Design, Synthesis, and Biological Evaluation of New 5-HT(4) Receptor Agonists: Application as Amyloid Cascade Modulators and Potential Therapeutic Utility in Alzheimer's Disease

作者：Russo Olivier; Cachard Chastel Marthe; Riviere Celine; Giner Mireille; Soulier Jean Louis; Berthouze Magali; Richard Tristan; Monti Jean Pierre; Sicsic Sames; Lezoualc'h Frank; Berque Bestel Isabelle^*

来源：Journal of Medicinal Chemistry, 2009, 52(8): 2214-2225.

DOI：10.1021/jm801327q

Serotonin 5-HT(4) receptor (5-HT(4)R) 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 beta-protein (A beta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML 10302, a highly specific and partial 5-HT(4)R 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 (sAPP alpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit A fibril formation in vitro.

• 出版日期2009-4-23