X7, and P2Y12Rs play critical roles in maladaptive
pain neuroplasticity, and their antagonists reduce chronic or inflammatory
pain, and, therefore,
purine receptor modulation is a promising approach for future
pain therapeutics. Structurally novel antagonists for these
nucleotide receptors were discovered recently.