• Aubrie A Harland, Larisa Yeomans, Nicholas W Griggs, Jessica P Anand, Irina D Pogozheva, Emily M Jutkiewicz, John R Traynor, and Henry I Mosberg.
• Interdepartmental Program in Medicinal Chemistry, ‡Department of Medicinal Chemistry, College of Pharmacy, and §Department of Pharmacology, Medical School, University of Michigan , Ann Arbor, Michigan 48109, United States.
• J. Med. Chem. 2015 Nov 25; 58 (22): 8952-69.

AbstractIn a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.

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