Treatment of chronic neuropathic pain: purine receptor modulation.

摘要: 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 the associated enzymes transporters that regulate native agonist levels. Purinergic signaling modulators, such receptor agonists antagonists, potential treating chronic pain. Adenosine its analogues potently suppress nociception preclinical models activating A1 and/or A3 (ARs), but safely harnessing this pathway clinically treat pain has not been achieved. Both A2AAR antagonists are efficacious models. Highly selective A3AR offer a novel approach We explored structure activity relationship of nucleoside derivatives at subtype using computational structure-based approach. Novel control containing bicyclic ring system (bicyclo [3.1.0] hexane) place ribose were designed screened an vivo phenotypic model, which reflected both pharmacokinetic pharmacodynamic parameters. High specificity (>10,000-fold A3AR) was achieved with aid homology based on related GPCR structures. These tolerated highly neuropathic Furthermore, molecules acting P2X3, P2X4, P2X7, P2Y12Rs play critical roles maladaptive neuroplasticity, their reduce or inflammatory pain, and, therefore, purine modulation is promising future therapeutics. Structurally these nucleotide discovered recently.