Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 178, Issue -, Pages 544-551Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2019.06.028
Keywords
Nalbuphine; Nalbuphine-6-glucuronide; Nalbuphine-3-glucuronide; N6G; N3G; Opioid analgesic
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Funding
- Ministry of Science and Technology, Taipei, Taiwan [MOST103-2320-B-016-007-MY3]
- Hualien Armed Forces General Hospital, Hualien, Taiwan [805-C107-10]
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Nalbuphine, a partial agonistiantagonist opioid analgesic, is structurally related to morphine. It is equipotent to morphine and has no serious side effects. In the past few decades, studies focusing on morphine metabolism have indicated that one of its sugar-conjugated metabolites, morphine-6-glucuronide, exerts a higher analgesic effect than its parent drug. Considering that nalbuphine is a morphine analog that follows a similar metabolic scheme, nalbuphine glucuronides were synthesized in this study and their potential analgesic effects were assessed. Nalbuphine-3-glucuronide (N3G) and nalbuphine-6-glucuronide (N6G) were synthesized based on Schmidt's glycosylation with OPiv protections on the glycosyl donor. In a pharmacodynamic study, paw pressure and cold-ethanol tail-flick tests were conducted in rats to evaluate the analgesic response after intracisternal and intraperitoneal administrations of nalbuphine, N3G, or N6G. The antinociceptive response was evaluated for each compound by calculating the area under the curve and the duration spent at greater than 50% maximum possible analgesia. In conclusion, intracisternal administration of N6G exhibited a stronger analgesic response than nalbuphine in the pain tests after both cold and mechanical stimuli, but N3G had no obvious effect. Similar to that of morphine, the glucuronide metabolite of nalbuphine at the 6-O-position exerted at least threefold higher antinociceptive potency and five-fold longer analgesic duration than nalbuphine. (C) 2019 Elsevier Masson SAS. All rights reserved.
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