title: A-317491, a selective P2X3/P2X2/3 receptor antagonist, reverses inflammatory mechanical hyperalgesia through action at peripheral receptors in rats.
abstract: The effect of A-317491 (5-([(3-Phenoxybenzyl)[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl)-1,2,4-benzenetricarboxylic acid), a recently described selective P2X3 and P2X(2/3) receptor antagonist, on inflammatory mechanical hyperalgesia was examined. In the rat Freund's complete adjuvant model of inflammatory pain, s.c. administration of A-317491 dose-dependently reversed mechanical hyperalgesia. Maximum percent reversal (72%) was seen 3 h after administration at 10 mg/kg. Substantial plasma concentrations were measured for A-317491 after s.c. dosing 3, 10 and 30 mg/kg. However, the brain-to-plasma concentration ratio, determined 1 h after a 10 mg/kg s.c. dose, indicated limited penetration of A-317491 into the central nervous system. As revealed by neural activity recorded from single C-fiber nociceptive afferent in a Freund's complete adjuvant-inflamed rat skin-nerve preparation, topical application of A-317491 completely blocked afferent activation and mechanical sensitization induced by alpha,beta-methylene ATP, a P2X agonist. These results suggest that A-317491 is a peripherally acting P2X blocker. Its efficacy demonstrates the importance of peripheral P2X3/P2X(2/3) receptors in mediating ATP-associated mechanical hyperalgesia following inflammation, confirming previous suggestions of a significant role for P2X(2/3).
authors.affiliation: Purdue Pharma Discovery Research, 6 Cedar Brook Drive, Cranbury, NJ 08512, USA. gang.wu@pharma.com
authors.forename: Gang
authors.initials: G
authors.lastname: Wu
authors.forename: Garth T
authors.initials: GT
authors.lastname: Whiteside
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Scott
authors.initials: S
authors.lastname: Nolan
authors.forename: Mark
authors.initials: M
authors.lastname: Niosi
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Pearson
authors.forename: Victor I
authors.initials: VI
authors.lastname: Ilyin
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006930:Hyperalgesia / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use*; D010812:Physical Stimulation / Q000379:methods; D011083:Polycyclic Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3
chemical_list: C470346:A-317491; D000894:Anti-Inflammatory Agents, Non-Steroidal; C546403:P2rx2 protein, rat; C546410:P2rx3 protein, rat; D010636:Phenols; D011083:Polycyclic Compounds; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058476:Receptors, Purinergic P2X2; D058477:Receptors, Purinergic P2X3