ArticleMedicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents2026
Discovery of a Potent Small Molecule Antagonist of GRPR for the Treatment of Pruritus.
Article in Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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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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