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

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB(2)R) 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 hCB(1)R and hAChE. A homology model for the hCB(2)R was developed based on the hCB(1)R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved hCB(2)R agonism. Unwanted mu-oproid receptor affinity could be designed out. One well-balanced dual-acting and selective hBChE inhibitor/hCB(2)R 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.