Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management,Journal of Medicinal Chemistry

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Novel Sigma 1 Receptor Antagonists as Potential Therapeutics for Pain Management
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-29 , DOI: 10.1021/acs.jmedchem.0c01964
Youyi Peng ₁ , Qiang Zhang ₂ , William J Welsh _{1,

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Affiliation

The sigma 1 receptor (S1R) is a molecular chaperone protein located in the endoplasmic reticulum and plasma membranes and has been shown to play important roles in various pathological disorders including pain and, as recently discovered, COVID-19. Employing structure- and QSAR-based drug design strategies, we rationally designed, synthesized, and biologically evaluated a series of novel triazole-based S1R antagonists. Compound 10 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable in vitro metabolic stability, slow clearance in liver microsomes, and excellent blood–brain barrier permeability in rats. Further in vivo studies in rats showed that 10 exhibited negligible acute toxicity in the rotarod test and statistically significant analgesic effects in the formalin test for acute inflammatory pain and paclitaxel-induced neuropathic pain models during cancer chemotherapy. These encouraging results promote further development of our triazole-based S1R antagonists as novel treatments for pain of different etiologies.

中文翻译：

新型 Sigma 1 受体拮抗剂作为疼痛管理的潜在疗法

sigma 1 受体 (S1R) 是一种位于内质网和质膜中的分子伴侣蛋白，已被证明在各种病理性疾病中发挥重要作用，包括疼痛以及最近发现的 COVID-19。采用基于结构和QSAR的药物设计策略，我们合理设计、合成和生物学评价了一系列新型三唑类S1R拮抗剂。化合物10对 S1R 表现出强大的结合亲和力，对 S2R 和 87 个其他人类靶标具有高选择性，可接受的体外代谢稳定性，肝微粒体中的缓慢清除以及大鼠中优异的血脑屏障通透性。进一步的大鼠体内研究表明， 10 种在转棒试验中表现出可忽略不计的急性毒性，在癌症化疗期间的急性炎性疼痛和紫杉醇诱导的神经性疼痛模型的福尔马林试验中表现出统计学上显着的镇痛效果。这些令人鼓舞的结果促进了我们基于三唑的 S1R 拮抗剂的进一步开发，作为治疗不同病因疼痛的新疗法。

更新日期：2021-01-14

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