Novel µ opioid antagonists derived from the µ opioid agonists endomorphin and [Dmt1 ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 ).,Chemical Biology & Drug Design

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Novel µ opioid antagonists derived from the µ opioid agonists endomorphin and [Dmt1 ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2 ).
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2020-06-11 , DOI: 10.1111/cbdd.13743
Saijian Shi ₁ , Jian Xu ₁ , LingLing Feng ₁ , Xin Fan ₁ , Zhen Chen ₁ , Yajuan Qin ₁ , Nga N Chung ₂ , Tingyou Li _{1,

3} , Peter W Schiller _{2,

4}

Affiliation

Hybrid analogues of the µ opioid agonists endomorphin and [Dmt¹]DALDA (H‐Dmt‐D‐Arg‐Phe‐Lys‐NH₂, Dmt = 2′,6′‐dimethyltyrosine) containing cis‐4‐amino‐Pro, trans‐4‐amino‐Pro, cis‐4‐aminoethyl‐Pro or cis‐4‐guanidinylethyl‐Pro in the 2 position of the peptide sequence were synthesized. None of the compounds retained high µ opioid agonist activity and, unexpectedly, substitution of cis‐4‐amino‐Pro resulted in a novel class of potent µ opioid antagonists. In particular, the compound H‐Dmt‐cis‐4‐amino‐Pro‐Trp‐Lys‐NH₂ (CZ‐1) turned out to be a highly selective µ opioid antagonist with ~1 nM µ receptor binding affinity.

中文翻译：

新型 µ 阿片拮抗剂源自 µ 阿片激动剂内吗啡肽和 [Dmt1 ] DALDA (H-Dmt-D-Arg-Phe-Lys-NH2)。

µ 阿片类激动剂内吗啡肽和 [Dmt ¹ ]DALDA（H-Dmt-D-Arg-Phe-Lys-NH ₂，Dmt = 2',6'-二甲基酪氨酸）的杂合类似物，含有顺式-4-氨基-Pro，反式合成了肽序列第 2 位的-4-氨基-Pro、顺式-4-氨基乙基-Pro 或顺式-4-胍基乙基-Pro 。没有一种化合物保持高μ阿片类激动剂活性，出人意料的是，顺式-4-氨基-Pro的取代产生了一类新型的强效μ阿片拮抗剂。特别是，化合物 H-Dmt- cis -4-amino-Pro-Trp-Lys-NH ₂ (CZ-1) 是一种高度选择性的 µ 阿片拮抗剂，具有 ~1 nM µ 受体结合亲和力。

更新日期：2020-06-11

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