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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Departments of Pharmacology (D.C.B., D.J.M., E.B.), Biochemistry and Molecular Biology (M.E.B., R.M., S.C., J.E.K., D.N.C.), Electrophysiology (M.M., K.K.F., W.Y.), Medicinal Chemistry (J.Y., D.J.W.), and Toxicology (R.O.), Neurogen Corporation, Branford, Connecticut; and Institute of Neuroscience, National Yang Ming University, Taipei, Taiwan, Republic of China (S.H.S.)

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.

Address correspondence to: Dr. Daniel C. Broom, 65 Pine Orchard Rd., Branford, CT 06405. E-mail: danbroom{at}hotmail.com

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