Synthesis and Evaluation of a Novel Bivalent Selective Antagonist for the Mu-Delta Opioid Receptor Heterodimer that Reduces Morphine Withdrawal in Mice
Synthesis and Evaluation of a Novel Bivalent Selective Antagonist for the Mu-Delta Opioid Receptor Heterodimer that Reduces Morphine Withdrawal in Mice
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DOI：
10.1021/acs.jmedchem.8b00403
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发表时间：
2018-07-26
影响因子：
7.3
通讯作者：
Streicher, John M.
中科院分区：
文献类型：
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作者：
Olson, Keith M.;Keresztes, Attila;Streicher, John M.
对mu- δ倍体受体异二聚体（MDOR）研究的一个主要限制是选择性药物工具很少，而且没有异二聚体选择性拮抗剂。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，这些肽具有选择性，但对mu和delta阿片受体具有中等/低亲和力的药效团。我们在体外观察到一个u型的MDOR效价/亲和力分布，24原子间隔长度（D24M）产生最高的MDOR效价/亲和力（= 89倍）。我们在小鼠中进一步评估了D24M，并观察到D24M剂量依赖性地拮抗由MDOR激动剂CYM51010和Deltorphin-II产生的尾弹抗刺激，而不拮抗单体激动剂DAMGO和DSLET。我们还观察到D24M显著减少了戒断行为
A major limitation in the study of the mu-delta oploid 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 (= 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