Peripherally Restricted Fused Heterocyclic Peptidomimetic Multifunctional Opioid Agonists as Novel, Potent Analgesics.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-02-06 eCollection Date: 2025-03-13 DOI:10.1021/acsmedchemlett.4c00333

Haylee R Hammond, Prakash Chaudhari, Ashley Bunnell, Khadija Nefzi, Chongguang Chen, Pingwei Zhao, Shainnel O Eans, Sabrina R Masood, Colette T Dooley, Lee-Yuan Liu-Chen, Jay P McLaughlin, Adel Nefzi

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引用次数: 0

Abstract

Heterocyclic peptidomimetics are constrained compounds that mimic the biological efficacy of peptides while offering increased stability. We have previously generated a diazaheterocyclic peripherally selective, mixed-opioid agonist peptidomimetic that produced synergistic antinociception with decreased side effects. Working from two earlier templates, we report here the synthesis of 15 new diazaheterocyclic analogues. In vitro screening with radioligand competition binding assays and [³⁵S]GTPγS assays demonstrated variable affinity for and activity at μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with three (2663-48, 2638-28 and 2638-33) displaying good affinity for DOR and/or KOR. All three compounds produced dose-dependent, opioid-receptor mediated antinociception in the mouse 55 °C warm-water tail-withdrawal and acetic-acid writhing assay, although a ratio of ED₅₀ values in these assays suggested poor BBB penetration by 2638-33; results confirmed by testing with naloxone-methiodide. The data suggest these diazaheterocyclic mixed-activity, peripherally restricted opioid receptor agonists may hold potential as new, safer analgesics.

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外周受限融合杂环拟肽多功能阿片激动剂作为新型强效镇痛药。

杂环类肽模拟物是一种受限制的化合物，它模仿肽的生物功效，同时提供更高的稳定性。我们之前已经产生了重氮杂环外周选择性，混合阿片激动剂拟肽，产生协同抗痛觉减少副作用。从两个早期的模板工作，我们在这里报告了15个新的重氮杂环类似物的合成。用放射配体竞争结合试验和[35S]GTPγS试验进行体外筛选，发现该系列阿片受体对μ (MOR)、δ (DOR)和κ (KOR)具有不同的亲和力和活性，其中3个（2663-48、2638-28和2638-33）对DOR和/或KOR具有良好的亲和力。在小鼠55°C温水脱尾和醋酸扭转实验中，所有三种化合物均产生剂量依赖性阿片受体介导的抗痛觉作用，尽管这些实验中ED50值的比值表明血脑屏障穿透性差（2638-33）；结果经纳洛酮-甲氧基醚试验证实。数据表明，这些重氮杂环混合活性，外周限制性阿片受体激动剂可能具有潜力，作为新的，更安全的镇痛药。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.