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

被引：43

作者：

Perez-Medrano, Arturo ^{[1
]}

Donnelly-Roberts, Diana L. ^{[1
]}

Honore, Prisca ^{[1
]}

Hsieh, Gin C. ^{[1
]}

Namovic, Marian T. ^{[1
]}

Peddi, Sridhar ^{[1
]}

Shuai, Qi ^{[1
]}

Wang, Ying ^{[1
]}

Faltynek, Connie R. ^{[1
]}

Jarvis, Michael F. ^{[1
]}

Carroll, William A. ^{[1
]}

机构：

[1] Abbott Labs, Neurosci Res Global Pharmaceut Res & Dev, Abbott Pk, IL 60064 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 10期

关键词：

POTASSIUM CHANNEL OPENERS; RECEPTOR ANTAGONISTS; P2; RECEPTORS; OVERACTIVE BLADDER; POTENT ANTAGONIST; HUMAN-LYMPHOCYTES; MICROGLIAL CELLS; ATP; EXPRESSION; NEURONS;

D O I：

10.1021/jm8015848

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We disclose the design of a novel series of cyanoguanidines that are potent (IC50 similar or equal to 10-100 nM) and selective (>= 100-fold) P2X(7) receptor antagonists against the other P2 receptor subtypes such as the P2Y(2), P2X(4), and P2X(3). We also found that these P2X(7) 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 mu mol/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 P2X(7) receptors in neuropathic pain and therefore a potential use of P2X(7) antagonists as novel therapeutic tools for the treatment of this type of pain.

引用

页码：3366 / 3376

页数：11

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