Dual-acting small molecules : subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an Alzheimer's disease mouse model
- Author
- Philipp Spatz, Sophie A. M. Steinmüller, Anna Tutov, Eleonora Poeta, Axelle Morilleau, Allison Carles, Marie Deventer (UGent) , Julian Hofmann, Christophe Stove (UGent) , Barbara Monti, Tangui Maurice and Michael Decker
- Organization
- Project
- Abstract
- We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabi-noid receptor 2 (hCB2R) ligands for the treatment of neuro-degeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholines-terases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a beta-arrestin 2 (beta arr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier pene-tration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of A beta 25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short-and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo.
- Keywords
- BUTYRYLCHOLINESTERASE INHIBITORS, OXIDATIVE STRESS, BENZIMIDAZOLE DERIVATIVES, CHOLINERGIC HYPOTHESIS, BIOLOGICAL EVALUATION, CB2 RECEPTOR, CELL-DEATH, POTENT, ANTAGONIST, LIGANDS
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Citation
Please use this url to cite or link to this publication: http://hdl.handle.net/1854/LU-01H97TCMPZNEBF185X6Z2EDAPH
- MLA
- Spatz, Philipp, et al. “Dual-Acting Small Molecules : Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model.” JOURNAL OF MEDICINAL CHEMISTRY, vol. 66, no. 9, 2023, pp. 6414–35, doi:10.1021/acs.jmedchem.3c00541.
- APA
- Spatz, P., Steinmüller, S. A. M., Tutov, A., Poeta, E., Morilleau, A., Carles, A., … Decker, M. (2023). Dual-acting small molecules : subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an Alzheimer’s disease mouse model. JOURNAL OF MEDICINAL CHEMISTRY, 66(9), 6414–6435. https://doi.org/10.1021/acs.jmedchem.3c00541
- Chicago author-date
- Spatz, Philipp, Sophie A. M. Steinmüller, Anna Tutov, Eleonora Poeta, Axelle Morilleau, Allison Carles, Marie Deventer, et al. 2023. “Dual-Acting Small Molecules : Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model.” JOURNAL OF MEDICINAL CHEMISTRY 66 (9): 6414–35. https://doi.org/10.1021/acs.jmedchem.3c00541.
- Chicago author-date (all authors)
- Spatz, Philipp, Sophie A. M. Steinmüller, Anna Tutov, Eleonora Poeta, Axelle Morilleau, Allison Carles, Marie Deventer, Julian Hofmann, Christophe Stove, Barbara Monti, Tangui Maurice, and Michael Decker. 2023. “Dual-Acting Small Molecules : Subtype-Selective Cannabinoid Receptor 2 Agonist/Butyrylcholinesterase Inhibitor Hybrids Show Neuroprotection in an Alzheimer’s Disease Mouse Model.” JOURNAL OF MEDICINAL CHEMISTRY 66 (9): 6414–6435. doi:10.1021/acs.jmedchem.3c00541.
- Vancouver
- 1.Spatz P, Steinmüller SAM, Tutov A, Poeta E, Morilleau A, Carles A, et al. Dual-acting small molecules : subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an Alzheimer’s disease mouse model. JOURNAL OF MEDICINAL CHEMISTRY. 2023;66(9):6414–35.
- IEEE
- [1]P. Spatz et al., “Dual-acting small molecules : subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an Alzheimer’s disease mouse model,” JOURNAL OF MEDICINAL CHEMISTRY, vol. 66, no. 9, pp. 6414–6435, 2023.
@article{01H97TCMPZNEBF185X6Z2EDAPH,
abstract = {{We present the synthesis and characterization of merged human butyrylcholinesterase (hBChE) inhibitor/cannabi-noid receptor 2 (hCB2R) ligands for the treatment of neuro-degeneration. In total, 15 benzimidazole carbamates were synthesized and tested for their inhibition of human cholines-terases, also with regard to their pseudoirreversible binding mode and affinity toward both cannabinoid receptors in radioligand binding studies. After evaluation in a calcium mobilization assay as well as a beta-arrestin 2 (beta arr2) recruitment assay, two compounds with balanced activities on both targets were tested for their immunomodulatory effect on microglia activation and regarding their pharmacokinetic properties and blood-brain barrier pene-tration. Compound 15d, containing a dimethyl carbamate motif, was further evaluated in vivo, showing prevention of A beta 25-35-induced learning impairments in a pharmacological mouse model of Alzheimer's disease for both short-and long-term memory responses. Additional combination studies proved a synergic effect of BChE inhibition and CB2R activation in vivo.}},
author = {{Spatz, Philipp and Steinmüller, Sophie A. M. and Tutov, Anna and Poeta, Eleonora and Morilleau, Axelle and Carles, Allison and Deventer, Marie and Hofmann, Julian and Stove, Christophe and Monti, Barbara and Maurice, Tangui and Decker, Michael}},
issn = {{0022-2623}},
journal = {{JOURNAL OF MEDICINAL CHEMISTRY}},
keywords = {{BUTYRYLCHOLINESTERASE INHIBITORS,OXIDATIVE STRESS,BENZIMIDAZOLE DERIVATIVES,CHOLINERGIC HYPOTHESIS,BIOLOGICAL EVALUATION,CB2 RECEPTOR,CELL-DEATH,POTENT,ANTAGONIST,LIGANDS}},
language = {{eng}},
number = {{9}},
pages = {{6414--6435}},
title = {{Dual-acting small molecules : subtype-selective cannabinoid receptor 2 agonist/butyrylcholinesterase inhibitor hybrids show neuroprotection in an Alzheimer's disease mouse model}},
url = {{http://doi.org/10.1021/acs.jmedchem.3c00541}},
volume = {{66}},
year = {{2023}},
}
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