Exploring the Function of (+)-Naltrexone Precursors: Their Activity as TLR4 Antagonists and Potential in Treating Morphine Addiction.
J Med Chem
; 67(4): 3127-3143, 2024 Feb 22.
Article
em En
| MEDLINE
| ID: mdl-38306598
ABSTRACT
Disruptions in the toll-like receptor 4 (TLR4) signaling pathway are linked to chronic inflammation, neuropathic pain, and drug addiction. (+)-Naltrexone, an opioid-derived TLR4 antagonist with a (+)-isomer configuration, does not interact with classical opioid receptors and has moderate blood-brain barrier permeability. Herein, we developed a concise 10-step synthesis for (+)-naltrexone and explored its precursors, (+)-14-hydroxycodeinone (1) and (+)-14-hydroxymorphinone (3). These precursors exhibited TLR4 antagonistic activities 100 times stronger than (+)-naltrexone, particularly inhibiting the TLR4-TRIF pathway. In vivo studies showed that these precursors effectively reduced behavioral effects of morphine, like sensitization and conditioned place preference by suppressing microglial activation and TNF-α expression in the medial prefrontal cortex and ventral tegmental area. Additionally, 3 displayed a longer half-life and higher oral bioavailability than 1. Overall, this research optimized (+)-naltrexone synthesis and identified its precursors as potent TLR4 antagonists, offering potential treatments for morphine addiction.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dependência de Morfina
/
Naltrexona
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article