Synthesis and Pharmacological Evaluation of Novel C‑8 Substituted Tetrahydroquinolines as Balanced-Affinity Mu/Delta Opioid Ligands for the Treatment of Pain

The
use of opioids for the treatment of pain, while largely effective,
is limited by detrimental side effects including analgesic tolerance,
physical dependence, and euphoria, which may lead to opioid abuse.
Studies have shown that compounds with a μ-opioid receptor (MOR)
agonist/δ-opioid receptor (DOR) antagonist profile reduce or
eliminate some of these side effects including the development of
tolerance and dependence. Herein we report the synthesis and pharmacological
evaluation of a series of tetrahydroquinoline-based peptidomimetics
with substitutions at the C-8 position. Relative to our lead peptidomimetic
with no C-8 substitution, this series affords an increase in DOR affinity
and provides greater balance in MOR and DOR binding affinities. Moreover,
compounds with carbonyl moieties at C-8 display the desired MOR agonist/DOR
antagonist profile whereas alkyl substitutions elicit modest DOR agonism.
Several compounds in this series produce a robust antinociceptive
effect in vivo and show antinociceptive activity for greater than
2 h after intraperitoneal administration in mice.