Cited by 67Cholinesterase and Neurodegenerative DiseasesCannabis and Cannabinoid ResearchComputational Drug Discovery Methods

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

Dolles, Dominik, Hoffmann, Matthias, Gunesch, Sandra, Marinelli, Oliviero, Möller, Jan, Santoni, Giorgio, Chatonnet, Arnaud, Lohse, Martin J. +5 more·2018·Journal of Medicinal Chemistry

Abstract

The enzyme butyrylcholinesterase (BChE) and the human cannabinoid receptor 2 ( h CB 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 h CB 1 R and h AChE. A homology model for the h CB 2 R was developed based on the h CB 1 R crystal structure and used for molecular dynamics studies to investigate binding modes. In vitro studies proved h CB 2 R agonism. Unwanted μ-opioid receptor affinity could be designed out. One well-balanced dual-acting and selective h BChE inhibitor/ h CB 2 R agonist showed superior in vivo activity over the lead CB 2 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.

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Crossref · 10.1021/acs.jmedchem.7b01760

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Authors
Dolles, D., Hoffmann, M., Gunesch, S., Marinelli, O., Möller, J., Santoni, G., Chatonnet, A., Lohse, M. J., Wittmann, H.-J., Strasser, A., Nabissi, M., Maurice, T., & Decker, M.
Affiliations
  • University of Würzburg (DE)
  • Università di Camerino (IT)
  • Institute of Pharmacology and Toxicology, Julius Maximilian University of Würzburg, Versbacher Strabe 9, D-97078 Würzburg, Germany
  • Université de Montpellier (FR)
  • University of Regensburg (DE)
  • Inserm (FR)
Corresponding author
Decker, Michael
Venue
Journal of Medicinal Chemistry
Published
2018-02-05
Volume
61
Issue
4
Pages
1646-1663
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
OpenAlex
W2787270055
Cited by
67
References
76
Citations by year
2026: 5 · 2025: 3 · 2024: 8 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 12 · 2019: 12 · 2018: 5
FWCI
7.74
Type
journal article
Language
en
Open access
closed
Locations
  • Journal of Medicinal Chemistry (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (submittedVersion)
  • Unicam Scientific Publications (University of Camerino) (submittedVersion)
Funders
  • Deutscher Akademischer Austauschdienst (57396178)
  • Bayerisches Staatsministerium f?r Bildung und Kultus, Wissenschaft und Kunst
  • Deutsche Forschungsgemeinschaft (DE/1546/6-3)
  • Studienstiftung des Deutschen Volkes
Topics
  • Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
butyrylcholinesterase inhibitors, cannabinoid receptor 2 agonist, Alzheimer's disease, benzimidazole derivatives, structure-activity relationship, pharmacophore design, homology modeling, molecular dynamics, binding mode, mu-opioid receptor selectivity, cognitive enhancement
MeSH terms
Alzheimer Disease, Benzimidazoles, Butyrylcholinesterase, Cognition, Enzyme Inhibitors, Humans, Ligands, Protein Binding, Structure-Activity Relationship, Receptors, G-Protein-Coupled, Receptor, Cannabinoid, CB2

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