Novel quinazolinone derivatives as 5-HT7 receptor ligands

5-HT7 receptor antagonists generated antidepressant-like effects in animal model and the involvement of the 5-HT7 receptor in other pathophysiological mechanisms such as thermoregulation, learning and memory, and sleep has been highlighted by various studies. As one of our efforts to discover a new type of 5-HT7 receptor antagonists, we here report on the synthesis and binding affinities to the 5-HT7 receptor of the quinazolinone library 1, which was designed with various substituents (X, Y, R1, and R2) on the aromatic rings and different carbon chain length. Total 85 compounds of the quinazolinone library 1 were synthesized and the binding affinities of all the synthesized compounds were obtained by radioligand binding assay for the 5-HT7 receptor. Among the 85 compounds, 24 compounds show very good binding affinities with IC50 values below 100 nM. Mainly the compounds with IC50 values below 100 nM have o-OMe or o-OEt as R2 substituent. The compound with the best binding affinity is 1-68 of which the IC50 value is 12 nM. In in vivo animal study, some synthesized compounds really have the antidepressant activity in the forced swimming test in mice.

A small molecule library of quinazolinone derivatives 1 was synthesized and biologically evaluated to estimate binding affinity to the 5-HT7 receptor.Figure optionsDownload as PowerPoint slide