New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology

European Journal of Pharmacology
F ZadorMahmoud Al-Khrasani

Abstract

Opioid antagonists, naloxone and naltrexone have long been used in clinical practice and research. In addition to their low selectivity, they easily pass through the blood-brain barrier. Quaternization of the amine group in these molecules, (e.g. methylnaltrexone) results in negligible CNS penetration. In addition, zwitterionic compounds have been reported to have limited CNS access. The current study, for the first time gives report on the synthesis and the in vitro [competition binding, G-protein activation, isolated mouse vas deferens (MVD) and mouse colon assay] pharmacology of the zwitterionic compound, naltrexone-14-O-sulfate. Naltrexone, naloxone, and its 14-O-sulfate analogue were used as reference compounds. In competition binding assays, naltrexone-14-O-sulfate showed lower affinity for µ, δ or κ opioid receptor than the parent molecule, naltrexone. However, the μ/κ opioid receptor selectivity ratio significantly improved, indicating better selectivity. Similar tendency was observed for naloxone-14-O-sulfate when compared to naloxone. Naltrexone-14-O-sulfate failed to activate [35S]GTPγS-binding but inhibit the activation evoked by opioid agonists (DAMGO, Ile5,6deltorphin II and U69593), similarly to the reference com...Continue Reading

References

Sep 3, 1984·European Journal of Pharmacology·A E Takemori, P S Portoghese
Jan 10, 1998·European Journal of Pharmacology·M D AcetoE R Bowman
Aug 4, 2015·Brain Research Bulletin·Kornel KiralyMahmoud Al-Khrasani

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Citations

Dec 6, 2019·Peptides·Richard J Bodnar

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