Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors.
Kowal NM
,
Ahring PK
,
Liao VWY
,
Indurti DC
,
Harvey BS
,
O'Connor SM
,
Chebib M
,
Olafsdottir ES
,
Balle T
.
???displayArticle.abstract???
BACKGROUND AND PURPOSE: The alkaloid galantamine was originally isolated from the green snowdrop Galanthus woronowii and is currently marketed as a drug for treatment of mild to moderate dementia in patients with Alzheimer's disease. In addition to a well-documented proficiency to inhibit acetylcholinesterase, galantamine has been reported to increase neuronal nicotinic ACh (nACh) receptor function by acting as a positive allosteric modulator. Yet there remains controversy regarding these findings in the literature. To resolve this conundrum, we evaluated galantamine actions at α4β2 and α7, which represent the nACh receptors most commonly associated with mammalian cognitive domains.
EXPERIMENTAL APPROACH: α4β2 [in (α4)3 (β2)2 and (α4)2 (β2)3 stoichiometries] and α7 nACh receptors were expressed in Xenopus laevis oocytes and subjected to two-electrode voltage-clamp electrophysiological experiments. Galantamine (10 nM to 100 μM) was evaluated for direct agonist effects and for positive modulation by co-application with sub-maximally efficacious concentrations of ACh. In addition, similar experiments were performed with α7 nACh receptors stably expressed in HEK293 cells using patch-clamp electrophysiology.
KEY RESULTS: In concentrations ranging from 10 nM to 1 μM, galantamine did not display direct agonism nor positive modulatory effects at any receptor combination tested. At concentrations from 10 μM and above, galantamine inhibited the activity with a mechanism of action consistent with open-channel pore blockade at all receptor types.
CONCLUSION AND IMPLICATIONS: Based on our data, we conclude that galantamine is not a positive allosteric modulator of α7 or α4β2 receptors, which represent the majority of nACh receptors in mammalian brain.
Ago,
Pharmacological aspects of the acetylcholinesterase inhibitor galantamine.
2011, Pubmed
Ago,
Pharmacological aspects of the acetylcholinesterase inhibitor galantamine.
2011,
Pubmed
Ahring,
A pharmacological assessment of agonists and modulators at α4β2γ2 and α4β2δ GABAA receptors: The challenge in comparing apples with oranges.
2016,
Pubmed
,
Xenbase
Akk,
Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site.
2005,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Enzymes.
2017,
Pubmed
Alexander,
THE CONCISE GUIDE TO PHARMACOLOGY 2017/18: Ligand-gated ion channels.
2017,
Pubmed
Cooper,
Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes.
1996,
Pubmed
,
Xenbase
Curtis,
Experimental design and analysis and their reporting: new guidance for publication in BJP.
2015,
Pubmed
Dajas-Bailador,
The allosteric potentiation of nicotinic acetylcholine receptors by galantamine is transduced into cellular responses in neurons: Ca2+ signals and neurotransmitter release.
2003,
Pubmed
Dunlop,
Old and new pharmacology: positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor by the 5-hydroxytryptamine(2B/C) receptor antagonist SB-206553 (3,5-dihydro-5-methyl-N-3-pyridinylbenzo[1,2-b:4,5-b']di pyrrole-1(2H)-carboxamide).
2009,
Pubmed
Echeverria,
Positive modulators of the α7 nicotinic receptor against neuroinflammation and cognitive impairment in Alzheimer's disease.
2016,
Pubmed
Erkkila,
Picrotoxin-mediated antagonism of alpha3beta4 and alpha7 acetylcholine receptors.
2004,
Pubmed
,
Xenbase
Goh,
Pharmacokinetic and pharmacodynamic properties of cholinesterase inhibitors donepezil, tacrine, and galantamine in aged and young Lister hooded rats.
2011,
Pubmed
Halevi,
The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors.
