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- Title
Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.
- Authors
Raffaele, Marco; Kovacovicova, Kristina; Biagini, Tommaso; Lo Re, Oriana; Frohlich, Jan; Giallongo, Sebastiano; Nhan, James D.; Giannone, Antonino Giulio; Cabibi, Daniela; Ivanov, Martin; Tonchev, Anton B.; Mistrik, Martin; Lacey, Matthew; Dzubak, Petr; Gurska, Sona; Hajduch, Marian; Bartek, Jiri; Mazza, Tommaso; Micale, Vincenzo; Curran, Sean P.
- Abstract
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.
- Subjects
PFIZER Inc.; NOCICEPTIN; OPIOID receptors; CELLULAR aging; HUMAN migrations; TOLL-like receptors; GENE regulatory networks; BIOACTIVE glasses
- Publication
GeroScience, 2022, Vol 44, Issue 1, p463
- ISSN
2509-2715
- Publication type
Article
- DOI
10.1007/s11357-021-00487-y