Galantamine is an allosterically potentiating ligand of the human α4/β2 nAChR

Abstract

Galantamine (ReminylTM) is a novel drug treatment for mild to moderate Alzheimer's disease (AD). Originally established as a reversible inhibitor of the acetylcholine‐degrading enzyme acetylcholinesterase (AChE), galantamine also acts as an allosterically potentiating ligand (APL) on nicotinic acetylcholine receptors (nAChR). Having previously established this second mode of action on nAChRs from murine brain, we demonstrate here the same action of galantamine on the most abundant nAChR in the human brain, the α4/β2 subtype. This nAChR‐sensitizing action is not a common property of all, or most, AChE inhibitors, as is shown by the absence of this effect for other therapeutically applied AChE inhibitors including tacrine, metrifonate, rivastigmine and donepezil. The possible benefits for therapy of AD of an APL action on nicotinic receptors is discussed.

Unconventional ligands and modulators of nicotinic receptors

“…al., 1985) was the finding that physostigmine-induced inhibition of ␣4␤4 and ␣4␤2 nAChR activity was voltage dependent . As we have shown previously for galantamine (Schrattenholz et al, 1996;Samochocki et al, 2000), physostigmineinduced potentiation of nAChR activity was only evident at subsaturating concentrations of classical agonists . Based on the finding that the potentiating effect of physostigmine faded away as the agonist concentration was increased and that physostigmine displaced the binding of the classical nicotinic agonist epibatidine from ␣4␤4 nAChRs ectopically expressed in oocytes, Zwart and collaborators (2000) concluded that the potentiating action of physostigmine is the result of its interaction with the ACh-recognition sites on the nAChRs.…”

“…These effects can be detected as early as 30 s after beginning the perfusion of the slices with galantamine-containing artificial cerebrospinal fluid (ACSF). In contrast, cholinesterase inhibitors devoid of nicotinic APL action, including methamidophos, donepezil, and rivastigimine (Samochocki et al, 2000), cause no significant changes in evoked EPSCs or IPSCs in hippocampal slices (Santos et al, 2002). Numerous lines of evidence demonstrated that facilitation of glutamatergic and GABAergic transmissions by galantamine cannot be accounted for by changes in the electrical properties of the neurons or in the activity of postsynaptic glutamate or GABA A receptors.…”

“…Although the exact mechanism by which nicotinic APLs sensitize nAChRs to activation by classical agonists is still unclear, studies from our laboratories have indicated that nicotinic APLs can increase the probability of nAChR channel openings induced by ACh in outside-out patches excised from PC12 cells and enhance the apparent potency, but not the efficacy of nicotinic agonists in activating different nAChR subtypes (Storch et al, 1995;Samochocki et al, 2000). These results support the notion that APLs enhance the binding affinity of agonists and/or frequency of channel openings for a given level of receptor occupancy as long as receptor activation is still submaximal.…”

“…In fact, the highly potent cholinesterase inhibitors donepezil and rivastigmine are devoid of the nicotinic APL action (Samochocki et al, 2000). Some structural requirements seem to be essential in a compound that acts as a nicotinic APL.…”

“…In both conditions, there is a bell-shaped concentration/ dose-response relationship that may be due to the fact that galantamine up to 1 M increases agonist-induced nAChR activation and reduces/prevents agonist-induced nAChR desensitization, whereas at higher concentrations it inhibits nAChR activation (Pereira et al, 1993;Schrattenholz et al, 1996;Samochocki et al, 2000). In addition, the brain concentration of galantamine achieved after treatment of rats with the most behaviorally active dose (2.5 mg/kg, p.o.)…”