title: Characterization of N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 antagonist in animal models of pain and inflammation.
abstract: Recent evidence suggests that the P2X(7) receptor may play a role in the pathophysiology of preclinical models of pain and inflammation. Therefore, pharmacological agents that target this receptor may potentially have clinical utility as anti-inflammatory and analgesic therapy. We investigated and characterized the previously reported P2X(7) antagonist N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt (AACBA; GSK314181A). In vitro, AACBA was a relatively potent inhibitor of both human P2X(7)-mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC(50) values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X(7) receptor, with IC(50) values of 29 and 980 nM in the calcium flux and YO-PRO-1 assays, respectively. In acute in vivo models of pain and inflammation, AACBA dose-dependently reduced lipopolysaccharide-induced plasma interleukin-6 release and prevented or reversed carrageenan-induced paw edema and mechanical hypersensitivity. In chronic in vivo models of pain and inflammation, AACBA produced a prophylactic, but not therapeutic-like, prevention of the clinical signs and histopathological damage of collagen-induced arthritis. Finally, AACBA could not reverse L(5) spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X(7) receptors do play a role in animal models of pain and inflammation. Further study of P2X(7) antagonists both in preclinical and clinical studies will help elucidate the role of the P2X(7) receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.
authors.affiliation: Department of Pharmacology, Neurogen Corporation, Branford, Connecticut, USA. danbroom@hotmail.com
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Broom
authors.forename: David J
authors.initials: DJ
authors.lastname: Matson
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bradshaw
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Buck
authors.forename: Robin
authors.initials: R
authors.lastname: Meade
authors.forename: Susan
authors.initials: S
authors.lastname: Coombs
authors.forename: Michele
authors.initials: M
authors.lastname: Matchett
authors.forename: Kristen K
authors.initials: KK
authors.lastname: Ford
authors.forename: Weifeng
authors.initials: W
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Yuan
authors.forename: Synthia H
authors.initials: SH
authors.lastname: Sun
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ochoa
authors.forename: James E
authors.initials: JE
authors.lastname: Krause
authors.forename: David J
authors.initials: DJ
authors.lastname: Wustrow
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Cortright
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001168:Arthritis / Q000139:chemically induced / Q000188:drug therapy; D001549:Benzamides / Q000494:pharmacology*; D001583:Benzoxazoles; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D010146:Pain / Q000188:drug therapy*; D058919:Purinergic P2 Receptor Antagonists; D011806:Quinolinium Compounds; D051381:Rats; D058486:Receptors, Purinergic P2X7
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001549:Benzamides; D001583:Benzoxazoles; C533859:N-(adamantan-1-ylmethyl)-5-((3-aminopyrrolidin-1-yl)methyl)-2-chlorobenzamide; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D058919:Purinergic P2 Receptor Antagonists; D011806:Quinolinium Compounds; D058486:Receptors, Purinergic P2X7; C089813:YO-PRO 1; D000218:Adamantane; D002118:Calcium