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

Dominik Dolles (1) , Matthias Hoffmann (1) , Sandra Gunesch (1) , Oliviero Marinelli (2) , Jan Möller (3) , Giorgio Santoni (2) , Arnaud Chatonnet (4) , Martin J. Lohse (3) , Hans-Joachim Wittmann (5) , Andrea Strasser (5) , Massimo Nabissi (2) , Tangui Maurice (6) , Michael Decker (1)

1 Pharmaceutical and Medicinal Chemistry, Institute of Pharmacy and Food Chemistry
2 School of Pharmacy, Department of Experimental Medicine
3 Institute of Pharmacology and Toxicology [Würzburg]
4 DMEM - Dynamique Musculaire et Métabolisme
5 Pharmaceutical and Medicinal Chemistry II, Institute of Pharmacy
6 MMDN - Mécanismes moléculaires dans les démences neurodégénératives

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.

Domaines: Sciences du Vivant [q-bio]

Dominik Dolles, Matthias Hoffmann, Sandra Gunesch, Oliviero Marinelli, Jan Möller, et al.. 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 Chemistry, 2018, 18 p. ⟨10.1021/acs.jmedchem.7b01760⟩. ⟨hal-01837661⟩