Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro[3.4]octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.

阿片类药物是治疗疼痛的有效镇痛药。但大剂量重复使用常导致镇痛耐受，限制了其临床应用。据报道，Sigma-1 受体 (σ1R) 拮抗剂可协同增强mu阿片受体 (MOR) 激动剂的镇痛效果，且不会放大不良反应。因此，σ1R 被认为是一个有前途的疼痛管理药物靶点。基于最近阐明的σ1R与4-IBP的共晶结构，我们设计并开发了一系列含有2,6-diazaspiro[3.4]octan-7-one支架的σ1R拮抗剂。通过详细的构效关系研究，我们确定化合物32是一种有效的 σ1R 拮抗剂，可显着增强吗啡的镇痛作用并挽救吗啡引起的镇痛耐受。我们的结果支持 σ1R 拮抗作为开发新型镇痛药的有前途的策略，并强调化合物32预防吗啡耐受的治疗潜力。