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

J Pharmacol Exp Ther. 2003 Jun;305(3):1024-36. doi: 10.1124/jpet.102.045773. Epub 2003 Mar 20.

Abstract

Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD), is a potent allosteric potentiating ligand (APL) of human alpha 3 beta 4, alpha 4 beta 2, and alpha 6 beta 4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric alpha 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 microM), which correlates with the cerebrospinal fluid concentration of the drug at the recommended daily dosage of 16 to 24 mg. At concentrations >10 microM, 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Allosteric Regulation
  • Animals
  • Carbamates / pharmacology
  • Cells, Cultured
  • Cholinesterase Inhibitors / pharmacology
  • Donepezil
  • Galantamine / pharmacology*
  • Humans
  • Indans / pharmacology
  • Mice
  • Neurons / drug effects*
  • Neurons / metabolism
  • Phenylcarbamates*
  • Piperidines / pharmacology
  • Receptors, Muscarinic / metabolism*
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism*
  • Recombinant Fusion Proteins / drug effects
  • Rivastigmine
  • Tacrine / pharmacology
  • Trichlorfon / pharmacology

Substances

  • Carbamates
  • Cholinesterase Inhibitors
  • Indans
  • Phenylcarbamates
  • Piperidines
  • Receptors, Muscarinic
  • Receptors, Nicotinic
  • Recombinant Fusion Proteins
  • nicotinic receptor alpha4beta2
  • Galantamine
  • Tacrine
  • Donepezil
  • Trichlorfon
  • Rivastigmine