[Abbott - P2X3 and P2X2/3 receptor antagonist]
Published online before print December 13, 2002
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.252537299
Pharmacology
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
Michael F. Jarvis *, Edward C. Burgard *, Steve McGaraughty *, Prisca Honore *, Kevin Lynch *, Timothy J. Brennan , Alberto Subieta , Tim van Biesen *, Jayne Cartmell *, Bruce Bianchi *, Wende Niforatos *, Karen Kage *, Haixia Yu *, Joe Mikusa *, Carol T. Wismer *, Chang Z. Zhu *, Katharine Chu *, Chih-Hung Lee *, Andrew O. Stewart *, James Polakowski *, Bryan F. Cox *, Elizabeth Kowaluk *, Michael Williams *, James Sullivan *, and Connie Faltynek *
*Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123; and Department of Anesthesiology, University of Iowa, Iowa City, IA 52242-1079
Edited by John W. Daly, National Institutes of Health, Bethesda, MD, and approved October 25, 2002 (received for review September 4, 2002)
P2X3 and P2X2/3 receptors are highly localized on peripheral and central processes of sensory afferent nerves, and activation of these channels contributes to the pronociceptive effects of ATP. A-317491 is a novel non-nucleotide antagonist of P2X3 and P2X2/3 receptor activation. A-317491 potently blocked recombinant human and rat P2X3 and P2X2/3 receptor-mediated calcium flux (Ki = 22-92 nM) and was highly selective (IC50 >10 µM) over other P2 receptors and other neurotransmitter receptors, ion channels, and enzymes. A-317491 also blocked native P2X3 and P2X2/3 receptors in rat dorsal root ganglion neurons. Blockade of P2X3 containing channels was stereospecific because the R-enantiomer (A-317344) of A-317491 was significantly less active at P2X3 and P2X2/3 receptors. A-317491 dose-dependently (ED50 = 30 µmol/kg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 µmol/kg s.c.) in attenuating both thermal hyperalgesia and mechanical allodynia after chronic nerve constriction injury. The R-enantiomer, A-317344, was inactive in these chronic pain models. Although active in chronic pain models, A-317491 was ineffective (ED50 >100 µmol/kg s.c.) in reducing nociception in animal models of acute pain, postoperative pain, and visceral pain. The present data indicate that a potent and selective antagonist of P2X3 and P2X2/3 receptors effectively reduces both nerve injury and chronic inflammatory nociception, but P2X3 and P2X2/3 receptor activation may not be a major mediator of acute, acute inflammatory, or visceral pain.<<
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