Terpene-Based Thiazole Hydrazines as Negative Allosteric Modulators of MRGPRX4: In Vitro Evaluation and Binding Site Analysis

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-08-10 DOI:10.1021/acsmedchemlett.5c00354

Saqlain Haider, Manal M. Alhusban, Pankaj Pandey, Suresh Chandra V. A. R. Annam, Robert B. Laprairie and Amar G. Chittiboyina*,

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Abstract

The human MAS-related G-protein-coupled receptors (MRGPRs) represent a promising therapeutic target for managing chronic itch and pain. Among them, MRGPRX4 is activated by bile acids in dorsal root ganglia (DRG) neurons and contributes to the cholestatic itch. Here, we report the design, synthesis, and in vitro evaluation of a focused library of functionalized terpene-based thiazole hydrazines targeting MRGPRX receptors. Functional assays identified two compounds, 1C and 3G, as negative allosteric modulators (NAMs) of MRGPRX4 with IC₅₀ values of 337 nM and 15.5 μM, respectively, and showed weak activity at MRGPRX2. Computational analysis suggested a putative NAM binding site adjacent to the orthosteric pocket involving key interactions with residues H92^3.22, K96^3.26, and R159^4.62. The resulting site overlaps with the receptor activity-modifying protein 2 (RAMP2) interaction region, where RAMP2 antagonizes MRGPRX4 as a NAM. These findings provide a foundation for developing selective MRGPRX4 NAMs as novel therapeutic agents for chronic itch and pain.

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萜烯基噻唑肼作为MRGPRX4的负变构调节剂：体外评价和结合位点分析

人类mas相关的g蛋白偶联受体（MRGPRs）是治疗慢性瘙痒和疼痛的一个有希望的治疗靶点。其中MRGPRX4被DRG神经元胆汁酸激活，参与胆汁淤积性瘙痒。在这里，我们报道了针对MRGPRX受体的功能化萜烯基噻唑肼集中文库的设计、合成和体外评价。功能分析发现，1C和3G是MRGPRX4的负变构调节剂（NAMs）， IC50值分别为337 nM和15.5 μM，对MRGPRX2的活性较弱。计算分析表明，在正位袋附近存在一个假定的NAM结合位点，涉及与残基H923.22、K963.26和R1594.62的关键相互作用。由此产生的位点与受体活性修饰蛋白2 （RAMP2）相互作用区域重叠，其中RAMP2作为NAM拮抗MRGPRX4。这些发现为开发选择性MRGPRX4 NAMs作为慢性瘙痒和疼痛的新型治疗剂提供了基础。

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.