Novel multi target-directed ligands targeting 5-HT4 receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease

Caroline Lanthier; Hugo Payan; Irene Liparulo; Bérénice Hatat; Cédric Lecoutey; Marc Since; Audrey Davis; Christian Bergamini; Sylvie Claeysen; Patrick Dallemagne; Maria-Laura Bolognesi; Christophe Rochais

doi:10.1016/j.ejmech.2019.111596

Novel multi target-directed ligands targeting 5-HT₄ receptors with in cellulo antioxidant properties as promising leads in Alzheimer's disease

Eur J Med Chem. 2019 Nov 15:182:111596. doi: 10.1016/j.ejmech.2019.111596. Epub 2019 Aug 6.

Affiliations

¹ Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN, 14000, Caen, France.
² IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
³ Department of Pharmacy and Biotechnology, Alma Mater Studiorum, University of Bologna, I-40126, Bologna, Italy.
⁴ Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN, 14000, Caen, France; IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France.
⁵ Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN, 14000, Caen, France. Electronic address: christophe.rochais@unicaen.fr.

PMID: 31419776
DOI: 10.1016/j.ejmech.2019.111596

Abstract

Facing the complexity of Alzheimer's disease (AD), it is now currently admitted that a therapeutic pleiotropic intervention is needed to alter its progression. Among the major hallmarks of the disease, the amyloid pathology and the oxidative stress are closely related. We propose in this study to develop original Multi-Target Directed Ligands (MTDL) able to impact at the same time Aβ protein accumulation and toxicity of Reactive Oxygen Species (ROS) in neuronal cells. Such MTDL were obtained by linking on a central piperidine two scaffolds of interest: a typical aminochlorobenzophenone present in numerous 5-HT₄R agonists, and diverse antioxidant chemotypes. Interestingly, the most active compound 9g possesses a Ki of 12.7 nM towards 5-HT₄R and an antioxidant activity in vitro and in cellulo.

Keywords: 5-HT(4) receptor; Alzheimer's disease; Antioxidant; MTDL; Phenol.

MeSH terms

Alzheimer Disease / drug therapy
Alzheimer Disease / metabolism
Animals
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Biphenyl Compounds / antagonists & inhibitors
Biphenyl Compounds / metabolism
COS Cells
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Chlorocebus aethiops
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Ligands
Molecular Structure
Picrates / antagonists & inhibitors
Picrates / metabolism
Reactive Oxygen Species / analysis
Reactive Oxygen Species / metabolism
Receptors, Serotonin, 5-HT4 / metabolism*
Serotonin 5-HT4 Receptor Agonists / chemical synthesis
Serotonin 5-HT4 Receptor Agonists / chemistry
Serotonin 5-HT4 Receptor Agonists / pharmacology*
Structure-Activity Relationship

Substances

Antioxidants
Biphenyl Compounds
Ligands
Picrates
Reactive Oxygen Species
Serotonin 5-HT4 Receptor Agonists
Receptors, Serotonin, 5-HT4
1,1-diphenyl-2-picrylhydrazyl