• Sean Henry, Jessica P Anand, Jack J Twarozynski, Ashley C Brinkel, Irina D Pogozheva, Bryan F Sears, Emily M Jutkiewicz, John R Traynor, and Henry I Mosberg.
• Department of Medicinal Chemistry, College of Pharmacy , University of Michigan , 428 Church Street , Ann Arbor , Michigan 48109 , United States.
• J. Med. Chem. 2020 Feb 27; 63 (4): 1671-1683.

AbstractWe 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.

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