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 mu-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.
Dolles D, Hoffmann M, Gunesch S, Marinelli O, Moller J, Santoni G, Chatonnet A, Lohse MJ, Wittmann HJ, Strasser A, Nabissi M, Maurice T, Decker M (2018) 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 Journal of Medicinal Chemistry61: 1646-1663
Dolles D, Hoffmann M, Gunesch S, Marinelli O, Moller J, Santoni G, Chatonnet A, Lohse MJ, Wittmann HJ, Strasser A, Nabissi M, Maurice T, Decker M (2018) Journal of Medicinal Chemistry61: 1646-1663