Dual-Acting Cholinesterase–Human Cannabinoid Receptor 2 Ligands Show Pronounced Neuroprotection in Vitro and Overadditive and Disease-Modifying Neuroprotective Effects in Vivo
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We have designed and synthesized a series of 14 hybrid molecules out of the cholinesterase (ChE) inhibitor tacrine and a benzimidazole-based human cannabinoid receptor subtype 2 (hCB 2 R) agonist and investigated them in vitro and in vivo. The compounds are potent ChE inhibitors, and for the most promising hybrids, the mechanism of human acetylcholinesterase (hAChE) inhibition as well as their ability to interfere with AChE-induced aggregation of β-amyloid (Aβ), and Aβ self-aggregation was assessed. All hybrids were evaluated for affinity and selectivity for hCB 1 R and hCB 2 R. To ensure that the hybrids retained their agonist character, the expression of cAMP-regulated genes was quantified, and potency and efficacy were determined. Additionally, the effects of the hybrids on microglia activation and neuroprotection on HT-22 cells were investigated. The most promising in vitro hybrids showed pronounced neuroprotection in an Alzheimer’s mouse model at low dosage (0.1 mg/kg, i.p.), lacking hepatotoxicity even at high dose (3 mg/kg, i.p.).
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The developed tacrine-cannabinoid hybrids show no hepatotoxicity effect at 3 mg/kg dose.
“Keeping in mind the hepatotoxicity of tacrine, it is extremely relevant that the developed hybrids showed no hepatotoxicity effect at 3 mg/kg dose.134”
From From combinations to multitarget-directed ligands: A continuum in Alzheimer’s disease polypharmacology (2021) · cites this paper as [134]
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Fulp, A. B., Zhang, Y., Bortoff, K. D., et al. (2016) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2016.01.033 · Cited by 22 · see citing works
In-vitro stability and metabolism of a tacrine–silibinin codrug
Zenger, K., Chen, X., Decker, M., & Kraus, B. (2013) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.12070 · Cited by 13 · see citing works
Self-citationSchramm, S., Gunesch, S., Lang, F. J. W., et al. (2018) · Archiv der Pharmazie · doi:10.1002/ardp.201800206 · Cited by 9 · see citing works
Self-citationDual-Acting Compounds Acting as Receptor Ligands and Enzyme Inhibitors
Dolles, D., & Decker, M. W. (2017) · Elsevier eBooks · doi:10.1016/b978-0-08-101011-2.00005-2 · Cited by 7 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- [22]Van Sickle MD; Duncan M; Kingsley PJ; Mouihate A; Urbani P; Mackie K; Stella N; Makriyannis A; Piomelli D; Davison JS; Marnett LJ; Di Marzo V; Pittman QJ; Patel KD; Sharkey KA Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 2005, 310, 329– 332. 16224028
Cited by
Sorted by citations
Albertini, C., Salerno, A., de Sena Murteira Pinheiro, P., & Bolognesi, M. L. (2021) · Medicinal Research Reviews · doi:10.1002/med.21699 · Cited by 179 · see citing works
Viayna, E., Coquelle, N., Cieslikiewicz-Bouet, M., Cisternas, P., Oliva, C. A., Sánchez-López, E., Ettcheto, M., Bartolini, M., De Simone, A., Ricchini, M., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01775 · Cited by 106 · see citing works
Self-citationHe, F., Chou, C. J., Scheiner, M., Poeta, E., Yuan Chen, N., Gunesch, S., Hoffmann, M., Sotriffer, C., Monti, B., Maurice, T., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c01940 · Cited by 66 · see citing works
Self-citation
- Authors
- Scheiner, M., Dolles, D., Gunesch, S., Hoffmann, M., Nabissi, M., Marinelli, O., Naldi, M., Bartolini, M., Petralla, S., Poeta, E., Monti, B., Falkeis, C., Vieth, M., Hübner, H., Gmeiner, P., Maitra, R., Maurice, T., & Decker, M.
- Affiliations
- University of Würzburg (DE)
- Università di Camerino (IT)
- University of Bologna (IT)
- Bayreuth Medical Center (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- RTI International (US)
- Inserm (FR)
- Corresponding author
- Decker, Michael
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-10-14
- Volume
- 62
- Issue
- 20
- Pages
- 9078-9102
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- PMC
- PMC7640639
- OpenAlex
- W2981117974
- Cited by
- 49
- References
- 101
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 10 · 2023: 8 · 2022: 5 · 2021: 8 · 2020: 11 · 2019: 1
- FWCI
- 4.34
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, other-oa)
- Unicam Scientific Publications (University of Camerino) (submittedVersion, other-oa)
- Funders
- Bundesministerium f?r Bildung und Forschung
- Elitenetzwerk Bayern
- Deutscher Akademischer Austauschdienst
- Campus France
- Ministero dell?Istruzione, dell?Universit? e della Ricerca
- Deutsche Forschungsgemeinschaft (DFG DE 1546/6-3)
- Studienstiftung des Deutschen Volkes
- Topics
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Keywords
- cholinesterase inhibitors, tacrine, benzimidazole, hybrid molecules, acetylcholinesterase inhibition, amyloid-beta aggregation, Alzheimer's disease, neuroprotection, microglial activation, cAMP signaling, disease-modifying therapy, hepatotoxicity
- MeSH terms
- Animals, Cholinesterases, Humans, Ligands, Neuroprotective Agents, Receptor, Cannabinoid, CB2, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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