0000000000420124
AUTHOR
Marek Samochocki
Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors.
Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD), is a potent allosteric potentiating ligand (APL) of human alpha 3 beta 4, alpha 4 beta 2, and alpha 6 beta 4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric alpha 7/5-hydroxytryptamine3 receptor, as was shown by whole-cell patch-clamp studies of human embryonic kidney-293 cells stably expressing a single nAChR subtype. Galantamine potentiates agonist responses of the four nAChR subtypes studied in the same window of concentrations (i.e., 0.1-1 microM), which correlates with the cerebrospinal fluid concentration of the drug at the recommended daily dosage of 16 to 24 mg. At concentrations10 microM, gal…
The expression level of the orphan nuclear receptor GCNF (germ cell nuclear factor) is critical for neuronal differentiation.
The germ cell nuclear factor (GCNF) is essential for normal embryonic development and gametogenesis. To test the prediction that GCNF is additionally required for neuronal differentiation, we used the mouse embryonal carcinoma cell line PCC7-Mz1, which represents an advantageous model to study neuronal cells from the stage of fate choice until the acquirement of functional competence. We generated stable transfectants that express gcnf sense or antisense RNA under the control of a tetracycline-regulated promoter. After retinoic acid-induced withdrawal from the cell cycle, sense clones developed a neuron network with changed properties, and the time course of neuron maturation was shortened.…
Synthesis and in vitro evaluation of galanthamine derivatives for examination of nicotinic acetylcholine receptor system
ISunmrary: The syntheses and radioactive labeling of several galanthamine derivatives, 6-O-demethyl-6-O-fluoroethylgalanthamine, 10-N-demethyl-lO-Nfluoroethylgalanthamine and N-methylgalanthaminium are reported. First ill vitro evaluations were carried out to determine their properties as allosterically potentiating ligands of nicotinic receptors. N-methylgalanthaminium was found to be a promising candidate for further investigations. The most commonly applied therapeutic approach to balance nicotinic cholinergic deficits in Alzheimer’s disease (AD) patients is the administration of acetylcholinesterase inhibitors (AChE-I) although they have been proven to be of limited therapeutic value [ …
Allosteric sensitization of nicotinic receptors by galantamine, a new treatment strategy for Alzheimer’s disease
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 unex…
Allosterically potentiating ligands of nicotinic receptors as a treatment strategy for Alzheimer's disease.
Abstract One of the most prominent cholinergic deficit in Alzheimer’s disease (AD) is the reduced number of nicotinic acetylcholine receptors (nAChR) in the hippocampus and cortex of AD patients, as compared to age-matched controls. This deficit results in reduced nicotinic cholinergic excitation which may not only impair postsynaptic depolarization but also presynaptic neurotransmitter release and Ca 2+ -dependent intracellular signaling, including transcriptional activity. Presently, the most common approach to correct the nicotinic cholinergic deficit in AD is the application of cholinesterase inhibitors. Due to the resulting increase in synaptic acetylcholine levels, both in concentrati…
α-Conotoxins EpI and AuIB switch subtype selectivity and activity in native versus recombinant nicotinic acetylcholine receptors
The Xenopus laevis oocyte expression system was used to determine the activities of alpha-conotoxins EpI and the ribbon isomer of AuIB, on defined nicotinic acetylcholine receptors (nAChRs). In contrast to previous findings on intracardiac ganglion neurones, alpha-EpI showed no significant activity on oocyte-expressed alpha3beta4 and alpha3beta2 nAChRs but blocked the alpha7 nAChR with an IC50 value of 30 nM. A similar IC50 value (103 nM) was obtained on the alpha7/5HT3 chimeric receptor stably expressed in mammalian cells. Ribbon AuIB maintained its selectivity on oocyte-expressed alpha3beta4 receptors but unlike in native cells, where it was 10-fold more potent than native alpha-AuIB, had…
Synthesis and evaluation of tritium labelled 10-methylgalanthamine iodide: a novel compound to examine the mechanism of interaction of galanthamine derivatives with the nicotinic acetylcholine receptors
Summary A new promising galanthamine derivative, 10-[ 3 H]methylgalanthamine iodide, was synthesized for binding studies to nicotinic acetylcholine receptors expressed in Torpedo electric ray electroplaques. Galanthamine was reacted with [ 3 H]methyl iodide to yield 10-[ 3 H]methylgalanthamine iodide with a radiochemical yield of >70% and a specific activity of 32 Ci/mmol after purification via solid phase extraction. To test the ligand properties of the radioligand, calcium imaging and electrophysiology of the non-radioactive analogue were performed to obtain an EC50 of 270 nM, a Hill coefficient of 1.9 and the induced cell current. Copyright # 2003 John Wiley & Sons, Ltd.
Corrigendum to: α-Conotoxins EpI and AuIB switch subtype selectivity and activity in native versus recombinant nicotinic acetylcholine receptors (FEBS 27779)
Corrigendum to: K-Conotoxins EpI and AuIB switch subtype selectivity and activity in native versus recombinant nicotinic acetylcholine receptors (FEBS 27779) [FEBS Letters 554 (2003) 219^223]C Annette Nickea;1, Marek Samochockib, Marion L. Loughnana, Paramjit S. Bansala, Alfred Maelickeb, Richard J. Lewisa; aInstitute for Molecular Bioscience, University of Queensland, Brisbane, Qld. 4072, Australia bInstitute for Physiological Chemistry and Pathobiochemistry, University of Mainz, D-55099 Mainz, Germany First published online 24 December 2003
Galantamine is an allosterically potentiating ligand of the human α4/β2 nAChR
Galantamine (ReminyI ) is a novel drug treatment for mild to moderate Alzheimer's disease (AD). Originally established as a reversible inhibitor of the acetylcholine-degrading enzyme acetylcholinesterase (AChE), galantamine also acts as an allosterically potentiating ligand (APL) on nicotinic acetylcholine receptors (nAChR). Having previously established this second mode of action on nAChRs from murine brain, we demonstrate here the same action of galantamine on the most abundant nAChR in the human brain, the α4/β2 subtype. This nAChR-sensitizing action is not a common property of all, or most, AChE inhibitors, as is shown by the absence of this effect for other therapeutically applied AChE…