biostudies-literature00560Raffaele MMinisterstvo Zdravotnictví Ceské RepublikyNIA NIH HHSHorizon 2020 Framework ProgrammeCzech Ministry of Education, Youth and SportsNational Institute on AgingEuropean Regional Development Fund463-483https://www.ebi.ac.uk/biostudies/studies/S-EPMC8612119biostudies-literatureUnknown44(1)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.GeroScienceNociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.PMC8612119P30 AG068345RF1 AG063947NV18-03-00058P30AG068345CZ.02.1.01/0.0/0.0/16_019/0000868CZ-OPENSCREEN– LM2018130EATRIS-CZ – LM2018133856871R01 AG058610CZ.02.1.01/0.0/0.0/15_003/0000492R01AG058610Mistrik MGurska SFrohlich JCabibi DMicale VLacey MGiannone AGBiagini TKovacovicova KLo Re OIvanov MNhan JDTonchev ABMazza TCurran SPBartek JRaffaele MGiallongo SDzubak PHajduch MVinciguerra M56falseNociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.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.2022-01-01T00:00:00Z2022 Feb2024-12-03T19:30:22.612Z2022-02-11T13:12:31.219ZS-EPMC86121193482076410.1007/s11357-021-00487-y