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A-317491 is a high-affinity and selective antagonist of P2X2/3 and P2X3 receptors with Ki values of 9 and 22 nM, respectively for human P2X2/3 and P2X3 [1].

The P2X3 receptor is an ATP-sensitive ligand-gated ion channel expressed on sensory afferent neurons. When it combines with the P2X2 receptor, they form as a heteromeric receptor P2X2/3. Unlike the P2X2 receptor, P2X2/3 can be activated by low concentration of α, β-me ATP which was the agonist of P2X3. As an ion channel, the P2X3 receptor plays roles in the pain signaling propagation. A-317491 is the first non-nucleotide antagonist of P2X2/3 and P2X3 receptors with high selectivity. It showed anti-nociceptive in animal models of neuropathic pain and chronic inflammatory [2].

In cell membrane of 1321N1 human astrocytoma cells stably transfected with individual human P2X2 and P2X3 receptors, 3 nM of A-317491 showed 60% of total binding and the binding could be enhanced by the addition of CaCl2. Besides that, the binding was found to be reversible. In rat DRG neurons, A-317491 blocked DRG currents dose-dependently with IC50 value of 15 nM. A-317491 is highly selective against P2X2/3 and P2X3, it showed less potent effects against other P2X and the P2Y2 receptors such as P2X1 (Ki value of 2.5 μM) and P2X2 (Ki value of 4.1 μM) [2 and 3].

In rat model with CFA-induced thermal hyperalgesia, intrathecal administration of A-317491 at doses of 30 and 100 nM both showed significant anti-hyperalgesia effects. When delivered as intraplantar administration, A-317491 showed notably anti-hyperalgesia effects only at dose of 300 nM. In carrageenan-treated rats, intrathecal administration of A-317491 at doses of 30 and 100 nM also exerted anti-hyperalgesia effects. In both CCI and L5-L6 models of neuropathic allodynia, intrathecal administration of A-317491 at doses of 10 and 30 nM resulted in significant withdrawal responses to von Frey hair stimulation [4].

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