Dolles, Dominik and Hoffmann, Matthias and Gunesch, Sandra and Marinelli, Oliviero and Moeller, Jan and Santoni, Giorgio and Chatonnet, Arnaud and Lohse, Martin J. and Wittmann, Hans Joachim and Strasser, Andrea and Nabissi, Massimo and Maurice, Tangui and Decker, Michael (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 CHEMISTRY, 61 (4). pp. 1646-1663. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR MODELING INVESTIGATIONS; CB2 RECEPTOR; BIOLOGICAL-PROPERTIES; ACHE INHIBITORS; TACRINE HYBRIDS; DRUG DISCOVERY; AGONIST; DERIVATIVES; ALZHEIMER; DISEASE; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 19 Mar 2020 12:00 |
| Last Modified: | 19 Mar 2020 12:00 |
| URI: | https://pred.uni-regensburg.de/id/eprint/15022 |
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