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

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• 作者：Aubrie A. Harland ; Larisa Yeomans ; Nicholas W. Griggs ; Jessica P. Anand ; Irina D. Pogozheva ; Emily M. Jutkiewicz ; John R. Traynor ; Henry I. Mosberg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2015
• 出版时间：November 25, 2015
• 年：2015
• 卷：58
• 期：22
• 页码：8952-8969
• 全文大小：749K
• ISSN：1520-4804

文摘

In a previously described peptidomimetic series, we reported the development of bifunctional 渭-opioid receptor (MOR) agonist and 未-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 魏-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.