[Dmt1] DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile
[Dmt1] DALDA analogues with enhanced μ opioid agonist potency and with a mixed μ/κ opioid activity profile
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DOI：
10.1016/j.bmc.2014.02.011
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发表时间：
2014-04-01
影响因子：
3.5
通讯作者：
Schiller, Peter W.
中科院分区：
文献类型：
--
作者：
Bai, Longxiang;Li, Ziyuan;Schiller, Peter W.
[Dmt(1)]DALDA （h -Dmt- d - arg - ph - lys - nh2）的类似物Dmt = 2',6'-二甲基酪氨酸)是一种具有线粒体靶向抗氧化活性的强效阿片受体激动剂肽，通过用各种2',6'-二烷基化的Phe类似物取代Phe(3)，包括2',6'-二甲基苯基丙氨酸（Dmp）， 2',4',6'-三甲基苯基丙氨酸（Tmp）， 2'-异丙基-6'-甲基苯基丙氨酸（Imp）和2'-乙基-6'-甲基苯基丙氨酸（Emp），或用大量氨基酸3'-（1-萘基）丙氨酸（1-Nal）， 3'-（2-萘基）丙氨酸（2- nal）或Trp。几种化合物显示出明显增加的mu受体激动剂效力，保留了mu受体的选择性，并作为神经性疼痛治疗的候选药物。令人惊讶的是，含有Dmp(3)-、Imp(3)-、Emp(3)-和1-Nal(3)-的类似物显示出大大增加的kappa受体结合亲和力，并且具有混合的mu/kappa特性。在这些情况下，分子动力学研究表明，由于Xxx(3)残基的c - β - c - γ键周围的旋转限制，未结合肽配体的构象预组织与观察到的kappa受体结合增强有关。已知具有混合mu/kappa阿片活性谱的化合物具有治疗可卡因滥用的治疗潜力。(c) 2014 Elsevier Ltd.版权所有。
Analogues of [Dmt(1)]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6'-dimethyltyrosine), a potent mu opioid agonist peptide with mitochondria-targeted antioxidant activity, were prepared by replacing Phe(3) with various 2',6'-dialkylated Phe analogues, including 2',6'-dimethylphenylalanine (Dmp), 2',4',6'-trimethylphenylalanine (Tmp), 2'-isopropyl-6'-methylphenylalanine (Imp) and 2'-ethyl-6'-methylphenylalanine (Emp), or with the bulky amino acids 3'-(1-naphthyl)alanine (1-Nal), 3'-(2-naphthyl)alanine (2-Nal) or Trp. Several compounds showed significantly increased mu agonist potency, retained mu receptor selectivity and are of interest as drug candidates for neuropathic pain treatment. Surprisingly, the Dmp(3)-, Imp(3)-, Emp(3)- and 1-Nal(3)-containing analogues showed much increased kappa receptor binding affinity and had mixed mu/kappa properties. In these cases, molecular dynamics studies indicated conformational preorganization of the unbound peptide ligands due to rotational restriction around the C-beta-C-gamma bond of the Xxx(3) residue, in correlation with the observed kappa receptor binding enhancement. Compounds with a mixed mu/kappa opioid activity profile are known to have therapeutic potential for treatment of cocaine abuse. (c) 2014 Elsevier Ltd. All rights reserved.