Synthesis and Biological Evaluation of Novel σ1 Receptor Ligands for Treating Neuropathic Pain: 6-Hydroxypyridazinones

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• 作者：Xudong Cao ; Yin Chen ; Yifang Zhang ; Yu Lan ; Juecheng Zhang ; Xiangqing Xu ; Yinli Qiu ; Song Zhao ; Xin Liu ; Bi-Feng Liu ; Guisen Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：2942-2961
• 全文大小：798K
• 年卷期：0
• ISSN：1520-4804

文摘

By use of the 6-hydroxypyridazinone framework, a new series of potent σ₁ receptor ligands associated with pharmacological antineuropathic pain activity was synthesized and is described in this article. In vitro receptor binding studies revealed high σ₁ receptor affinity (K_i σ₁ = 1.4 nM) and excellent selectivity over not only σ₂ receptor (1366-fold) but also other CNS targets (adrenergic, μ-opioid, sertonerigic receptors, etc.) for 2-(3,4-dichlorophenyl)-6-(3-(piperidin-1-yl)propoxy)pyridazin-3(2H)-one (compound 54). Compound 54 exhibited dose-dependent antiallodynic properties in mouse formalin model and rats chronic constriction injury (CCI) model of neuropathic pain. In addition, functional activity of compound 54 was evaluated using phenytoin and indicated that the compound was a σ₁ receptor antagonist. Moreover, no motor impairments were found in rotarod tests at antiallodynic doses and no sedative side effect was evident in locomotor activity tests. Last but not least, good safety and favorable pharmacokinetic properties were also noted. These profiles suggest that compound 54 may be a member of a novel class of candidate drugs for treatment of neuropathic pain.