Biomedical Informatics Shared Resource, Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, 195 Little Albany Street, New Brunswick, New Jersey 08903, United States.
Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, 661 Hoes Lane West, Piscataway, New Jersey 08854, United States.
J Med Chem. 2021 Jan 14;64(1):890-904. doi: 10.1021/acs.jmedchem.0c01964. Epub 2020 Dec 29.
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 exhibited potent binding affinity for S1R, high selectivity over S2R and 87 other human targets, acceptable metabolic stability, slow clearance in liver microsomes, and excellent blood-brain barrier permeability in rats. Further studies in rats showed that 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.
西格玛 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疾病中发挥重要作用，包括疼痛，以及最近发现的 COVID-19。我们采用基于结构和定量构效关系的药物设计策略，合理设计、合成和生物评估了一系列新型三唑类 S1R 拮抗剂。化合物 表现出对 S1R 的强大结合亲和力、对 S2R 和 87 种其他人类靶标的高选择性、可接受的代谢稳定性、在肝微粒体中的缓慢清除率以及在大鼠中的良好血脑屏障通透性。进一步的大鼠研究表明， 在旋转棒试验中表现出可忽略的急性毒性，并且在福尔马林试验中对急性炎症性疼痛和紫杉醇诱导的神经病理性疼痛模型具有统计学显著的镇痛作用，在癌症化疗期间。这些令人鼓舞的结果促进了我们基于三唑的 S1R 拮抗剂作为不同病因疼痛的新型治疗方法的进一步发展。
