PUBLICATION
Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents
- Authors
- Linciano, P., Sorbi, C., Rossino, G., Rossi, D., Marsala, A., Denora, N., Bedeschi, M., Marino, N., Miserocchi, G., Dondio, G., Peviani, M., Tesei, A., Collina, S., Franchini, S.
- ID
- ZDB-PUB-230131-26
- Date
- 2023
- Source
- European Journal of Medicinal Chemistry 249: 115163115163 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Humans
- N-Methylaspartate/metabolism
- N-Methylaspartate/pharmacology
- Neuroblastoma*/drug therapy
- Neurodegenerative Diseases*/drug therapy
- Neuroprotective Agents*/pharmacology
- Neuroprotective Agents*/therapeutic use
- Oxidative Stress
- Piperidines/therapeutic use
- Receptors, sigma*
- Zebrafish/metabolism
- PubMed
- 36716640 Full text @ Eur. J. Med. Chem.
Citation
Linciano, P., Sorbi, C., Rossino, G., Rossi, D., Marsala, A., Denora, N., Bedeschi, M., Marino, N., Miserocchi, G., Dondio, G., Peviani, M., Tesei, A., Collina, S., Franchini, S. (2023) Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents. European Journal of Medicinal Chemistry. 249:115163115163.
Abstract
Sigma-1 receptor (S1R) has been considered a promising therapeutic target for several neurodegenerative diseases and S1R agonists have shown neuroprotective activity against glutamate excitotoxicity and oxidative stress. Starting from a previously identified low nanomolar S1R agonist, in this work we prepared and tested novel benzylpiperidine/benzylpiperazine-based compounds designed by applying a ring opening strategy. Among them, 4-benzyl-1-(2-phenoxyethyl)piperidine 6b (S1R Ki = 0.93 nM) and 4-benzyl-1-(3-phenoxypropyl)piperidine 8b (S1R Ki = 1.1 nM) emerged as high affinity S1R ligands and showed selectivity over S2R and N-methyl-d-aspartate receptor (NMDAR). Candidate compounds behaved as potent S1R agonists being able to enhance the neurite outgrowth induced by nerve growth factor (NGF) in PC12 cell lines. In SH-SY5Y neuroblastoma cell lines they exhibited a neuroprotective effect against rotenone- and NMDA-mediated toxic insults. The neuroprotective activity of 6b and 8b was reverted by co-treatment with an S1R antagonist, PB212. Compounds 6b and 8b were tested for cytotoxicity in-vitro against three human cancer cell lines (A549, LoVo and Panc-1) and in-vivo zebrafish model, resulting in a good efficacy/safety profile, comparable or superior to the reference drug memantine. Overall, these results encourage further preclinical investigations of 6b and 8b on in-vivo models of neurodegenerative diseases.
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping