Extracellular nucleosides and nucleotides have widespread functions in controlling physiological homeostasis. The “purinome” encompasses four G protein–coupled receptors (GPCRs) for adenosine, eight GPCRs activated by nucleotides (P2YRs), seven ATP-gated P2X ion channels, and the associated enzymes and transporters that regulate the levels of the native agonists. Modulators of purinergic signaling, such as receptor agonists and antagonists, have potential for treating chronic pain. Signaling molecules acting at P2X3, P2X4, P2X7 and P2Y12 receptors play critical roles in maladaptive pain neuroplasticity. Recent efforts have provided structurally novel ligands for these nucleotide receptors. Adenosine and its analogues potently suppress nociception in preclinical models by activating A1 and/or A3 adenosine receptors (ARs), but safely harnessing this endogenous pathway to clinically treat pain has not been achieved. However, we discovered that this can be achieved through selective targeting of A3AR (1,2) sprompting exploration of the structure activity relationship of nucleoside derivatives at this subtype using a computational structure-based approach. Novel A3AR agonists for pain control that contained a bicyclic ring system (bicyclo[3.1.0]hexane) in place of ribose were designed and screened using an in vivo phenotypic model (3), which reflected both pharmacokinetic and pharmacodynamic parameters. High specificity (&gt;10,000-fold selective for the A3AR) was achieved with the aid of receptor homology models based on related GPCR structures. These A3AR agonists were well tolerated in vivo and highly efficacious in models of chronic neuropathic pain.

Purine receptors as drug targets in pain

254th National Meeting (2017)

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