Abstract
Recent evidence suggests that the P2X7 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 P2X7 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 P2X7-mediated calcium flux and quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide (YO-PRO-1) uptake assays, with IC50 values of approximately 18 and 85 nM, respectively. Compared with the human receptor, AACBA was less potent at the rat P2X7 receptor, with IC50 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 L5 spinal nerve ligation-induced tactile allodynia when given therapeutically. Consistent with previous literature, these results suggest that P2X7 receptors do play a role in animal models of pain and inflammation. Further study of P2X7 antagonists both in preclinical and clinical studies will help elucidate the role of the P2X7 receptor in pain and inflammatory mechanisms and may help identify potential clinical benefits of such molecules.
Footnotes
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D.C.B., D.J.M., E.B., M.E.B., R.M., S.C., M.M., K.K.F., W.Y., J.Y., R.O., J.E.K., D.J.W., and D.N.C. were employees of Neurogen Corporation when this work was completed.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.108.141853.
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ABBREVIATIONS: IL, interleukin; TNF, tumor necrosis factor; CFA, complete Freund's adjuvant; A-740003, N-(1-{[(cyanoimino)(5-quinolinylamino)-methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenul)acetamide; AACBA, N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide, hydrochloride salt; BzATP, 2′,3′-O-(4-benzoyl benzoyl)-ATP; LPS, lipopolysaccharide; HPBCD, hydroxypropyl-β-cyclodextrin; TPGS, d-α-tocopheryl polyethylene glycol 1000 succinate; MTX, methotrexate; DMSO, dimethyl sulfoxide; h, human; r, rat; YO-PRO-1, quinolinium,4-[(3-methyl-2(3H)-benzoxazolylidene)methyl]-1-[3-(triemethylammonio)propyl]-diiodide; ANOVA, analysis of variance; LSD, least significant difference; SNL, spinal nerve ligation; Veh, vehicle; Dex, dexamethasone; CIA, collagen-induced arthritis; CNS, central nervous system; A-438079, 3-[[5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl]pyridine hydrochloride; AZ11657312, 2-(adamantan-1-yl)-N-[2-methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-ylcarbonyl)phenyl]acetamide monohydrochloride.
- Received June 16, 2008.
- Accepted September 2, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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