1. Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT 2B receptor antagonist scaffold.
- Author
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Kim M, Truss M, Pagare PP, Essandoh MA, Zhang Y, and Williams DA
- Subjects
- Chromones chemical synthesis, Chromones chemistry, Dose-Response Relationship, Drug, Humans, Ligands, Molecular Structure, Structure-Activity Relationship, Chromones pharmacology, Receptor, Serotonin, 5-HT2B metabolism
- Abstract
Antagonists for the serotonin receptor 2B (5-HT
2B ) have clinical applications towards migraine, anxiety, irritable bowl syndrome, and MDMA abuse; however, few selective 5-HT2B antagonists have been identified. Previous studies from these labs identified a natural product, 5-hydroxy-2-(2-phenylethyl)chromone (5-HPEC, 2) as the first non-nitrogenous ligand for the 5-HT2B receptor. Studies on 5-HPEC optimization led to the identification of 5-hydroxy-2-(3-phenylpropyl)chromone (5-HPPC, 3), which showed a tenfold improvement in binding affinity over 2 at 5-HT2B . This study aimed to further improve receptor pharmacology of this unique scaffold. Guided by molecular modeling studies modifications at the C-3' and C-4' positions of 3 were made to probe their effects on ligand binding affinity and efficacy. Among the derivatives synthesized 5-hydroxy-2-(3-(3-cyanophenyl)propyl)chromone (5-HCPC, 3d) showed the most promise with a multifold improvement in binding affinity (pKi = 7.1 ± 0.07) over 3 with retained antagonism., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)- Published
- 2020
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