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

Bioorg Med Chem Lett. 2019 Jan 1;29(1):73-77. doi: 10.1016/j.bmcl.2018.11.007. Epub 2018 Nov 7.

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.

Keywords: Morphinan; Opioid-induced constipation; Opioid-induced emesis/vomiting; Peripherally selective; μ- and δ-opioid receptor antagonist.

MeSH terms

  • Administration, Oral
  • Analgesics, Opioid / administration & dosage
  • Analgesics, Opioid / adverse effects
  • Analgesics, Opioid / pharmacology*
  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • HEK293 Cells
  • Humans
  • Molecular Structure
  • Naltrexone / administration & dosage
  • Naltrexone / adverse effects
  • Naltrexone / analogs & derivatives*
  • Naltrexone / pharmacology
  • Rats
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, delta / metabolism
  • Receptors, Opioid, mu / antagonists & inhibitors*
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship

Substances

  • Analgesics, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • naldemedine
  • Naltrexone