Asymmetric Synthesis and in Vitro and in Vivo Activity of Tetrahydroquinolines Featuring a Diverse Set of Polar Substitutions at the 6 Position as Mixed-Efficacy μ Opioid Receptor/δ Opioid Receptor Ligands

We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure–activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (<b>10j</b>, <b>10k</b>, <b>10m</b>, and <b>10n</b>) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for <b>10j</b>, <b>10k</b>, <b>10m</b>, and <b>10n</b> are also reported and show the antinociceptive potency and duration of action of compounds <b>10j</b> and <b>10m</b> to be comparable to those of morphine