Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands

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• 作者：Dwight A. Williams ; Saheem A. Zaidi ; Yan Zhang
• 刊名：Journal of Natural Products
• 出版年：2015
• 出版时间：August 28, 2015
• 年：2015
• 卷：78
• 期：8
• 页码：1859-1867
• 全文大小：454K
• ISSN：1520-6025

文摘

The involvement of the neurotransmitter serotonin (5-HT) in numerous physiological functions is often attributed to the diversity of receptors with which it interacts. Ligands targeting serotonin receptor 2B (5-HT_2B) have received renewed interest for their potential to help understand the role of 5-HT_2B in migraines, drug abuse, neurodegenerative diseases, and irritable bowel syndrome. To date, most of the ligands targeting 5-HT_2B have been nitrogen-containing compounds. The natural product 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT_2B receptor (pK_i = 5.6). This report describes further progress on the study of the structure鈥揳ctivity relationship of both naturally occurring and synthetic compounds bearing the 2-(2-phenylethyl)chromone scaffold at the 5-HT_2B receptor. The inhibitory activity of the newly synthesized compounds (at 10 渭M) was tested against each of the 5-HT₂ receptors. Following this assay, the binding affinity and antagonism of the most promising compounds were then evaluated at 5-HT_2B. Among all the analogues, 5-hydroxy-2-(2-phenylpropyl)chromone (5-HPPC, 22h) emerged as a new lead compound, showing a 10-fold improvement in affinity (pK_i = 6.6) over 5-HPEC with reasonable antagonist properties at 5-HT_2B. Additionally, ligand docking studies have identified a putative binding pocket for 5-HPPC and have helped understand its improved affinity.