Discovery of a Potent Small Molecule Antagonist of GRPR for the Treatment of Pruritus

IF 3.5 4区医学 Q3 CHEMISTRY, MEDICINAL

Medicinal Chemistry Research Pub Date : 2026-05-26 DOI:10.1007/s00044-026-03566-x

Mingzhou Zhou, Roland E Dolle, Amruta R Poreddy, Edmund C Hudson, Michelle A Schmidt, Margaret L Grapperhaus, Tom Gordon, Huaping Chen, Mike Prinsen, Xianyu Liu, Zhiyong E. Tao, Jinbin Xu, Ma Xenia G Ilagan, Zhou-Feng Chen

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引用次数: 0

Abstract

Persistent pruritus (itch) affects the quality of life, and many itch syndromes remain untreatable. Previously, we identified the gastrin-releasing peptide receptor (GRPR) playing a critical role in mediating histamine-independent itch signaling. In this study, we aimed to identify small-molecule GRPR antagonists to treat histamine-independent itch. Starting with the known small-molecule GRPR antagonist PD 176,252, we conducted systematical structure-activity relationship studies. This effort led to the discovery of antagonists that exhibit up to an 11-fold increase in binding affinity compared to PD 176,252. Compound 45 (MP-4222), a GRPR antagonist with a four-fold increased binding affinity and equal selectivity over the neuromedin B receptor (NMBR), significantly inhibited itch behavior in the chloroquine (CQ)-induced acute itch mouse model. Additionally, we attempted to reconcile the discrepancy between our in vitro experimental data and the computational docking outcome using the recently reported GRPR-PD176252 cryo-EM structure. Our studies also suggested several potential modifications to improve potency, as well as identified functional groups that have the potential in radiolabeling for targeted GRPR imaging.

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一种治疗瘙痒症的强效GRPR小分子拮抗剂的发现

持续瘙痒（痒）影响生活质量，许多瘙痒综合征仍然无法治愈。先前，我们发现胃泌素释放肽受体（GRPR）在介导组胺非依赖性瘙痒信号传导中起关键作用。在这项研究中，我们旨在鉴定小分子GRPR拮抗剂来治疗组胺非依赖性瘙痒。从已知的小分子GRPR拮抗剂PD 176252开始，我们进行了系统的构效关系研究。这一努力导致拮抗剂的发现，与PD 176,252相比，其结合亲和力增加了11倍。化合物45 （MP-4222）是一种GRPR拮抗剂，对神经介质B受体（NMBR）具有4倍的结合亲和力和相同的选择性，可显著抑制氯喹（CQ）诱导的急性瘙痒小鼠模型中的瘙痒行为。此外，我们试图使用最近报道的GRPR-PD176252冷冻电镜结构来调和我们的体外实验数据与计算对接结果之间的差异。我们的研究还提出了几种潜在的修饰以提高效力，并确定了具有靶向GRPR成像放射性标记潜力的官能团。

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

Medicinal Chemistry Research 医学-医药化学

CiteScore

4.70

自引率

3.80%

发文量

162

审稿时长

5.0 months

期刊介绍： Medicinal Chemistry Research (MCRE) publishes papers on a wide range of topics, favoring research with significant, new, and up-to-date information. Although the journal has a demanding peer review process, MCRE still boasts rapid publication, due in part, to the length of the submissions. The journal publishes significant research on various topics, many of which emphasize the structure-activity relationships of molecular biology.