Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors
- Marek Samochocki,
- Anja Höffle,
- Andreas Fehrenbacher,
- Ruth Jostock,
- Jürgen Ludwig,
- Claudia Christner,
- Martin Radina,
- Marion Zerlin,
- Christoph Ullmer,
- Edna F. R. Pereira,
- Hermann Lübbert,
- Edson X. Albuquerque and
- Alfred Maelicke
- 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.)
- 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
Abstract
Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD), is a potent allosteric potentiating ligand (APL) of human α3β4, α4β2, and α6β4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric α7/5-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.
Footnotes
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This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Stiftung Rheinland-Pfalz für Innovation, and the Fonds der Chemischen Industrie (all to A.M.). Further funds and materials were obtained from Janssen Research Foundation (to A.M. and E.X.A.) and from Biofrontera Pharmaceuticals AG (Leverkusen) (to A.M.). E.X.A. has received additional grants from the United States Army Medical Research and Development Command (DAMD-17-95-c-5063), and the United States Public Health Service (NS25296).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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DOI: 10.1124/jpet.102.045773.
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ABBREVIATIONS: AD, Alzheimer's disease; ACh, acetylcholine; ChE, cholinesterase; mAChR, muscarinic acetylcholine receptor; nAChR, nicotinic acetylcholine receptor; APL, allosterically potentiating ligand; 5-HT, 5-hydroxytryptamine; HEK, human embryonic kidney; DMEM, Dulbecco's modified Eagle's medium; PCR, polymerase chain reaction; RT-PCR, reverse transcription-PCR; CHO, Chinese hamster ovary; SRE, serum-response element.
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- Received November 7, 2002.
- Accepted February 6, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
