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
Identifieur interne : 000149 ( Hal/Corpus ); précédent : 000148; suivant : 000150Structure–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
Auteurs : Dominik Dolles ; Matthias Hoffmann ; Sandra Gunesch ; Oliviero Marinelli ; Jan Möller ; Giorgio Santoni ; Arnaud Chatonnet ; Martin J. Lohse ; Hans-Joachim Wittmann ; Andrea Strasser ; Massimo Nabissi ; Tangui Maurice ; Michael DeckerSource :
- Journal of Medicinal Chemistry [ 0022-2623 ] ; 2018.
Abstract
The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promisingtargets 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 affinitycould 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.
Url:
DOI: 10.1021/acs.jmedchem.7b01760
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Hal:hal-01837661Le document en format XML
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<abstract xml:lang="en"> <p>The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 (hCB2R) represent promisingtargets 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 affinitycould 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.</p>
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