Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy

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• 作者：Hao Sun ; Min Shi ; Wei Zhang ; Yue-Ming Zheng ; Ya-Zhou Xu ; Jun-Jie Shi ; Ting Liu ; Hendra Gunosewoyo ; Tao Pang ; Zhao-Bing Gao ; Fan Yang ; Jie Tang ; Li-Fang Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6329-6343
• 全文大小：688K
• 年卷期：0
• ISSN：1520-4804

文摘

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (K_i < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.