Accumulation of senescent cells may drive age-associated alterations and pathologies. Senolytics are promising therapeutics that can preferentially eliminate senescent cells. Here, we performed a high-throughput automatized screening (HTS) of the commercial LOPAC®Pfizer library on aphidicolin-induced senescent human fibroblasts, to identify novel senolytics. We discovered the nociceptin receptor FQ opioid receptor (NOP) selective ligand 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole (MCOPPB, a compound previously studied as potential anxiolytic) as the best scoring hit. The ability of MCOPPB to eliminate senescent cells in in vitro models was further tested in mice and in C. elegans. MCOPPB reduced the senescence cell burden in peripheral tissues but not in the central nervous system. Mice and worms exposed to MCOPPB also exhibited locomotion and lipid storage changes. Mechanistically, MCOPPB treatment activated transcriptional networks involved in the immune responses to external stressors, implicating Toll-like receptors (TLRs). Our study uncovers MCOPPB as a NOP ligand that, apart from anxiolytic effects, also shows tissue-specific senolytic effects.

衰老细胞的积累可能会导致与年龄相关的变化和病理。 Senolytics 是一种很有前途的治疗方法，可以优先消除衰老细胞。在这里，我们对阿非迪霉素诱导的衰老人成纤维细胞的商业 LOPAC®Pfizer 文库进行了高通量自动筛选 (HTS)，以鉴定新型衰老药物。我们发现了伤害感受素受体 FQ 阿片受体 (NOP) 选择性配体 1-[1-(1-甲基环辛基)-4-哌啶基]-2-[(3R)-3-哌啶基]-1H-苯并咪唑 (MCOPPB，以前的一种化合物)研究为潜在的抗焦虑药）作为最佳得分热门。 MCOPPB 在体外模型中消除衰老细胞的能力在小鼠和秀丽隐杆线虫中进行了进一步测试。 MCOPPB 减少了外周组织中的衰老细胞负担，但没有减少中枢神经系统中的衰老细胞负担。暴露于 MCOPPB 的小鼠和蠕虫也表现出运动和脂质储存的变化。从机制上讲，MCOPPB 治疗激活了参与对外部应激源的免疫反应的转录网络，涉及 Toll 样受体 (TLR)。我们的研究发现 MCOPPB 作为 NOP 配体，除了抗焦虑作用外，还显示出组织特异性的抗衰老作用。