期刊
JOURNAL OF NATURAL PRODUCTS
卷 78, 期 8, 页码 1859-1867出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jnatprod.5b00118
关键词
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资金
- NIH/NIDA [DA007027]
- PHS Research Funds [DA024022]
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2008-00025-C]
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-HT2B) have received renewed interest for their potential to help understand the role of 5-HT2B in migraines, drug abuse, neurodegenerative diseases, and irritable bowel syndrome. To date, most of the ligands targeting 5-HT2B have been nitrogen-containing compounds. The natural product S-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT2B receptor (pK(i) = 5.6). This report describes further progress on the study of the structure activity relationship of both naturally occurring and synthetic compounds bearing the 2(2-phenylethyl)chromone scaffold at the 5-HT2B receptor. The inhibitory activity of the newly synthesized compounds (at 10 mu 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-HT2B. 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-HT2B. Additionally, ligand docking studies have identified a putative binding pocket for 5-HPPC and have helped understand its improved affinity.
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