N -Phenethyl Substitution in 14-Methoxy- N -methylmorphinan-6-ones Turns Selective µ Opioid Receptor Ligands into Dual µ/δ Opioid Receptor Agonists

Morphine and structurally-derived compounds are µ opioid receptor (µOR) agonists, and the most effective analgesic drugs. However, their usefulness is limited by serious side effects, including dependence and abuse potential. The N-substituent in morphinans plays an important role in opioid activities in vitro and in vivo . This study presents the synthesis and pharmacological evaluation of new N -phenethyl substituted 14- O -methylmorphinan-6-ones. Whereas substitution of the N -methyl substituent in morphine ( 1 ) and oxymorphone ( 2 ) by an N -phenethyl group enhances binding affinity, selectivity and agonist potency at the µOR of 1a and 2a , the N- phenethyl substitution in 14-methoxy- N -methylmorphinan-6-ones ( 3 and 4 ) converts selective µOR ligands into dual µ/δOR agonists ( 3a and 4a ). Contrary to N -methylmorphinans 1 – 4 , the N -phenethyl substituted morphinans 1a – 4a produce effective and potent antinociception without motor impairment in mice. Using docking and molecular dynamics simulations with the µOR, we establish that N -methylmorphinans 1–4 and their N -phenethyl counterparts 1a – 4a share several essential receptor-ligand interactions, but also interaction pattern differences related to specific structural features, thus providing a structural basis for their pharmacological profiles. The emerged structure-activity relationships in this class of morphinans provide important information for tuning in vitro and in vivo opioid activities towards discovery of effective and safer analgesics.