Probe and Assay Dependent Pharmacology of Dantrolene Analogues at the GPR35

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-07-09 Epub Date: 2026-06-24 DOI:10.1021/acsmedchemlett.6c00056

Yaopeng Zhao, Jingmin Cui, Hui Wen, Xiaoyue Dai, Liangsheng Jiang and Ye Fang*,

引用次数: 0

Abstract

The G-protein-coupled receptor 35 (GPR35) plays a key role in various physiological and pathological processes and has emerged as a potential therapeutic target for the treatment of pain, inflammation, and metabolic diseases. Herein, we report the discovery and characterization of dantrolene analogues as GPR35 ligands. Pharmacological profiling with label-free dynamic mass redistribution and Tango arrestin assays showed that the 2,4-imidazolidinedione-containing analogues of dantrolene act as partial agonists of the GPR35, while its urea, thiourea, or amido derivatives display probe and assay dependent antagonism against the receptor.

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丹曲林类似物在GPR35的探针依赖性药理学研究

g蛋白偶联受体35 （GPR35）在多种生理和病理过程中发挥关键作用，已成为治疗疼痛、炎症和代谢性疾病的潜在治疗靶点。在此，我们报道了作为GPR35配体的丹曲林类似物的发现和表征。通过无标记动态质量重分布和Tango抑制试验的药理学分析表明，含有2,4-咪唑烷二酮的丹曲伦类似物作为GPR35的部分激动剂，而其尿素、硫脲或酰胺衍生物对受体表现出探针依赖性和测定依赖性的拮抗作用。

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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.