Structure–Activity Relationships and Computational Investigations into the Development of Potent and Balanced Dual-Acting Butyrylcholinesterase Inhibitors and Human Cannabinoid Receptor 2 Ligands with Pro-Cognitive in Vivo Profiles

Abstract

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB₂R) represent promising targets for pharmacotherapy in the later stages of Alzheimer's disease. We merged pharmacophores for both targets into small benzimidazole-based molecules, investigated SARs, and identified several dual-acting ligands with a balanced affinity/inhibitory activity and an excellent selectivity over both hCB₁R and hAChE. A homology model for the hCB₂R was developed based on the hCB₁R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB₂R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB₂R agonist showed superior in vivo activity over the lead CB₂ agonist with regards to cognition improvement. The data shows the possibility to combine a small molecule with selective and balanced GPCR-activity/enzyme inhibition and in vivo activity for the therapy of AD and may help to rationalize the development of other dual-acting ligands.