Synthesis and Characterization of 5-Hydroxy-2-(2-phenylethyl)chromone (5-HPEC) and Its Analogues as Non-nitrogenous 5-HT2B Ligands.
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.
Department of Pharmacology and Toxicology, Virginia Commonwealth University , 410 North 12th Street, P.O. Box 980613, Richmond, Virginia 23298-0613, United States.
Dwight A
DA
Williams
Department of Medicinal Chemistry, Virginia Commonwealth University, BioTech One , Suite 205, 800 E. Leigh Street, P.O. Box 980540, Richmond, Virginia 23298-0540, United States.
Saheem A
SA
Zaidi
Department of Medicinal Chemistry, Virginia Commonwealth University, BioTech One , Suite 205, 800 E. Leigh Street, P.O. Box 980540, Richmond, Virginia 23298-0540, United States.
Yan
Y
Zhang
D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques; D005419:Flavonoids / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D044403:Receptor, Serotonin, 5-HT2B / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D013329:Structure-Activity Relationship
C508837:5-hydroxy-2-(2-phenylethyl)chromone; D002867:Chromones; D005419:Flavonoids; D008024:Ligands; D044403:Receptor, Serotonin, 5-HT2B; D012701:Serotonin; C062550:2-(2-phenylethyl)chromone