J Med Chem. 2018 Jul 26;61(14):6075-6086. doi: 10.1021/acs.jmedchem.8b00403. Epub 2018 Jul 16.
A major limitation in the study of the mu-delta opioid receptor heterodimer (MDOR) is that few selective pharmacological tools exist and no heteromer-selective antagonists. We thus designed a series of variable-length (15-41 atoms) bivalent linked peptides with selective but moderate/low-affinity pharmacophores for the mu and delta opioid receptors. We observed a U-shaped MDOR potency/affinity profile in vitro, with the 24-atom spacer length (D24M) producing the highest MDOR potency/affinity (<1 nM) and selectivity (≥89-fold). We further evaluated D24M in mice and observed that D24M dose-dependently antagonized tail flick antinociception produced by the MDOR agonists CYM51010 and Deltorphin-II, without antagonizing the monomer agonists DAMGO and DSLET. We also observed that D24M sharply reduced withdrawal behavior in models of acute and chronic morphine dependence. These findings suggest that D24M is a first-in-class high-potency MDOR-selective antagonist both in vitro and in vivo.
在研究 μ-δ 阿片受体异源二聚体 (MDOR) 时，主要的限制因素是缺乏选择性的药理学工具，而且没有异源二聚体选择性拮抗剂。因此，我们设计了一系列具有选择性但中等/低亲和力药效团的可变长度（15-41 个原子）双价连接肽，用于 μ 和 δ 阿片受体。我们在体外观察到 MDOR 效力/亲和力呈 U 型，其中 24 个原子间隔物长度（D24M）产生最高的 MDOR 效力/亲和力（<1 nM）和选择性（≥89 倍）。我们进一步在小鼠中评估了 D24M，并观察到 D24M 剂量依赖性拮抗 MDOR 激动剂 CYM51010 和 Deltorphin-II 产生的尾部摆动镇痛作用，而不拮抗单体激动剂 DAMGO 和 DSLET。我们还观察到 D24M 显著减少了急性和慢性吗啡依赖模型中的戒断行为。这些发现表明，D24M 是一种具有高效力的 MDOR 选择性拮抗剂，无论是在体外还是体内。
