2,6-diazaspiro[3.4]octan-7-one derivatives as potent sigma-1 receptor antagonists that enhanced the antinociceptive effect of morphine and rescued morphine tolerance.
Eur J Med Chem
; 249: 115178, 2023 Mar 05.
Article
em En
| MEDLINE
| ID: mdl-36753922
ABSTRACT
Opioids are efficacious analgesics for pain treatments. However, their repeated use in large doses often leads to analgesic tolerance, which limits the clinical application. Sigma-1 receptor (σ1R) antagonists were reported to synergistically enhance the analgesic effect of mu opioid receptor (MOR) agonists without amplifying the adverse effects. Therefore, the σ1R is considered a promising drug target for pain management. Based on the recently elucidated co-crystal structure of σ1R with 4-IBP, we designed and developed a series of σ1R antagonists harboring the 2,6-diazaspiro[3.4]octan-7-one scaffold. Through a detailed structure-activity relationship study, we identified compound 32 as a potent σ1R antagonist, which significantly enhanced the antinociceptive effect of morphine and rescued morphine-induced analgesic tolerance. Our results support σ1R antagonism as a promising strategy to develop novel analgesics and highlight the therapeutic potential of compound 32 to prevent morphine tolerance.
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01-internacional
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MEDLINE
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article