SAR Matrices Enable Discovery of Mixed Efficacy μ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore.
SAR Matrices Enable Discovery of Mixed Efficacy μ-Opioid Receptor Agonist Peptidomimetics with Simplified Structures through an Aromatic-Amine Pharmacophore.
复制标题
SAR 矩阵能够通过芳香胺药效团发现具有简化结构的混合功效 γ-阿片受体激动剂肽模拟物。
DOI：
10.1021/acschemneuro.0c00693
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发表时间：
2021
影响因子：
5
通讯作者：
Mosberg,HenryI
中科院分区：
文献类型：
--
作者：
Henry,Sean;Anand,JessicaP;Brinkel,AshleyC;McMillan,DouglasM;Twarozynski,JackJ;Loo,ChristianE;Traynor,JohnR;Mosberg,HenryI
我们之前描述了强效μ-阿片受体（MOR）激动剂/δ-阿片受体（DOR）拮抗剂拟肽配体的开发，作为一种减少副作用的有效镇痛药的方法。在该系列中，采用四氢喹啉 (THQ) 或取代的苯基来连接两个关键药效基团元件：二甲基酪氨酸氨基酸和通常的芳香族侧链。使用新的和先前报道的类似物，我们构建了一个构效关系（SAR）矩阵，以探讨先前报道的胺悬垂物的效用。该矩阵表明，当使用四氢异喹啉 (THIQ) 悬垂物时，尽管去除了核心苯环上的取代基，这些配体的 MOR 激动剂/DOR 拮抗剂性质不会改变。基于这一观察，我们保留了 THIQ 侧链，并用更简单的脂肪链结构取代了苯基核心。这些更简单的类似物被证明是有效的 MOR 激动剂，对 DOR 和 κ-阿片受体 (KOR) 的作用具有高度可变性。这些数据表明，THIQ 悬垂物的胺可能是一种有利于高 MOR 功效的新型药效团元素，而 THIQ 悬垂物的芳香环可能产生高 MOR 效力。 THIQ 吊坠内的两个药效团相结合，可能是一种结构上有效的方法，可将阿片肽和拟肽转化为强效且有效的 MOR 激动剂。
We previously described the development of potent μ-opioid receptor (MOR)-agonist/δ-opioid receptor (DOR)-antagonist peptidomimetic ligands as an approach toward effective analgesics with reduced side effects. In this series, a tetrahydroquinoline (THQ) or substituted phenyl is employed to link two key pharmacophore elements, a dimethyltyrosine amino acid and typically an aromatic pendant. Using new and previously reported analogues, we constructed a structure–activity relationship (SAR) matrix that probes the utility of previously reported amine pendants. This matrix reveals that the MOR-agonist/DOR-antagonist properties of these ligands do not change when a tetrahydroisoquinoline (THIQ) pendant is used, despite removal of substituents on the core phenyl ring. Based on this observation, we retained the THIQ pendant and replaced the phenyl core with simpler aliphatic chain structures. These simpler analogues proved to be potent MOR-agonists with high variability in their effects at the DOR and the κ-opioid receptor (KOR). These data show that the amine of the THIQ pendant may be a novel pharmacophore element that favors high MOR-efficacy, whereas the aromatic ring of the THIQ pendant may produce high MOR-potency. Combined, the two pharmacophores within the THIQ pendant may be a structurally efficient means of converting opioid peptides and peptidomimetics into potent and efficacious MOR-agonists.