Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy ?-Opioid Receptor (MOR) Agonists/?-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities.

ABSTRACT: In a previously described peptidomimetic series, we reported the development of bifunctional ?-opioid receptor (MOR) agonist and ?-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 ?-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.

SUBMITTER: Harland AA 

PROVIDER: S-EPMC4772774 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature