![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, Mainz, Germany (M.S., A.H., A.F., R.J., J.L., C.C., M.R., M.Z., A.M.); Biofrontera Pharmaceuticals AG, Leverkusen, Germany (C.U., H.L., A.M.); Department of Pharmacology and Experimental Therapeutics, University of Maryland Medical School, Baltimore, Maryland (E.F.R.P., E.X.A.); and Departamento de Farmacologia Básica e Clínica, Instituto de Ciências Biomédicas, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil (E.X.A.)
Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD),
is a potent allosteric potentiating ligand (APL) of human 
3
4,
42, and 64 nicotinic receptors (nAChRs), and of the
chicken/mouse chimeric 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 µM), which correlates with the
cerebrospinal fluid concentration of the drug at the recommended daily dosage
of 16 to 24 mg. At concentrations >10 µM, galantamine acts as an nAChR
inhibitor. The other presently approved AD drugs, donepezil and rivastigmine,
are devoid of the nicotinic APL action; at micromolar concentrations they also
block nAChR activity. Using five CHO-SRE-Luci cell lines, each of them
expressing a different human muscarinic receptor, and a reporter gene assay,
we show that galantamine does not alter the activity of M1–M5 receptors,
thereby confirming that galantamine modulates selectively the activity of
nAChRs. These studies support our previous proposal that the therapeutic
action of galantamine is mainly produced by its sensitizing action on nAChRs
rather than by general cholinergic enhancement due to cholinesterase
inhibition. Galantamine's APL action directly addresses the nicotinic deficit
in AD.
Address correspondence to: Prof. Dr. Alfred Maelicke, Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, Duesbergweg 6, D-55099 Mainz, Germany. E-mail: alfred.maelicke{at}uni-mainz.de
This article has been cited by other articles:
|
|
 |
|
  E. X. Albuquerque, E. F. R. Pereira, M. Alkondon, and S. W. Rogers Mammalian Nicotinic Acetylcholine Receptors: From Structure to Function Physiol Rev, January 1, 2009; 89(1): 73 - 120. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Erkinjuntti, S. Gauthier, R. Bullock, A. Kurz, G. Hammond, S. Schwalen, Y. Zhu, and R. Brashear Galantamine treatment in Alzheimer's disease with cerebrovascular disease: responder analyses from a randomized, controlled trial (GAL-INT-6) J Psychopharmacol, September 1, 2008; 22(7): 761 - 768. [Abstract] [PDF]
|
|
|
|
 |
|
 S. Nirthanan, G. Garcia III, D. C. Chiara, S. S. Husain, and J. B. Cohen Identification of Binding Sites in the Nicotinic Acetylcholine Receptor for TDBzl-etomidate, a Photoreactive Positive Allosteric Effector J. Biol. Chem., August 8, 2008; 283(32): 22051 - 22062. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kuryatov, J. Onksen, and J. Lindstrom Roles of Accessory Subunits in {alpha}4{beta}2* Nicotinic Receptors Mol. Pharmacol., July 1, 2008; 74(1): 132 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Buchanan, R. R. Conley, D. Dickinson, M. P. Ball, S. Feldman, J. M. Gold, and R. P. McMahon Galantamine for the Treatment of Cognitive Impairments in People With Schizophrenia Am J Psychiatry, January 1, 2008; 165(1): 82 - 89. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Yoshimura, D. J. Hogenkamp, W. Y. Li, M. B. Tran, J. D. Belluzzi, E. R. Whittemore, F. M. Leslie, and K. W. Gee Negative Allosteric Modulation of Nicotinic Acetylcholine Receptors Blocks Nicotine Self-Administration in Rats J. Pharmacol. Exp. Ther., December 1, 2007; 323(3): 907 - 915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K.-J. Bar, M. K. Boettger, N. Seidler, H. J. Mentzel, C. Terborg, and H. Sauer Influence of Galantamine on Vasomotor Reactivity in Alzheimer's Disease and Vascular Dementia Due to Cerebral Microangiopathy Stroke, December 1, 2007; 38(12): 3186 - 3192. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. W. Buchanan, R. Freedman, D. C. Javitt, A. Abi-Dargham, and J. A. Lieberman Recent Advances in the Development of Novel Pharmacological Agents for the Treatment of Cognitive Impairments in Schizophrenia Schizophr Bull, September 1, 2007; 33(5): 1120 - 1130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Halvard Gronlien, M. Hakerud, H. Ween, K. Thorin-Hagene, C. A. Briggs, M. Gopalakrishnan, and J. Malysz Distinct Profiles of {alpha}7 nAChR Positive Allosteric Modulation Revealed by Structurally Diverse Chemotypes Mol. Pharmacol., September 1, 2007; 72(3): 715 - 724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Andersen, T. Werge, and A. Fink-Jensen The Acetylcholinesterase Inhibitor Galantamine Inhibits d-Amphetamine-Induced Psychotic-Like Behavior in Cebus Monkeys J. Pharmacol. Exp. Ther., June 1, 2007; 321(3): 1179 - 1182. