Structure-Based Discovery of Novel and Selective 5-Hydroxytryptamine 2B Receptor Antagonists for the Treatment of Irritable Bowel Syndrome

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• 作者：Yu Zhou ; Jing Ma ; Xingyu Lin ; Xi-Ping Huang ; Kaichun Wu ; Niu Huang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：January 28, 2016
• 年：2016
• 卷：59
• 期：2
• 页码：707-720
• 全文大小：710K
• ISSN：1520-4804

文摘

Here we employed structure-based ligand discovery techniques to explore a recently determined crystal structure of the 5-hydroxytryptamine 2B (5-HT_2B) receptor. Ten compounds containing a novel chemical scaffold were identified; among them, seven molecules were active in cellular function assays with the most potent one exhibiting an IC₅₀ value of 27.3 nM. We then systematically probed the binding characteristics of this scaffold by designing, synthesizing, and testing a series of structural modifications. The structure–activity relationship studies strongly support our predicted binding model. The binding profiling across a panel of 11 5-HT receptors indicated that these compounds are highly selective for the 5-HT_2B receptor. Oral administration of compound 15 (30 mg/kg) produced significant attenuation of visceral hypersensitivity in a rat model of irritable bowel syndrome (IBS). We expect this novel scaffold will serve as the foundation for the development of 5-HT_2B antagonists for the treatment of IBS.