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.

中文翻译：

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合成和评估新型二价选择性拮抗剂的Mu-δ阿片受体异二聚体，减少小鼠吗啡撤回。

mu-delta阿片受体异二聚体（MDOR）研究的主要局限性在于，几乎没有选择性药理学工具存在，也没有异聚体选择性拮抗剂。因此，我们设计了一系列可变长度（15-41个原子）的二价连接肽，具有针对mu和delta类阿片受体的选择性但中等/低亲和力的药效基团。我们在体外观察到U型MDOR效能/亲和力分布，其中24原子间隔基长度（D24M）产生最高的MDOR效能/亲和力（<1 nM）和选择性（≥89倍）。我们进一步评估了小鼠中的D24M，并观察到D24M由MDOR激动剂CYM51010和Deltorphin-II产生的剂量依赖性拮抗的甩尾抗伤害感受，而没有拮抗DAMGO和DSLET单体激动剂。我们还观察到，在急性和慢性吗啡依赖性模型中，D24M显着降低了戒断行为。这些发现表明，D24M在体外和体内都是一流的高效MDOR选择性拮抗剂。