Journal Article
Discovery of a Potent Small Molecule Antagonist of GRPR for the Treatment of Pruritus
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
Medicinal Chemistry Research · Vol. 35, Issue 6 · pp. 1119-1140 · 2026
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.