Structure activity relationship exploration of 5-hydroxy-2-(3-phenylpropyl)chromones as a unique 5-HT2B receptor antagonist scaffold. Issue 21 (1st November 2020)

• Record Type: Journal Article
• Authors: Kim, Minsoo; Truss, Myles; Pagare, Piyusha P.; Essandoh, Martha A.; Zhang, Yan; Williams, Dwight A.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 30:Issue 21(2020)
• Publication Date: 2020-11-01
• Subjects: 5-HT2B -- Chromone -- Antagonist -- 5-HPEC -- 5-HPPC -- G-protein coupled receptors; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2020.127511
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Antagonists for the serotonin receptor 2B (5-HT2B ) 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.