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. J. Ng, E. R. Whittemore, M. B. Tran, D. J. Hogenkamp, R. S. Broide, T. B. Johnstone, L. Zheng, K. E. Stevens, and K. W. Gee Nootropic {alpha}7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators PNAS, May 8, 2007; 104(19): 8059 - 8064. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. Broad, R. Zwart, K. H. Pearson, M. Lee, L. Wallace, G. I. McPhie, R. Emkey, S. P. Hollinshead, C. P. Dell, S. R. Baker, et al. Identification and Pharmacological Profile of a New Class of Selective Nicotinic Acetylcholine Receptor Potentiators J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1108 - 1117. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Geerts and G. T. Grossberg Pharmacology of Acetylcholinesterase Inhibitors and N-methyl-D-aspartate Receptors for Combination Therapy in the Treatment of Alzheimer's Disease J. Clin. Pharmacol., July 1, 2006; 46(suppl_1): 8S - 16S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Hernandez, D. A. Gearhart, V. Parikh, E. J. Hohnadel, L. W. Davis, M. L. Middlemore, S. P. Warsi, J. L. Waller, and A. V. Terry Jr Comparison of Galantamine and Donepezil for Effects on Nerve Growth Factor, Cholinergic Markers, and Memory Performance in Aged Rats J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 679 - 694. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Goekoop, P. Scheltens, F. Barkhof, and S. A. R. B. Rombouts Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation--a pharmacological fMRI study Brain, January 1, 2006; 129(1): 141 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kuryatov, J. Luo, J. Cooper, and J. Lindstrom Nicotine Acts as a Pharmacological Chaperone to Up-Regulate Human {alpha}4{beta}2 Acetylcholine Receptors Mol. Pharmacol., December 1, 2005; 68(6): 1839 - 1851. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Moriguchi, X. Zhao, W. Marszalec, J. Z. Yeh, and T. Narahashi Modulation of N-Methyl-D-aspartate Receptors by Donepezil in Rat Cortical Neurons J. Pharmacol. Exp. Ther., October 1, 2005; 315(1): 125 - 135. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Mega, I. D. Dinov, V. Porter, G. Chow, E. Reback, P. Davoodi, S. M. O'Connor, M. F. Carter, H. Amezcua, and J. L. Cummings Metabolic Patterns Associated With the Clinical Response to Galantamine Therapy: A Fludeoxyglucose F 18 Positron Emission Tomographic Study Arch Neurol, May 1, 2005; 62(5): 721 - 728. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Akk and J. H. Steinbach Galantamine Activates Muscle-Type Nicotinic Acetylcholine Receptors without Binding to the Acetylcholine-Binding Site J. Neurosci., February 23, 2005; 25(8): 1992 - 2001. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Sacco, K. L. Bannon, and T. P. George Nicotinic receptor mechanisms and cognition in normal states and neuropsychiatric disorders J Psychopharmacol, December 1, 2004; 18(4): 457 - 474. [Abstract] [PDF]
|
|
|
|
|
|
S. Moriguchi, W. Marszalec, X. Zhao, J. Z. Yeh, and T. Narahashi Mechanism of Action of Galantamine on N-Methyl-D-Aspartate Receptors in Rat Cortical Neurons J. Pharmacol. Exp. Ther., September 1, 2004; 310(3): 933 - 942. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fayuk and J. L. Yakel Regulation of Nicotinic Acetylcholine Receptor Channel Function by Acetylcholinesterase Inhibitors in Rat Hippocampal CA1 Interneurons Mol. Pharmacol., September 1, 2004; 66(3): 658 - 666. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Sharp, M. Yatsula, and Y. Fu Effects of Galantamine, a Nicotinic Allosteric Potentiating Ligand, on Nicotine-Induced Catecholamine Release in Hippocampus and Nucleus Accumbens of Rats J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 1116 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. P. Weible, M. M. Oh, G. Lee, and J. F. Disterhoft Galantamine Facilitates Acquisition of Hippocampus-Dependent Trace Eyeblink Conditioning in Aged Rabbits Learn. Mem., January 1, 2004; 11(1): 108 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. A. Dajas-Bailador, K. Heimala, and S. Wonnacott The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Is Transduced into Cellular Responses in Neurons: Ca2+ Signals and Neurotransmitter Release. Mol. Pharmacol., November 1, 2003; 64(5): 1217 - 1226. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
