Article highlights • The interest of 5-HT4R modulators have been explored in several pathologies and approved by the FDA. • The progress in the development of 5-HT4R modulators patented between 2014 and 2019 is reviewed. • The exploration of multiple chemical scaffolds has led to the discovery of several potent and selective 5-HT4R modulators. • Several 5-HT4R modulators are currently being evaluated in clinical trials. • The potential therapeutic interest of 5-HT4R modulators in combination with other drugs could lead to synergistic combined therapies.

Highlights • Conception and synthesis of new MTDLs combining 5-HT4R agonist activity and antioxidant properties • All compounds showed good %inhibition at 10-6M on 5-HT4R, with 9b and 9g showing Ki < 15 nM on 5-HT4R as well as agonist profile. • In vitro and in cellulo antioxidant effects were evaluated • 9b is the best compromise regarding the 5-HT4R activity and antioxidant properties