A-317491

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].
References:
[1] Jarvis MF, Burgard EC, McGaraughty S, Honore P, Lynch K, Brennan TJ, Subieta A, Van Biesen T, Cartmell J, Bianchi B, Niforatos W, Kage K, Yu H, Mikusa J, Wismer CT, Zhu CZ, Chu K, Lee CH, Stewart AO, Polakowski J, Cox BF, Kowaluk E, Williams M, Sullivan J, Faltynek C. A-317491, a novel potent and selective non-nucleotide antagonist of P2X3 and P2X2/3 receptors, reduces chronic inflammatory and neuropathic pain in the rat. Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17179-84.
[2] Neelands TR, Burgard EC, Uchic ME, McDonald HA, Niforatos W, Faltynek CR, Lynch KJ, Jarvis MF. 2', 3'-O-(2,4,6,trinitrophenyl)-ATP and A-317491 are competitive antagonists at a slowly desensitizing chimeric human P2X3 receptor. Br J Pharmacol. 2003 Sep;140(1):202-10. Epub 2003 Jul 29.
[3] Jarvis MF, Bianchi B, Uchic JT, Cartmell J, Lee CH, Williams M, Faltynek C. [3H]A-317491, a novel high-affinity non-nucleotide antagonist that specifically labels human P2X2/3 and P2X3 receptors. J Pharmacol Exp Ther. 2004 Jul;310(1):407-16.
[4] McGaraughty S, Wismer CT, Zhu CZ, Mikusa J, Honore P, Chu KL, Lee CH, Faltynek CR, Jarvis MF. Effects of A-317491, a novel and selective P2X3/P2X2/3 receptor antagonist, on neuropathic, inflammatory and chemogenic nociception following intrathecal and intraplantar administration. Br J Pharmacol. 2003 Dec;140(8):1381-8.