title: 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.
abstract: 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 microM) 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 micromolkg s.c.) reduced complete Freund's adjuvant-induced thermal hyperalgesia in the rat. A-317491 was most potent (ED50 = 10-15 micromolkg 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 micromolkg 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.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064-6123, USA. michael.jarvis@abbott.com
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Edward C
authors.initials: EC
authors.lastname: Burgard
authors.forename: Steve
authors.initials: S
authors.lastname: McGaraughty
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Kevin
authors.initials: K
authors.lastname: Lynch
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Brennan
authors.forename: Alberto
authors.initials: A
authors.lastname: Subieta
authors.forename: Tim
authors.initials: T
authors.lastname: Van Biesen
authors.forename: Jayne
authors.initials: J
authors.lastname: Cartmell
authors.forename: Bruce
authors.initials: B
authors.lastname: Bianchi
authors.forename: Wende
authors.initials: W
authors.lastname: Niforatos
authors.forename: Karen
authors.initials: K
authors.lastname: Kage
authors.forename: Haixia
authors.initials: H
authors.lastname: Yu
authors.forename: Joe
authors.initials: J
authors.lastname: Mikusa
authors.forename: Carol T
authors.initials: CT
authors.lastname: Wismer
authors.forename: Chang Z
authors.initials: CZ
authors.lastname: Zhu
authors.forename: Katharine
authors.initials: K
authors.lastname: Chu
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Andrew O
authors.initials: AO
authors.lastname: Stewart
authors.forename: James
authors.initials: J
authors.lastname: Polakowski
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kowaluk
authors.forename: Michael
authors.initials: M
authors.lastname: Williams
authors.forename: James
authors.initials: J
authors.lastname: Sullivan
authors.forename: Connie
authors.initials: C
authors.lastname: Faltynek
mesh_terms: D018712:Analgesics, Non-Narcotic / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010636:Phenols / Q000494:pharmacology*; D011083:Polycyclic Compounds / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3
chemical_list: C470346:A-317491; D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; C546401:P2RX2 protein, human; C546407:P2RX3 protein, human; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3