Harland Aubrie A, Yeomans Larisa, Griggs Nicholas W, Anand Jessica P, Pogozheva Irina D, Jutkiewicz Emily M, Traynor John R, Mosberg Henry I
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. doi: 10.1021/acs.jmedchem.5b01270. Epub 2015 Nov 13.
In 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.
在之前描述的肽模拟物系列中，我们报道了双功能μ-阿片受体（MOR）激动剂和δ-阿片受体（DOR）拮抗剂配体的研发情况，其先导化合物在小鼠腹腔注射后可产生1小时的镇痛作用。在本文中，我们通过提出两种修饰来扩展我们原来的系列，这两种修饰均基于以下目标设计：（1）探究生物利用度并改善代谢稳定性；（2）平衡MOR和DOR之间的亲和力，同时降低对κ-阿片受体（KOR）的亲和力和效力；（3）提高体内疗效。在此，我们证实，通过对原来的肽模拟物系列进行N-乙酰化，我们能够提高DOR亲和力并增加相对于KOR的选择性，同时保持所需的MOR激动剂/DOR拮抗剂特性。从最初的体内研究中发现，一种化合物（14a）在外周给药后可产生剂量依赖性镇痛作用，且作用持续时间延长至3小时以上。
