Characterization of N-(Adamantan-1-ylmethyl)-5-[(3R-aminopyrrolidin-1-yl)methyl]-2-chloro-benzamide, a P2X7 Antagonist in Animal Models of Pain and Inflammation
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 ch...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 327; no. 3; p. 620 |
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Main Authors | , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.12.2008
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Subjects | |
Online Access | Get full text |
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Summary: | 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-[(3 R -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(3 H )-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. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.108.141853 |