Synthesis and evaluation of 14β-acyl substituted 17cyclopropylmethyl-7,8-dihydromorphinone derivatives: mixed partial agonists at mu opioid and nociception/orphanin FQ peptide receptors

Abstract

Opioids remain the standard of care for management of severe pain, but adverse effects limit their use, particularly for the treatment of chronic pain. Compounds that have dual partial agonist activity at mu opioid (MOP) and nociceptin opioid peptide (NOP) receptors have been shown, in non-human primates, to display excellent analgesic activity with greatly reduced adverse effect profile. In this study we looked to increase the range of MOP/NOP dual acting compounds and, in particular, provide ligands with a greater diversity of MOP:NOP profiles. Reduction of the C6 carbonyl in the naltrexone scaffold to methylene resulted in a balanced MOP:NOP receptor profile in this series, in particular increasing potency at the NOP receptor. Ultimately, this will allow us to determine the optimal profiles for a range of therapeutic indications including pain and drug use disorders.