Design, Synthesis and Biological Evaluation of 5-Hydroxy-2-(3-phenylpropyl) Chromone Derivatives as 5-HT28 Receptor Ligands
Kim, Min Soo
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Serotonin(5-HT)and its receptors are involved in a wide range of physiological functions. The serotonin receptor 2 (5-HT2)in particular, is known to interact with many psychopharmaceuticals. This clinical significance indicates that designingligands targeting the 5-HT2receptors may allow useful therapeutic exploitation. A recently isolated natural compound, 5-hydroxy-2-(2-phenylethyl) chromone (5-HPEC)has shown to be a 5-HT2Bantagonist and also possess neuroprotective properties in rat cortical cell cultures. Studies on 5-HPEC optimization led to a novel compound,5-hydroxy-2-(3-phenylpropyl) chromone (5-HPPC), which showed improved inhibition and affinity against 5-HT2B. This study aimed to design 5-HT2Bligands by modifying the 5-HPPC scaffold to further enhance its affinity and selectivity towards the receptor. Compounds with varying substituents on C-3, C-3′,and C-4′were synthesized, characterized and biologically evaluated. Among the derivatives, 5-hydroxy-2-(3-(3-cyanophenyl) propyl) chromone emerged as a new lead compound with 4-fold improvement in binding affinity over 5-HPPC. Computational data from ligand docking studies on compounds with promising profiles also confirmed the biological data. Potential improvements of the new lead were proposed based on the ligand docking results.