Opioid receptor binding requirements for the delta-selective peptide deltorphin. I: Phe3 replacement with ring-substituted and heterocyclic amino acids.
Opioid receptor binding requirements for the delta-selective peptide deltorphin. I: Phe3 replacement with ring-substituted and heterocyclic amino acids.
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δ-选择性肽 deltorphin 的阿片受体结合要求。
DOI：
10.1021/jm00007a020
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发表时间：
1995
影响因子：
7.3
通讯作者：
C. Mousigian
中科院分区：
文献类型：
--
作者：
D. Heyl;M. Dandabathula;K. Kurtz;C. Mousigian
为了评估空间、亲脂性和电子对阿片结合亲和力的影响，研究了δ受体选择性肽deltorphin I的类似物，（Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH 2），其中残基3苯丙氨酸被亲脂性氟代和甲基取代的苯丙氨酸或杂环芳族氨基酸3-（4-噻唑基）丙氨酸、3-（2-吡啶基）丙氨酸、3-（3-吡啶基）丙氨酸、组氨酸和3-（4-噻唑基）丙氨酸。mu结合是可变的，对于大多数类似物，KiS超过10，000 nM，并且所有类似物与k受体的结合都很差。在苯环取代的类似物中，那些含有较小的吸电子卤素的类似物比那些具有较大的释放电子的甲基基团的类似物更受欢迎，尽管在所有情况下δ阿片样物质结合亲和力都降低。间氟苯丙氨酸类似物表现出该组中最好的δ结合，Ki为4.79 nM。在杂环类似物组中，3-（2-噻吩基）丙氨酸被证明是最好的修饰，显示δ受体Ki为1.38 nM，而极性组氨酸类似物在δ结合中遭受最大损失（Ki = 317）。含有吡啶基丙氨酸和噻唑基丙氨酸的化合物的结合亲和力是中等的，Δ KiS范围为39.5至62.4 nM。影响大小相近的杂环化合物与阿片类药物结合的主要因素是相对亲脂性，而电子性质的影响较小。
In order to assess steric, lipophilic, and electronic influences on opioid binding affinity, analogs of the delta receptor selective peptide deltorphin I (Tyr-D-Ala-Phe-Asp-Val-Val-GlyNH2) were prepared in which the residue 3 phenylalanine was replaced with lipophilic fluoro- and methyl-substituted phenylalanines or with the heterocyclic aromatic amino acids 3-(4-thiazolyl)alanine, 3-(2-pyridyl)alanine, 3-(3-pyridyl)alanine, histidine, and 3-(4-thiazolyl)alanine. mu binding was variable, with KiS in excess of 10,000 nM for most analogs, and all of the analogs bound poorly to k receptors. Among the phenyl ring-substituted analogs, those containing the smaller and electron-withdrawing halogens were favored over those with larger, electron-releasing methyl groups, although delta opioid binding affinity was reduced in all cases. The m-fluorophenylalanine analog demonstrated the best delta binding of the group, with a Ki of 4.79 nM. Within the group of heterocyclic analogs, 3-(2-thienyl)alanine proved to be the best modification, displaying a delta receptor Ki of 1.38 nM, while the polar histidine analog suffered the greatest loss in delta binding (Ki = 317). Compounds containing pyridylalanine and thiazolylalanine were intermediate in binding affinity, with delta KiS ranging from 39.5 to 62.4 nM. The major factor influencing the opioid binding of the similar-sized heterocyclic compounds was relative lipophilicity, which outweighed electronic character.