A-317491

A-317491 is a non-nucleotide antagonist of the purinergic receptors P2X₃ and P2X_2/3 (K_is = 22-92 nM in a calcium influx assay) that is selective over other purinergic and neurotransmitter receptors, ion channels, and enzymes (IC₅₀s = >10 µM).¹ It reduces thermal hyperalgesia induced by complete Freund’s adjuvant in rats (ED₅₀ = 30 µmol/kg, s.c.) and nociceptive responses to chemically-induced pain. Chronic administration of A-317491 (30 µmol/kg, twice daily) reduces early, but not late, phase pain in a mouse model of bone cancer.² A-317491 does not readily cross the blood-brain barrier and reduces pain responses when applied topically in a rat model of inflammatory pain, indicating that it acts primarily at peripheral purinergic receptors.³

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1. Jarvis, M.F., Burgard, E.C., McGaraughty, S., et al. 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. USA 99(26), 17179-17184 (2002).

2. Hansen, R.R., Nasser, A., Falk, S., et al. Chronic administration of the selective P2X3, P2X2/3 receptor antagonist, A-317491, transiently attenuates cancer-induced bone pain in mice. Eur. J. Pharmacol. 688(1-3), 27-34 (2012).

3. Wu, G., Whiteside, G.T., Lee, G., et al. A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats. Eur. J. Pharmacol. 504(1-2), 45-53 (2004).