Alzheimer’s disease (AD) represents the most common form of dementia. As approved drugs only enable symptomatic treatment while neuron degradation is not decelerated, a causative medication may deliver the best results for therapy. To reach these goals, a combination of both a selective inhibitor of human butyrylcholine esterase (hBChE) and a cannabinoid receptor 2 (CB2R) agonist, was aimed for. As hBChE is upregulated during disease progession, its inhibition hints beneficial results during mid- and late stage of AD, while acetylcholine esterase (AChE) levels significantly decrease. To slow down disease progression itself, CB2R agonism is able to inhibit synaptic transmission and therefore regulate neurogenic inflammation by reduction of inflammatory peptide release and afferent firing. We addressed both targets by a small molecule with “balanced” activities, starting our scientific approach by organic synthesis guided by computational investigations leading to a multifaceted set of compounds based on a 2-benzylbenzimidazole core structure. In vitro screening revealed a heterogenous profile on the respective targets, ranging from one-digit nanomolar inhibitors of hBChE to “balanced”, submicromolar hBChE/CB2R ligands. Ellman`s assay on hAChE/hBChE and radioligand binding studies on CB1R/CB2R were furthermore complemented by kinetic investigations into the binding mode on hBChE, calcium mobilization assays on CB2R and exclusion of neurotoxic effects on HT-22 cells. Most promising hits were subsequently tested in vivo in an AD mouse model.

Nanomolar and selective human butyrylcholinesterase inhibitors showing CB2R agonism against neurodegenerative disorders

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.