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Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2015 Jun 25; Vol. 58 (12), pp. 5038-52. Date of Electronic Publication: 2015 Jun 05. - Publication Year :
- 2015
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Abstract
- Activation of Toll-like receptors has been linked to neuropathic pain and opioid dependence. (+)-Naltrexone acts as a Toll-like receptor 4 (TLR4) antagonist and has been shown to reverse neuropathic pain in rat studies. We designed and synthesized compounds based on (+)-naltrexone and (+)-noroxymorphone and evaluated their TLR4 antagonist activities by their effects on inhibiting lipopolysaccharide (LPS) induced TLR4 downstream nitric oxide (NO) production in microglia BV-2 cells. Alteration of the N-substituent in (+)-noroxymorphone gave us a potent TLR4 antagonist. The most promising analog, (+)-N-phenethylnoroxymorphone ((4S,4aR,7aS,12bR)-4a,9-dihydroxy-3-phenethyl-2,3,4,4a,5,6-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7(7aH)-one, 1j) showed ∼75 times better TLR-4 antagonist activity than (+)-naltrexone, and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 μM/1.4 μM) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia.
- Subjects :
- Analgesics, Opioid pharmacology
Animals
Cell Line
Drug Synergism
Humans
Lipopolysaccharides immunology
Male
Microglia cytology
Microglia drug effects
Microglia immunology
Morphine pharmacology
Nitric Oxide immunology
Rats
Rats, Sprague-Dawley
Structure-Activity Relationship
Toll-Like Receptor 4 immunology
Morphinans chemistry
Morphinans pharmacology
Naltrexone analogs & derivatives
Naltrexone pharmacology
Toll-Like Receptor 4 antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 58
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 26010811
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.5b00426