RT Journal Article
SR Electronic
T1 Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1024
OP 1036
DO 10.1124/jpet.102.045773
VO 305
IS 3
A1 Marek Samochocki
A1 Anja Höffle
A1 Andreas Fehrenbacher
A1 Ruth Jostock
A1 Jürgen Ludwig
A1 Claudia Christner
A1 Martin Radina
A1 Marion Zerlin
A1 Christoph Ullmer
A1 Edna F. R. Pereira
A1 Hermann Lübbert
A1 Edson X. Albuquerque
A1 Alfred Maelicke
YR 2003
UL http://jpet.aspetjournals.org/content/305/3/1024.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics