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

Zádor, Ferenc and Király, Kornél and Váradi, András and Balogh, Mihaly and Fehér, Ágnes and Kocsis, Dóra and Erdei, Anna I and Lackó, Erzsébet and Zádori, Zoltán S and Hosztafi, Sándor and Noszál, Béla and Riba, Pál and Benyhe, Sándor and Fürst, Zsuzsanna and Al-Khrasani, Mahmoud (2017) New opioid receptor antagonist: Naltrexone-14-O-sulfate synthesis and pharmacology. EUROPEAN JOURNAL OF PHARMACOLOGY, 809. pp. 111-121. ISSN 0014-2999

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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 compounds. Schild plot constructed in MVD revealed that naltrexone-14-O-sulfate acts as a competitive antagonist. In mouse colon, naltrexone-14-O-sulfate antagonized the inhibitory effect of morphine with lower affinity compared to naltrexone and higher affinity when compared to naloxone or naloxone-14-O-sulfate. In vivo (mouse tail-flick test), subcutaneously injected naltrexone-14-O-sulfate antagonized morphine's antinociception in a dose-dependent manner, indicating it's CNS penetration, which was unexpected from such zwitter ionic structure. Future studies are needed to evaluate it's pharmacokinetic profile.

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