Design, Synthesis, and Biological Evaluation of New 5-HT4 Receptor Agonists: Application as Amyloid Cascade Modulators and Potential Therapeutic Utility in Alzheimer’s Disease

• Published in: Journal of medicinal chemistry 2009-04, Vol.52 (8), p.2214-2225
• Main Authors: Russo, Olivier, Cachard-Chastel, Marthe, Rivière, Céline, Giner, Mireille, Soulier, Jean-Louis, Berthouze, Magali, Richard, Tristan, Monti, Jean-Pierre, Sicsic, Sames, Lezoualc’h, Frank, Berque-Bestel, Isabelle
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Aminobenzoates - chemical synthesis; Aminobenzoates - chemistry; Aminobenzoates - pharmacology; Amyloid - chemistry; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - metabolism; Animals; Biological and medical sciences; Biopolymers; Cell Line, Tumor; Cerebral Cortex - drug effects; Cerebral Cortex - metabolism; Cyclic AMP - biosynthesis; Drug Design; Hippocampus - drug effects; Hippocampus - metabolism; Humans; Male; Medical sciences; Mice; Mice, Inbred C57BL; Neuropharmacology; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; para-Aminobenzoates; Peptide Fragments - chemistry; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Radioligand Assay; Rats; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801327q

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.