2002,
Pubmed
,
Xenbase
Hamouda,
Physostigmine and galanthamine bind in the presence of agonist at the canonical and noncanonical subunit interfaces of a nicotinic acetylcholine receptor.
2013,
Pubmed
Hansen,
Galanthamine and non-competitive inhibitor binding to ACh-binding protein: evidence for a binding site on non-alpha-subunit interfaces of heteromeric neuronal nicotinic receptors.
2007,
Pubmed
Harding,
The IUPHAR/BPS Guide to PHARMACOLOGY in 2018: updates and expansion to encompass the new guide to IMMUNOPHARMACOLOGY.
2018,
Pubmed
Harpsøe,
Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors.
2011,
Pubmed
Kalueff,
Mapping convulsants' binding to the GABA-A receptor chloride ionophore: a proposed model for channel binding sites.
2007,
Pubmed
Kilkenny,
Animal research: reporting in vivo experiments: the ARRIVE guidelines.
2010,
Pubmed
Kowal,
Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors.
2018,
Pubmed
,
Xenbase
Lansdell,
RIC-3 enhances functional expression of multiple nicotinic acetylcholine receptor subtypes in mammalian cells.
2005,
Pubmed
,
Xenbase
Ludwig,
Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain.
2010,
Pubmed
Mazzaferro,
Additional acetylcholine (ACh) binding site at alpha4/alpha4 interface of (alpha4beta2)2alpha4 nicotinic receptor influences agonist sensitivity.
2011,
Pubmed
,
Xenbase
McGrath,
Implementing guidelines on reporting research using animals (ARRIVE etc.): new requirements for publication in BJP.
2015,
Pubmed
Mirza,
NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy.
2008,
Pubmed
Nelson,
Alternate stoichiometries of alpha4beta2 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Okonjo,
A second pathway of activation of the Torpedo acetylcholine receptor channel.
1991,
Pubmed
Olsen,
Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.
2014,
Pubmed
,
Xenbase
Papke,
Comparative pharmacology of rat and human alpha7 nAChR conducted with net charge analysis.
2002,
Pubmed
,
Xenbase
Pereira,
Physostigmine and galanthamine: probes for a novel binding site on the alpha 4 beta 2 subtype of neuronal nicotinic acetylcholine receptors stably expressed in fibroblast cells.
1994,
Pubmed
Pereira,
Identification and functional characterization of a new agonist site on nicotinic acetylcholine receptors of cultured hippocampal neurons.
1993,
Pubmed
Pereira,
A novel agonist binding site on nicotinic acetylcholine receptors.
1993,
Pubmed
Roman,
Nicotinic-receptor potentiator drugs, huprine X and galantamine, increase ACh release by blocking AChE activity but not acting on nicotinic receptors.
2005,
Pubmed
Samochocki,
Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors.
2003,
Pubmed
Samochocki,
Galantamine is an allosterically potentiating ligand of the human alpha4/beta2 nAChR.
2000,
Pubmed
Schrattenholz,
Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands.
1996,
Pubmed
Shelley,
Epik: a software program for pK( a ) prediction and protonation state generation for drug-like molecules.
2007,
Pubmed
Storch,
Physostigmine, galanthamine and codeine act as 'noncompetitive nicotinic receptor agonists' on clonal rat pheochromocytoma cells.
1995,
Pubmed
Texidó,
Effect of galantamine on the human alpha7 neuronal nicotinic acetylcholine receptor, the Torpedo nicotinic acetylcholine receptor and spontaneous cholinergic synaptic activity.
2005,
Pubmed
,
Xenbase
Timmermann,
Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors.
2012,
Pubmed
,
Xenbase
Timmermann,
An allosteric modulator of the alpha7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo.
2007,
Pubmed
,
Xenbase
Wilcock,
A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease.
2003,
Pubmed
Zwart,
Four pharmacologically distinct subtypes of alpha4beta2 nicotinic acetylcholine receptor expressed in Xenopus laevis oocytes.
1998,
Pubmed
,
Xenbase
