Allosteric Sensitization of Nicotinic Receptors by Galantamine, a New Treatment Strategy for Alzheimer’s Disease
Abstract
Cholinesterase inhibitors are the only approved drug treatment for patients with mild to moderately severe Alzheimer's disease. Interestingly, the clinical potency of these drugs does not correlate well with their activity as cholinesterase inhibitors, nor is their action as short lived as would be expected from purely symptomatic treatment. A few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated. These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. We have recently discovered a mechanism that could account, at least in part, for the above-mentioned unexpected properties of some cholinesterase inhibitors. We have found that a subgroup of cholinesterase inhibitors, including galantamine but excluding tacrine, directly interacts with nicotinic acetylcholine receptors. These compounds, named allosterically potentiating ligands, sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization. The allosterically potentiating ligand action, which is not necessarily associated with cholinesterase inhibition, has been demonstrated by whole-cell patch-clamp recordings to occur in natural murine and human neurons and in murine and human cell lines expressing various subtypes of neuronal nicotinic acetylcholine receptors.
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Galantamine acts as an allosterically potentiating ligand of nicotinic receptors, increasing their sensitivity to acetylcholine.
“the plant alkaloid galantamine additionally acts as an allosterically potentiating ligand of nicotinic receptors, increasing their sensitivity to the neurotransmitter acetylcholine [9].”
From Galantamine Slows Down Plaque Formation and Behavioral Decline in the 5XFAD Mouse Model of Alzheimer’s Disease (2014) · cites this paper as [9]
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- Authors
- Maelicke, A., Samochocki, M., Jostock, R., Fehrenbacher, A., Ludwig, J., Albuquerque, E. X., & Zerlin, M.
- Affiliations
- Johannes Gutenberg University Mainz (DE)
- Corresponding author
- Maelicke, Alfred
- ORCID
- Jostock, Ruth
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2001-02
- Volume
- 49
- Issue
- 3
- Pages
- 279-288
- ISSN
- 0006-3223 (ISSN-L)
- OpenAlex
- W2043467860
- Cited by
- 303
- References
- 80
- Citations by year
- 2026: 7 · 2025: 3 · 2024: 4 · 2023: 1 · 2022: 6 · 2021: 9 · 2020: 17 · 2019: 10 · 2018: 13 · 2017: 6 · 2016: 11 · 2015: 11 · 2014: 6 · 2013: 11 · 2012: 9
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Pharmacology › Cholinesterase and Neurodegenerative Diseases
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- galantamine, nicotinic acetylcholine receptors, Alzheimer's disease, cholinesterase inhibitors, tacrine, receptor desensitization, acetylcholine, off-target effects
- MeSH terms
- Allosteric Regulation, Allosteric Site, Alzheimer Disease, Animals, Cell Line, Cholinesterase Inhibitors, Galantamine, Humans, Neurons, Receptors, Nicotinic, Patch-Clamp Techniques, Nootropic Agents, Mice
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