Discovery of 3-aryl-3-methyl-1H-quinoline-2,4-diones as a new class of selective 5-HT6 receptor antagonists.

Abstract 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 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 6 receptor. In particular, 3-(4-hydroxyphenyl)-3-methyl-quinoline-2,4-dione ( 12f ) exhibits high affinity ( K i  = 12.3 nM) for 5-HT 6 receptor with good selectivity over other serotonin and dopamine (D 1 –D 4 ) receptor subtypes. In a functional adenylyl cyclase stimulation assay, this compound exhibited considerable antagonistic activity (IC 50  = 0.61 μM).