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A Dual Approach To Combat Alzheimer's Disease through Concomitant hBChE Inhibition and S1R Activation
Kora Reichau1, Lucie Crouzier2, Eleonora Poeta3
1Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg (JMU), Am Hubland, 97074 Würzburg, Germany.
ACS Chemical Neuroscience
|January 27, 2026
Summary
Novel Alzheimer's disease treatments target both butyrylcholinesterase and sigma-1 receptor. Compound 18c shows promise, improving memory in mouse models and reducing neuroinflammation.
Area of Science:
- Neuroscience
- Pharmacology
- Drug Discovery
Background:
- Alzheimer's disease (AD) is an incurable neurodegenerative disorder.
- Current treatments are insufficient, necessitating novel therapeutic strategies.
- Cholinergic dysfunction and neuroinflammation are key pathological features of AD.
Purpose of the Study:
- To develop multitarget-directed ligands for Alzheimer's disease therapy.
- To inhibit human butyrylcholinesterase (hBChE) and activate the sigma-1 receptor (S1R).
- To address both cholinergic dysfunction and neuroinflammation.
Main Methods:
- Design and synthesis of multitarget-directed ligands.
- Evaluation of hBChE inhibition and S1R agonistic activity.
- Assessment of anti-inflammatory effects in microglial cells and cognitive function in a mouse model.
Main Results:
- Compound 18c demonstrated potent and selective hBChE inhibition (IC50 = 3.3 nM) and strong S1R agonistic activity (IC50 = 25 nM).
- Its metabolite 14c also retained dual inhibitory and agonistic properties.
- Both compounds modulated inflammatory responses in microglial cells and improved cognitive deficits in vivo.
- Compound 18c enhanced memory in a mouse model of Aβ-induced neurotoxicity at low dosages (0.1-1 mg/kg).
Conclusions:
- Dual-targeting hBChE/S1R strategies represent a promising therapeutic approach for Alzheimer's disease.
- Compound 18c exhibits significant potential as a lead compound for AD drug development.
- The findings support the development of novel therapeutics addressing multiple AD pathologies.
Keywords:
4-IBPcholinergic dysfunctionmicroglial immunomodulationmultitarget-directed ligandsneuroinflammationneuroprotectionMore Related Videos
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