Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease

François-Xavier Toublet (1) , Cédric Lecoutey (1) , Julien Lalut (1) , Bérénice Hatat (1, 2) , Audrey Davis (1) , Marc Since (1) , Sophie Corvaisier (1) , Thomas Freret (3) , Jana Sopkova-de Oliveira Santos (1) , Sylvie Claeysen (2) , Michel Boulouard (3) , Patrick Dallemagne (1) , Cédric Lecoutey (1)

1 CERMN - Centre d'Etudes et de Recherche sur le Médicament de Normandie
2 IGF - Institut de Génomique Fonctionnelle
3 Cyceron - GIP Cyceron

Alzheimer's disease (AD) is a multifactorial neurodegenerative disease which is still poorly understood. The drugs currently used against AD, mainly acetylcholinesterase inhibitors (AChEI), are considered clinically insufficient and are responsible for deleterious side effects. AChE is, however, currently receiving renewed interest through the discovery of a chaperone role played in the pathogenesis of AD. But AChE could also serve as an activating protein for pleiotropic prodrugs. Indeed, inhibiting central AChE with brain-penetrating designed carbamates which are able to covalently bind to the enzyme and to concomitantly liberate active metabolites in the brain could constitute a clinically more efficient approach which, additionally, is less likely to cause peripheral side effects. We aim in this article to pave the road of this new avenue with an in vitro and in vivo study of pleiotropic prodrugs targeting both the 5-HT4 receptor and AChE, in order to display a neuroprotective activity associated with a sustained restoration of the cholinergic neurotransmission and without the usual peripheral side effects associated with classic AChEI. This plural activity could bring to AD patients effective, relatively safe, symptomatic and disease-modifying therapeutic benefits.

Mots clés: prodrug; Alzheimer’s disease; 5-HT4 receptors; acetylcholinesterase; MTDL

Domaines: Chimie thérapeutique; Neurobiologie

François-Xavier Toublet, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, et al.. Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease. Molecules, 2019, 24 (15), pp.2786. ⟨10.3390/molecules24152786⟩. ⟨hal-02399906⟩