Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects

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Authors

RAFFAELE M. KOVACOVICOVA K. BIAGINI T. LO RE O. FROHLICH J. GIALLONGO Sebastiano NHAN J. D. GIANNONE A. G. CABIBI D. IVANOV M. TONCHEV A. B. MISTRIK Martin LACEY M. DZUBAK Petr GURSKA Sona HAJDUCH Marian BARTEK Jiri MAZZA T. MICALE V. CURRAN S. P. VINCIGUERRA M.

Year of publication 2022
Type Article in Periodical
Magazine / Source GEROSCIENCE
MU Faculty or unit

Faculty of Medicine

Citation
Web https://link.springer.com/article/10.1007/s11357-021-00487-y
Doi http://dx.doi.org/10.1007/s11357-021-00487-y
Keywords Senolytic; NOP; Senescence; Aging
Description 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 (R) 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.
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