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

Olivier Russo; Marthe Cachard-Chastel; Céline Rivière; Mireille Giner; Jean-Louis Soulier; Magali Berthouze; Tristan Richard; Jean-Pierre Monti; Sames Sicsic; Frank Lezoualc'h; Isabelle Berque-Bestel

doi:10.1021/jm801327q

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

J Med Chem. 2009 Apr 23;52(8):2214-25. doi: 10.1021/jm801327q.

Authors

Olivier Russo¹, Marthe Cachard-Chastel, Céline Rivière, Mireille Giner, Jean-Louis Soulier, Magali Berthouze, Tristan Richard, Jean-Pierre Monti, Sames Sicsic, Frank Lezoualc'h, Isabelle Berque-Bestel

Affiliation

¹ 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.

PMID: 19334715
DOI: 10.1021/jm801327q

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

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
Biopolymers
Cell Line, Tumor
Cerebral Cortex / drug effects
Cerebral Cortex / metabolism
Cyclic AMP / biosynthesis
Drug Design
Hippocampus / drug effects
Hippocampus / metabolism
Humans
Male
Mice
Mice, Inbred C57BL
Neuroprotective Agents / chemical synthesis*
Neuroprotective Agents / chemistry
Neuroprotective Agents / pharmacology
Peptide Fragments / chemistry
Piperidines / chemical synthesis*
Piperidines / chemistry
Piperidines / pharmacology
Radioligand Assay
Rats
Serotonin 5-HT4 Receptor Agonists*
Structure-Activity Relationship
para-Aminobenzoates

Substances

2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate
Aminobenzoates
Amyloid
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Biopolymers
Neuroprotective Agents
Peptide Fragments
Piperidines
Serotonin 5-HT4 Receptor Agonists
amyloid beta-protein (25-35)
para-Aminobenzoates
Cyclic AMP