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

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.

在既往报道的肽模拟物（peptidomimetic）系列研究中，我们曾开发出兼具μ阿片受体（μ-opioid receptor, MOR）激动剂与δ阿片受体（δ-opioid receptor, DOR）拮抗剂活性的双功能配体，其先导化合物在小鼠腹腔给药后可维持1小时的镇痛作用。本文在原有研究系列的基础上，报道了两项修饰改造策略，均围绕以下三大目标设计：(1) 探究化合物的生物利用度并提升其代谢稳定性；(2) 平衡MOR与DOR的亲和力，同时降低对κ阿片受体（κ-opioid receptor, KOR）的亲和力与激动活性；(3) 优化体内药效。本研究证实，通过对原始肽模拟物系列进行N-乙酰化（N-acetylation）修饰，我们可在保留目标MOR激动剂/DOR拮抗剂活性谱的同时，增强对DOR的亲和力并提升相对于KOR的选择性。初步体内研究结果显示，化合物14a在外周给药后可产生剂量依赖性镇痛作用，且作用时长延长至3小时以上。