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-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 (Abeta). 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 ML10302, 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 (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.
Russo
Olivier
O
CNRS UMR C 8076 (BioCIS), Molecules Fluorees et Chimie Medicinale, UMR-S769, EA3544, Serotonine et Neuropharmacologie, IFR-141, Faculte de Pharmacie, Universite Paris-Sud, F- 92296 Chatenay-Malabry, France.
Cachard-Chastel
Marthe
M
Rivière
Céline
C
Giner
Mireille
M
Soulier
Jean-Louis
JL
Berthouze
Magali
M
Richard
Tristan
T
Monti
Jean-Pierre
JP
Sicsic
Sames
S
Lezoualc'h
Frank
F
Berque-Bestel
Isabelle
I