Design, synthesis, and biological evaluation of new 5-HT4 receptor agonists: application as amyloid cascade modulators and potential therapeutic utility in Alzheimer's disease.

Serotonin 5-HT4 receptor (5-HT4R) agonists are of particular interest for the treatment of Alzheimer’s disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid β-protein (Aβ). However, despite the range of 5-HT4R agonists synthesized to date, potent and selective 5-HT4R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT4R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPα) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Aβ fibril formation in vitro.