Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold

Minsoo Kim; Myles Truss; Piyusha P Pagare; Martha A Essandoh; Yan Zhang; Dwight A Williams

doi:10.1016/j.bmcl.2020.127511

Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT_2B receptor antagonist scaffold

Bioorg Med Chem Lett. 2020 Nov 1;30(21):127511. doi: 10.1016/j.bmcl.2020.127511. Epub 2020 Aug 24.

Authors

Minsoo Kim¹, Myles Truss¹, Piyusha P Pagare², Martha A Essandoh³, Yan Zhang², Dwight A Williams⁴

Affiliations

¹ Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006, USA.
² Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA 23298, USA.
³ Department of Chemistry, Oklahoma State University, Stillwater, OK 74078, USA.
⁴ Department of Chemistry, Kalamazoo College, Kalamazoo, MI 49006, USA. Electronic address: dwight.williams@kzoo.edu.

PMID: 32853682
DOI: 10.1016/j.bmcl.2020.127511

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-HT_2B 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-HT_2B 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-HT_2B. 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 (pK_i = 7.1 ± 0.07) over 3 with retained antagonism.

Keywords: 5-HPEC; 5-HPPC; 5-HT(2B); Antagonist; Chromone; G-protein coupled receptors.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Chromones / chemical synthesis
Chromones / chemistry
Chromones / pharmacology*
Dose-Response Relationship, Drug
Humans
Ligands
Molecular Structure
Receptor, Serotonin, 5-HT2B / metabolism*
Structure-Activity Relationship

Substances

Chromones
Ligands
Receptor, Serotonin, 5-HT2B