Aromatic–Amine Pendants Produce Highly Potent and Efficacious Mixed Efficacy μ‑Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Peptidomimetics with Enhanced Metabolic Stability

We
previously reported a novel SAR campaign that converted a metabolically
unstable series of μ-opioid receptor (MOR) agonist/δ-opioid
receptor (DOR) antagonist bicyclic core peptidomimetics with promising
analgesic activity and reduced abuse liabilities into a more stable
series of benzylic core analogues. Herein, we expanded the SAR of
that campaign and determined that the incorporation of amines into
the benzylic pendant produces enhanced MOR-efficacy in this series,
whereas the reincorporation of an aromatic ring into the pendant enhanced
MOR-potency. Two compounds, which contain a piperidine (14) or an isoindoline (17) pendant, retained the desired
opioid profile in vitro, possessed metabolic half-lives
of greater than 1 h in mouse liver microsomes (MLMs), and were active
antinociceptive agents in the acetic acid stretch assay (AASA) at
subcutaneous doses of 1 mg/kg.