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Allosteric sensitization of nicotinic receptors by galantamine,
a new treatment strategy for Alzheimer's disease.
Maelicke A, Samochocki M, Jostock R,
Fehrenbacher A, Ludwig J, Albuquerque EX
Laboratory of Molecular Neurobiology,
Institute of Physiological Chemistry and
Pathobiochemistry,
Johannes-Gutenberg University Medical School, Mainz, Germany
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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