Cited by 49Cholinesterase and Neurodegenerative DiseasesAlzheimer's disease research and treatmentsCannabis and Cannabinoid Research

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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Scheiner, Matthias, Dolles, Dominik, Gunesch, Sandra, Hoffmann, Matthias, Nabissi, Massimo, Marinelli, Oliviero, Naldi, Marina, Bartolini, Manuela +10 more·2019·Journal of Medicinal Chemistry

Abstract

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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  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

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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
Venue
Journal of Medicinal Chemistry
Published
2019-10-14
Volume
62
Issue
20
Pages
9078-9102
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
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
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

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