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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.

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