Discovery and Biological Evaluation of Novel Cyanoguanidine P2X7 Antagonists with Analgesic Activity in a Rat Model of Neuropathic Pain

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• 作者：Arturo Perez-Medrano ; Diana L. Donnelly-Roberts ; Prisca Honore ; Gin C. Hsieh ; Marian T. Namovic ; Sridhar Peddi ; Qi Shuai ; Ying Wang ; Connie R. Faltynek ; Michael F. Jarvis ; William A. Carroll
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 28, 2009
• 年：2009
• 卷：52
• 期：10
• 页码：3366-3376
• 全文大小：180K
• 年卷期：v.52,no.10(May 28, 2009)
• ISSN：1520-4804

文摘

We disclose the design of a novel series of cyanoguanidines that are potent (IC₅₀ 10−100 nM) and selective (≥100-fold) P2X₇ receptor antagonists against the other P2 receptor subtypes such as the P2Y₂, P2X₄, and P2X₃. We also found that these P2X₇ antagonists effectively reduced nociception in a rat model of neuropathic pain (Chung model). Particularly, analogue 53 proved to be effective in the Chung model, with an ED₅₀ of 38 μmol/kg after intraperitoneal administration. In addition compound 53 exhibited antiallodynic effects following oral administration and maintained its efficacy following repeated administration in the Chung model. These results suggest an important role of P2X₇ receptors in neuropathic pain and therefore a potential use of P2X₇ antagonists as novel therapeutic tools for the treatment of this type of pain.