Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy
Development of Novel Alkoxyisoxazoles as Sigma-1 Receptor Antagonists with Antinociceptive Efficacy
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具有抗伤害作用的新型烷氧基异恶唑作为 Sigma-1 受体拮抗剂的开发
DOI：
10.1021/acs.jmedchem.6b00571
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发表时间：
2016-07-14
影响因子：
7.3
通讯作者：
Yu, Li-Fang
中科院分区：
文献类型：
--
作者：
Sun, Hao;Shi, Min;Yu, Li-Fang
设计并合成了一系列基于烷氧基异恶唑骨架的新型σ受体配体。初步受体结合测定鉴定了与单胺转运蛋白DAT、NET和SERT没有结合相互作用的高效（Ki < 1 nM）和选择性σ 1配体。特别地，当以40和80 mg/kg腹膜内给药时，化合物53显示出在小鼠福尔马林诱导的炎症疼痛模型中具有显著的抗伤害感受活性。初步的药代动力学评价表明，在小鼠中口服给药后，脑暴露良好，这表明有必要进一步研究烷氧基异恶唑作为σ 1配体用于抗伤害感受。这项研究支持的概念，选择性σ 1拮抗可能是一个有用的策略，在新的抗疼痛治疗的发展。
A novel series of sigma (sigma) 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 sigma 1 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 sigma 1 ligands for antinociception is warranted. This study supports the notion that selective sigma 1 antagonism could be a useful strategy in the development of novel antipain therapy.