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 (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.