Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT sub(6) receptor antagonists

• Published in: Bioorganic & medicinal chemistry 2008-01, Vol.18 (2), p.738-743
• Main Authors: Seong, Churl Min, Park, Woo Kyu, Park, Chul Min, Kong, Jae Yang, Park, No Sang
• Format: Article
• Language: English
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmcl.2007.11.045

A 5,7-dichloro-3-phenyl-3-methyl-quinoline-2,4-dione ( 11a) has been identified in a random screen as a lead for 5-HT sub(6) antagonist. During the lead optimization process, several analogs were synthesized and their biological activities were investigated. Within this series, several compounds display high binding affinity and selectivity for the 5-HT sub(6) receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione ( 12f) exhibits high affinity (K sub(i) = 12.3 nM) for 5-HT sub(6) receptor with good selectivity over other serotonin and dopamine (D sub(1)-D sub(4)) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC sub(50) = 0.61 mu M).