Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT_2B Ligands

Abstract

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 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 5) has been shown previously to act as a non-nitrogenous antagonist for the 5-HT2B receptor (pKi = 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 μM) 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 (pKi = 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.

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…5-HPEC showed selectivity for the 5-HT 2B R over other 5-HT 2 Rs. A subsequent SAR study on a series of synthesized and 5-HPEC's natural analogs was performed and showed that the most potent analog, 5-hydroxy-2-(2phenylpropyl)chromone (5-HPPC) (24, Figure 7), exhibited a 10-fold improvement in the 5-HT 2B R affinity (K i = 251 nM) and was able to maintain the 5-HT 2B R antagonism [139]. Recently, further optimization of 5-HPPC guided by molecular modeling approaches helped to identify 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC) (25, Figure 7), which exhibited an improved binding affinity (K i = 79 nM) compared with 5-HPPC and maintained inhibitory activity (IC 50 = 6310 nM in calcium flux assay) at the 5-HT 2B R, as well as selectivity over the 5-HT 2A R and the 5-HT 2C R [140].…”

“…Figure 7. Representative chromone derivatives as non-nitrogenous 5-HT 2B R antagonists[138][139][140].…”

Chromone as a Privileged Scaffold in Drug Discovery: Recent Advances

“…Recently, chromones were described as an important scaffold for the development of novel 5-HT 2B ligands. Williams et al synthesized a chemical library inspired on the natural compound 2-(2-phenylethyl)­chromone (compound 10 , p K i = 5.6, Figure ) and screened it toward the 5-HT 2B receptor. Accordingly, 5-hydroxy-2-(2-phenylpropyl)­chromone (compound 11 , p K i = 6.6 at 5-HT 2B , Figure ) emerged as a potential 5-HT 2B ligand with potential therapeutic applicability on AD.…”

5-O-methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors

“…Chromone-like compounds were found to be opioid ligands [13], but their analgesic activities have also been associated with other types of receptors [10,14]. Some could also potentially interact within the endogenous analgesia system by acting as serotonin receptor ligands [15,16]. Besides, these compounds are considered promising for pharmaceutical development because they possess low toxicity and are available in the human diet, due to their wide distribution among edible plants [17].…”