Galantamine Is an Allosterically Potentiating Ligand of Neuronal Nicotinic but Not of Muscarinic Acetylcholine Receptors

Abstract

Galantamine (Reminyl), an approved treatment for Alzheimer's disease (AD), is a potent allosteric potentiating ligand (APL) of human ␣3␤4, ␣4␤2, and ␣6␤4 nicotinic receptors (nAChRs), and of the chicken/mouse chimeric ␣7/5-hydroxytryptamine 3 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 M), which correlates with the cerebrospinal fluid concentration of the drug at the recommended daily dosage of 16 to 24 mg. At concentrations Ͼ10 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 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.

Cholinergic drugs potentiate human nicotinic α4β2 acetylcholine receptors by a competitive mechanism

“…The muscarinic receptor antagonist atropine causes mixed coagonist and antagonist effects on rat neuronal nicotinic receptors (Zwart and Vijverberg, 1997). Effects resembling those of d-tubocurarine and atropine on rat nicotinic acetylcholine receptors have been described for several acetylcholinesterase inhibitors, e.g., for galanthamine (Schrattenholz et al, 1996;Samochocki et al, 2003), neostigmine (Nagata et al, 1997), and physostigmine (Zwart et al, 2000). Despite the similar coagonist and antagonist effects of these diverse cholinergic drugs on nicotinic acetylcholine receptors, the mechanism of potentiation has not been agreed upon yet, not in the least because of the large variability in potentiation and inhibition reported and in the nicotinic acetylcholine receptor subtypes involved.…”

Combining Galantamine and Memantine in Multitargeted, New Chemical Entities Potentially Useful in Alzheimer’s Disease

“…8 Unlike other AChE inhibitor drugs, 1 has a postulated dual mechanism of action: in addition to inhibiting AChE, 1 has shown a facilitating effect on the nicotinic receptor-mediated transmission via allosteric modulation of the α-subunit of nicotinic receptors. 9 In particular, 1 can enhance synaptic NMDAR activity 10,11 by activating α7 nicotinic receptors located on presynaptic glutamatergic neurons. 12 Working together, 1 and 2 may thus improve neurophysiological responses in AD patients, 13 and their combination might offer a promising therapeutic strategy for AD treatment.…”

Prolonged Nicotine Administration Results in Biphasic, Brain-Specific Changes in Kynurenate Levels in the Rat

“…Conversely, a7 nAChR stimulation normalizes the auditory gating deficit that is observed in rats that have been reared in social isolation (O'Neill et al, 2003). These considerations have stimulated the development of a7 nAChR agonists such as ARR-17779 (Mullen et al, 2000), which interact directly with the binding site for acetylcholine, or of drugs such as galantamine (Reminyl s ), which increase nAChR activity by interacting with a site close to, but distinct from, the acetylcholine-binding site (Pereira et al, 1994(Pereira et al, , 2002Samochocki et al, 2003). It is also noteworthy that one measure of sensory gating abnormalities, diminished inhibition of the P50 evoked response to repeated auditory stimuli, has been linked to the chromosome 15q14 locus of the a7 nAChR gene (Freedman et al, 1997;Riley et al, 2000).…”