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<p>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 <b>45</b> (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.</p><p></p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月26日

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  • 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

摘要

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.