Design, Synthesis, and Biological Evaluation of New 5-HT4 Receptor Agonists: Application as Amyloid Cascade Modulators and Potential Therapeutic Utility in Alzheimer’s Disease
| Autor: | Frank Lezoualc'h, Céline Rivière, Jean-Louis Soulier, Jean-Pierre Monti, Olivier Russo, Sames Sicsic, Marthe Cachard-Chastel, Isabelle Berque-Bestel, Tristan Richard, Mireille Giner, Magali Berthouze |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Agonist Amyloid medicine.drug_class 5-HT4 receptor Pharmacology Hippocampus Neuroprotection Amyloid beta-Protein Precursor Mice Radioligand Assay Serotonin 5-HT4 Receptor Agonists Structure-Activity Relationship Biopolymers Piperidines Alzheimer Disease In vivo Cell Line Tumor Drug Discovery Cyclic AMP para-Aminobenzoates medicine Amyloid precursor protein Animals Humans Aminobenzoates Receptor Cerebral Cortex Amyloid beta-Peptides biology Chemistry Peptide Fragments In vitro Rats Mice Inbred C57BL Neuroprotective Agents Biochemistry Drug Design biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 52:2214-2225 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm801327q |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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