Design, synthesis and biological evaluation of pleiotropic prodrugs activated by cholinesterases and releasing a 5-HT4R agonist, with in vivo antiamnesic activity
Abstract
Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are hydrolases that specialize in the cleavage of esters such as acetylcholine. However, they can also cleave the carbamate group of certain drugs, such as rivastigmine. This leads to inhibition of these ChEs and preservation of acetylcholine (ACh), their physiological substrate, providing symptomatic benefits in Alzheimer's disease (AD). The present work aims to exploit ChE's capacity to cleave synthetic carbamates, not only to inhibit these enzymes but also to release a potent 5-HT4 receptor partial agonist upon interaction, thereby exerting an additional disease-modifying effect in AD. Such carbamates would behave as pleiotropic prodrugs. This work relates to the synthesis of the latter compounds and the kinetic study of their enzymatic inhibition to select one of the best candidates from the synthesized compounds for a preliminary in vivo study in an AD model. The latter has been achieved by administering the drug intranasally to bypass the blood-brain barrier (BBB) and avoid peripheral side effects. This has required a special formulation, which was created using liposomes embedded in a thermosensitive mucoadhesive gel. When administered intranasally, the pleiotropic prodrug demonstrated a clear antiamnesic effect in vivo in mice, providing proof of concept for further investigations.
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BibTeX
@article{wang2026design,
title = {{Design, synthesis and biological evaluation of pleiotropic prodrugs activated by cholinesterases and releasing a 5-HT4R agonist, with in vivo antiamnesic activity}},
author = {Alice Wang and Caroline Lahogue and Thomas Curel and Caroline Lanthier and Anne-Claire Groo and Audrey Davis and Sophie Corvaisier and Dimitri Fayolle and Fabrice Modeste and Xavier Brazzolotto and Florian Nachon and Cédric Lecoutey and Sylvie Claeysen and Aurélie Malzert-Fréon and Thomas Freret and Michel Boulouard and Marc Since and Christophe Rochais and Patrick Dallemagne},
journal = {European Journal of Medicinal Chemistry},
year = {2026},
month = oct,
doi = {10.1016/j.ejmech.2026.119383},
url = {https://hal.science/hal-05845061v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Design, synthesis and biological evaluation of pleiotropic prodrugs activated by cholinesterases and releasing a 5-HT4R agonist, with in vivo antiamnesic activity
AU - Alice Wang
AU - Caroline Lahogue
AU - Thomas Curel
AU - Caroline Lanthier
AU - Anne-Claire Groo
AU - Audrey Davis
AU - Sophie Corvaisier
AU - Dimitri Fayolle
AU - Fabrice Modeste
AU - Xavier Brazzolotto
AU - Florian Nachon
AU - Cédric Lecoutey
AU - Sylvie Claeysen
AU - Aurélie Malzert-Fréon
AU - Thomas Freret
AU - Michel Boulouard
AU - Marc Since
AU - Christophe Rochais
AU - Patrick Dallemagne
PY - 2026
DA - 2026/10/10
JO - European Journal of Medicinal Chemistry
DO - 10.1016/j.ejmech.2026.119383
UR - https://hal.science/hal-05845061v1
AB - Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) are hydrolases that specialize in the cleavage of esters such as acetylcholine. However, they can also cleave the carbamate group of certain drugs, such as rivastigmine. This leads to inhibition of these ChEs and preservation of acetylcholine (ACh), their physiological substrate, providing symptomatic benefits in Alzheimer's disease (AD). The present work aims to exploit ChE's capacity to cleave synthetic carbamates, not only to inhibit these enzymes but also to release a potent 5-HT4 receptor partial agonist upon interaction, thereby exerting an additional disease-modifying effect in AD. Such carbamates would behave as pleiotropic prodrugs. This work relates to the synthesis of the latter compounds and the kinetic study of their enzymatic inhibition to select one of the best candidates from the synthesized compounds for a preliminary in vivo study in an AD model. The latter has been achieved by administering the drug intranasally to bypass the blood-brain barrier (BBB) and avoid peripheral side effects. This has required a special formulation, which was created using liposomes embedded in a thermosensitive mucoadhesive gel. When administered intranasally, the pleiotropic prodrug demonstrated a clear antiamnesic effect in vivo in mice, providing proof of concept for further investigations.
SN - 0223-5234
SN - 1768-3254
ER -