Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects.
Aging
NOP
Senescence
Senolytic
Journal
GeroScience
ISSN: 2509-2723
Titre abrégé: Geroscience
Pays: Switzerland
ID NLM: 101686284
Informations de publication
Date de publication:
02 2022
02 2022
Historique:
received:
11
10
2021
accepted:
05
11
2021
pubmed:
26
11
2021
medline:
15
3
2022
entrez:
25
11
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34820764
doi: 10.1007/s11357-021-00487-y
pii: 10.1007/s11357-021-00487-y
pmc: PMC8612119
doi:
Substances chimiques
Analgesics, Opioid
0
Anti-Anxiety Agents
0
Ligands
0
Narcotic Antagonists
0
Opioid Peptides
0
Piperidines
0
Receptors, Opioid
0
Senotherapeutics
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
463-483Subventions
Organisme : NIA NIH HHS
ID : P30 AG068345
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG058610
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG063947
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to American Aging Association.
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