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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
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