Galantamine is an allosterically potentiating ligand of neuronal nicotinic but not of muscarinic acetylcholine receptors.

Samochocki M, Hoffle A, Fehrenbacher A,
Jostock R, Ludwig J, Christner C, Radina M, Zerlin M,
Ullmer C, Pereira EF, Lubbert H, Albuquerque EX, Maelicke A.

University of Mainz.
J Pharmacol Exp Ther 2003 Mar 20

Abstract

Galantamine (Reminyl) an approved treatment for Alzheimer’s disease (AD), is a potent “allosteric potentiating ligand (APL)” of human alpha3beta4, alpha4beta2 and alpha6beta4 nicotinic receptors (nAChRs), and of the chicken/mouse chimaeric alpha7/5HT3 receptor, as was shown by whole-cell patch-clamp studies of HEK-293 cells stably expressing a single nAChR subtype. Galantamine potentiates agonist responses of the four subtypes studied in the same window of concentrations (i.e., 0.1-1 micro M) which correlates with the CSF concentration of the drug at the recommended daily dosage of 16-24 mg. At concentrations >10 micro M, 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 earlier proposal that the therapeutic action of galantamine is mainly produced by its sensitizing action on nicotinic receptors rather than by general cholinergic enhancement due to cholinesterase inhibition. Galantamine’s APL action directly addresses the nicotinic deficit in AD.