Discovery of naldemedine: A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects.

Graphical abstract Highlights • We discovered a new chemotype, 7-carboxamide morphinan derivatives as opioid antagonist. • This chemotype is suitable for acting on peripherally. • From our results, compounds which have over 100 of PSA values are difficult to pass BBB. • Naldemedine showed dual actions in one dose, inhibiting constipation and nausea/vomiting induced by opioids. Abstract Structure-activity relationship studies of several morphinan derivatives were conducted to obtain dual antagonists for μ- and δ-opioid receptors. We discovered peripherally restricted dual antagonists for μ/δ-opioid receptors as a new chemotype with a morphinan scaffold, which are orally available and do not easily pass the blood–brain barrier. As we expected, some of these compounds inhibit opioid-induced constipation and emesis/vomiting with limited potential to interfere the analgesic effects of morphine. Among them, naldemedine was selected as a potential drug candidate. [ABSTRACT FROM AUTHOR]